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Yao Y, Cui C, Shi Y, Lei J, Li T, Li M, Peng X, Yang X, Ren K, Yang J, Luo G, Du J, Chen S, Zhang P, Tian B. DRN-SNc serotonergic circuit drives stress-induced motor deficits and Parkinson's disease vulnerability. Neuropsychopharmacology 2025; 50:1051-1062. [PMID: 40097739 DOI: 10.1038/s41386-025-02080-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Revised: 01/31/2025] [Accepted: 02/25/2025] [Indexed: 03/19/2025]
Abstract
Stress is a recognized risk factor for Parkinson's disease (PD), but the mechanisms by which stress exacerbates PD symptoms through the serotonergic system are not fully understood. This study investigates the role of serotonergic (5-HT) neurons in the dorsal raphe nucleus (DRN) in mediating stress-induced motor deficits and PD progression. Acute and chronic stress were induced in mice using an elevated platform (EP) and combined with MPTP administration to model early-stage PD. Acute EP stress caused transient motor deficits and significant activation of DRN5-HT neurons projecting to substantia nigra compacta (SNc) dopaminergic (DA) neurons. Manipulating the DRN-SNc pathway with optogenetics and chemogenetics confirmed its critical role in stress-induced motor deficits. Activation of the SNc 5-HT2C receptor with an agonist replicated these deficits, while receptor inhibition prevented them, underscoring its importance. Chronic EP stress worsened MPTP-induced deficits and caused significant SNcDA neurons loss, suggesting it accelerates PD progression. Prolonged chemogenetic inhibition of the DRN-SNc circuit mitigated chronic stress effects in MPTP-treated mice. These findings highlight the crucial role of the DRN-SNc serotonergic circuit and 5-HT2C receptors in stress-related motor deficits, suggesting potential targets for therapies aimed at treating both stress-related motor disorders and Parkinson's disease.
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Affiliation(s)
- Yibo Yao
- Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China
| | - Chi Cui
- Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China
| | - Yulong Shi
- Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China
| | - Jie Lei
- Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China
| | - Tongxia Li
- Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China
| | - Ming Li
- Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China
| | - Xiang Peng
- Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China
| | - Xueke Yang
- Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China
| | - Kun Ren
- Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China
| | - Jian Yang
- Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China
| | - Gangan Luo
- Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China
| | - Junsong Du
- Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China
| | - Sitong Chen
- Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China
| | - Pei Zhang
- Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China.
- Institute for Brain Research, Huazhong University of Science and Technology, Wuhan, Hubei, PR China.
- Key Laboratory of Neurological Diseases, Ministry of Education, Wuhan, Hubei, PR China.
| | - Bo Tian
- School of Medicine, Wuhan University of Science and Technology, Wuhan, Hubei, PR China.
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Ren A, Zhu X, Lehmann J, Kasem M, Schrader TO, Dang H, Le M, Frazer J, Unett DJ, Grottick AJ, Whelan KT, Morgan ME, Sage CR, Srinivas NR, McLin D, Semple G. Diazepine Agonists of the 5-HT 2C Receptor with Unprecedented Selectivity: Discovery of Bexicaserin (LP352). J Med Chem 2025. [PMID: 40368335 DOI: 10.1021/acs.jmedchem.4c02923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/16/2025]
Abstract
The clinical development of novel 5-HT2C receptor (5-HT2CR) therapies has been limited due to concerns over lack of selectivity and potential for off-target effects. Here, we report that the introduction of a secondary amide substituent into a 6,5,7-tricyclic benzodiazepine scaffold provided compounds with unprecedented selectivity for the 5-HT2CR in both functional and binding assays. An early lead compound, 7b, had an in vivo half-life that was shorter than desired, which was improved by a targeted reduction in renal clearance. This provided the clinical candidate compound (+)-19m (later named bexicaserin), which displayed excellent oral bioavailability, good central nervous system partitioning, and decreased renal clearance in vivo. (+)-19m was also a potent inhibitor of acute refeeding in the fasted rat, suggesting on-target effects. (+)-19m demonstrated excellent selectivity for 5-HT2CR over 5-HT2AR and 5-HT2BR and maximal activity exceeding that induced by the endogenous ligand 5-HT. (+)-19m has since progressed into clinical development.
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Affiliation(s)
- Albert Ren
- Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, California 92121, United States
| | - Xiuwen Zhu
- Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, California 92121, United States
| | - Juerg Lehmann
- Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, California 92121, United States
| | - Michelle Kasem
- Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, California 92121, United States
| | - Thomas O Schrader
- Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, California 92121, United States
| | - Huong Dang
- Eurofins Beacon Discovery, 6118 Nancy Ridge Drive, San Diego, California 92121, United States
| | - Minh Le
- Longboard Pharmaceuticals, 4275 Executive Square, La Jolla, California 92037, United States
| | - John Frazer
- Eurofins Beacon Discovery, 6118 Nancy Ridge Drive, San Diego, California 92121, United States
| | - David J Unett
- Eurofins Beacon Discovery, 6118 Nancy Ridge Drive, San Diego, California 92121, United States
| | - Andrew J Grottick
- Eurofins Beacon Discovery, 6118 Nancy Ridge Drive, San Diego, California 92121, United States
| | - Kevin T Whelan
- Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, California 92121, United States
| | - Michael E Morgan
- Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, California 92121, United States
| | - Carleton R Sage
- Eurofins Beacon Discovery, 6118 Nancy Ridge Drive, San Diego, California 92121, United States
| | - Nuggehally R Srinivas
- Longboard Pharmaceuticals, 4275 Executive Square, La Jolla, California 92037, United States
| | - Dewey McLin
- Longboard Pharmaceuticals, 4275 Executive Square, La Jolla, California 92037, United States
| | - Graeme Semple
- Eurofins Beacon Discovery, 6118 Nancy Ridge Drive, San Diego, California 92121, United States
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Lu J, Yu P, Wang Y, Dai Y, Wang W, Liu C, Dong L, Lei H, Yang Y, Wang L, Zou F, Deng X, Wang B, Wei S, Ma M, Wang H, Ye L, Zhang J, Tian J. Rational Design of the First Dual Agonist at Trace Amine-Associated Receptor 1 and 5-HT 2C Receptors Based on Binding Pocket Similarity for the Treatment of Schizophrenia and Alzheimer's Disease-Related Psychosis. J Med Chem 2025; 68:7082-7105. [PMID: 40159850 DOI: 10.1021/acs.jmedchem.4c02291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/02/2025]
Abstract
The clinical-stage agonists for trace amine-associated receptor 1 (TAAR1) show insufficient clinical efficacy, requiring the design of new compounds beyond the TAAR1 receptor alone. Here, we provide evidence for the feasibility of designing TAAR1/5-HT2CR dual agonists based on structural basis of these two targets and similarities of their agonists. Three series of novel agonists were discovered, leading to a potent compound named 21b. 21b exhibits submicromolar potency on both TAAR1 and 5-HT2CR targets with high specificity confirmed by site-directed mutagenesis. Preclinical proof-of-concept studies showed that 21b was highly efficacious against the positive and negative symptoms of schizophrenia in mice models. 21b also alleviated cognitive deficits and psychoactive symptoms in Alzheimer's disease (AD) model mice. Four week repeated dosing of 21b is exceptionally well tolerated in rats and beagle dogs without hyperglycemia commonly seen with antipsychotics. Thus, the favorable druggability of compound 21b warrants further clinical development for the treatment of schizophrenia and AD-related psychosis.
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Affiliation(s)
- Jing Lu
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China
- State Key Laboratory of Advanced Drug Delivery and Release Systems, Shandong Luye Pharmaceutical Co., Ltd., Yantai 264003, China
| | - Pengfei Yu
- State Key Laboratory of Advanced Drug Delivery and Release Systems, Shandong Luye Pharmaceutical Co., Ltd., Yantai 264003, China
- School of Pharmacy, Binzhou Medical University, Yantai 256603, China
| | - Yunjie Wang
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China
- State Key Laboratory of Advanced Drug Delivery and Release Systems, Shandong Luye Pharmaceutical Co., Ltd., Yantai 264003, China
| | - Yusen Dai
- State Key Laboratory of Advanced Drug Delivery and Release Systems, Shandong Luye Pharmaceutical Co., Ltd., Yantai 264003, China
| | - Wenyan Wang
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China
- State Key Laboratory of Advanced Drug Delivery and Release Systems, Shandong Luye Pharmaceutical Co., Ltd., Yantai 264003, China
| | - Chunjiao Liu
- State Key Laboratory of Advanced Drug Delivery and Release Systems, Shandong Luye Pharmaceutical Co., Ltd., Yantai 264003, China
| | - Lin Dong
- State Key Laboratory of Advanced Drug Delivery and Release Systems, Shandong Luye Pharmaceutical Co., Ltd., Yantai 264003, China
| | - Hui Lei
- State Key Laboratory of Advanced Drug Delivery and Release Systems, Shandong Luye Pharmaceutical Co., Ltd., Yantai 264003, China
| | - Yifei Yang
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China
- State Key Laboratory of Advanced Drug Delivery and Release Systems, Shandong Luye Pharmaceutical Co., Ltd., Yantai 264003, China
| | - Lin Wang
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China
- State Key Laboratory of Advanced Drug Delivery and Release Systems, Shandong Luye Pharmaceutical Co., Ltd., Yantai 264003, China
| | - Fangxia Zou
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China
- State Key Laboratory of Advanced Drug Delivery and Release Systems, Shandong Luye Pharmaceutical Co., Ltd., Yantai 264003, China
| | - Xuan Deng
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China
| | - Bingsi Wang
- State Key Laboratory of Advanced Drug Delivery and Release Systems, Shandong Luye Pharmaceutical Co., Ltd., Yantai 264003, China
| | - Shujuan Wei
- State Key Laboratory of Advanced Drug Delivery and Release Systems, Shandong Luye Pharmaceutical Co., Ltd., Yantai 264003, China
| | - Mingxu Ma
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China
- State Key Laboratory of Advanced Drug Delivery and Release Systems, Shandong Luye Pharmaceutical Co., Ltd., Yantai 264003, China
| | - Hongbo Wang
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China
- State Key Laboratory of Advanced Drug Delivery and Release Systems, Shandong Luye Pharmaceutical Co., Ltd., Yantai 264003, China
| | - Liang Ye
- State Key Laboratory of Advanced Drug Delivery and Release Systems, Shandong Luye Pharmaceutical Co., Ltd., Yantai 264003, China
- School of Public Health, Binzhou Medical University, Yantai 256603, China
| | - Jianzhao Zhang
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China
- State Key Laboratory of Advanced Drug Delivery and Release Systems, Shandong Luye Pharmaceutical Co., Ltd., Yantai 264003, China
| | - Jingwei Tian
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China
- State Key Laboratory of Advanced Drug Delivery and Release Systems, Shandong Luye Pharmaceutical Co., Ltd., Yantai 264003, China
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da Fonseca STO, Alves CC, Dias CT, Mendes-da-Silva C. Probiotics and undernourishment impact on brain 5-Hydroxytryptamine system and neurotrophin BDNF in rats: Risk of depression and anxiety? Nutrition 2025; 132:112680. [PMID: 39904121 DOI: 10.1016/j.nut.2024.112680] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 11/14/2024] [Accepted: 12/26/2024] [Indexed: 02/06/2025]
Abstract
BACKGROUND Undernourishment can significantly affect the serotonergic system, potentially increasing the risk of neuropsychiatric disorders such as depression and anxiety. Probiotic therapy has emerged as a potential modulator of the serotonergic system and brain-derived neurotrophic factor (BDNF). Our hypothesis posits that probiotic treatment positively influences the serotonergic system and BDNF levels in the prefrontal cortex (PFC) and hippocampus (HIP), mitigating the effects of malnutrition. METHODS We conducted an experiment using 38 adult isogenic rats, divided into four groups: nourished control (n = 9), undernourished control (n = 9), nourished probiotic (n = 10), and undernourished probiotic (n = 10). The animals experienced undernourishment for 10 days, followed by probiotic supplementation while continuing food restriction for an additional 15 days. On the 25th day of the experiment, we euthanized the animals, microdissected their brains, and extracted samples from the HIP and PFC. We performed immunoblotting analysis to assess the expression levels of the following proteins: BDNF, tryptophan hydroxylase 2 enzyme, and 5-HT1A and 5-HT2C serotonergic receptors. RESULTS Our findings revealed the following effects of probiotic administration: tryptophan hydroxylase 2 expression increased in the PFC of nourished rats (P = 0.033) and in the HIP of undernourished rats (P = 0.013); improved 5-HT2C expression was observed in the PFC under both nutritional conditions (P < 0.01). The proBDNF levels were elevated in the HIP of undernourished rats (P = 0.001). CONCLUSION Probiotic administration effectively modulated the gut-microbiota-brain axis by enhancing serotonergic system proteins in the prefrontal cortex and hippocampus of both nourished and undernourished rats.
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Affiliation(s)
| | - Cláudia Cristina Alves
- Department of Biosciences, Clinical and Experimental Nutrition Research Laboratory, Federal University of São Paulo, Santos, São Paulo, Brazil
| | - Clarissa Tavares Dias
- Department of Biosciences, Laboratory of Neuroscience and Nutrition, Federal University of São Paulo, Santos, São Paulo, Brazil
| | - Cristiano Mendes-da-Silva
- Department of Biosciences, Laboratory of Neuroscience and Nutrition, Federal University of São Paulo, Santos, São Paulo, Brazil.
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Agahari FA, Stricker C. Modulation by serotonin reveals preferred recurrent excitatory connectivity in layer II of rat neocortex. Cereb Cortex 2025; 35:bhaf008. [PMID: 39937460 DOI: 10.1093/cercor/bhaf008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 12/17/2024] [Accepted: 01/16/2025] [Indexed: 02/13/2025] Open
Abstract
We reported that in layer II pyramidal cells of rat somatosensory cortex, 10 μM serotonin (5-HT) alters miniature excitatory postsynaptic current frequency in a subset of cells (47%, "responders", RC; "non-responders", NC otherwise) via 5-HT2 receptors (5-HT2R) but in all pairs reduced evoked excitatory postsynaptic current amplitude by ~50% (Agahari FA, Stricker C. 2021. Serotonergic modulation of spontaneous and evoked transmitter release in layer II pyramidal cells of rat somatosensory cortex. Cereb Cortex. 31:1182-1200. https://doi.org/10.1093/cercor/bhaa285.) suggestive of preferential connectivity. We provide different lines of evidence that distinguish these subsets. First, after 5-HT exposure, changes in miniature excitatory postsynaptic current, spontaneous EPSC frequency, or whole-cell noise (σw) were restricted to postsynaptic cells in pairs (PO) and RC but absent in presynaptic (PR) and NC. Second, exposure caused a large change in holding current with a small variability in NC, but a small one with a large variability in PO/RC. In addition, ΔRin in PO/RC was larger than in PR/NC, with a negative correlation between ΔIhold and ΔRin in NC, a positive in PO, but none in RC. Third, an unbiased classifier identified most PO as RC and all PR as NC. Our data establish two distinct sets of pyramidal cells having a preferred connectivity from NC → RC. 5-HT2R-mediated modulation of transmitter release may likely reduce the signal-to-noise ratio in the ipsilateral but leave the output to the contralateral side unaffected.
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Affiliation(s)
- Fransiscus Adrian Agahari
- Neuronal Network Laboratory, Eccles Institute of Neuroscience, The John Curtin School of Medical Research, Australian National University, Ward Rd, Acton, ACT 2601, Australia
- Brain Science Institute, Tamagawa University, 6-1-1 Tamagawa Gakuen, Machida-Shi, Tokyo 194-8610, Japan
| | - Christian Stricker
- Neuronal Network Laboratory, Eccles Institute of Neuroscience, The John Curtin School of Medical Research, Australian National University, Ward Rd, Acton, ACT 2601, Australia
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Balakin E, Yurku K, Ivanov M, Izotov A, Nakhod V, Pustovoyt V. Regulation of Stress-Induced Immunosuppression in the Context of Neuroendocrine, Cytokine, and Cellular Processes. BIOLOGY 2025; 14:76. [PMID: 39857306 PMCID: PMC11760489 DOI: 10.3390/biology14010076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Revised: 01/09/2025] [Accepted: 01/14/2025] [Indexed: 01/27/2025]
Abstract
Understanding the regulatory mechanisms of stress-induced immunosuppression and developing reliable diagnostic methods are important tasks in clinical medicine. This will allow for the development of effective strategies for the prevention and treatment of conditions associated with immune system dysfunction induced by chronic stress. The purpose of this review is to conduct a comprehensive analysis and synthesis of existing data on the regulatory mechanisms of stress-induced immunosuppression. The review is aimed at identifying key neuroendocrine, cytokine, and cellular processes underlying the suppression of the immune response under stress. This study involved a search of scientific literature covering the neuroendocrine, cellular, and molecular mechanisms of stress-induced immunosuppression regulation, as well as modern methods for its diagnosis. Major international bibliographic databases covering publications in biomedicine, psychophysiology, and immunology were selected for the search. The results of the analysis identified key mechanisms regulating stress-induced immunosuppression. The reviewed publications provided detailed descriptions of the neuroendocrine and cytokine processes underlying immune response suppression under stress. A significant portion of the data confirms that the activation of the hypothalamic-pituitary-adrenal (HPA) axis and subsequent elevation of cortisol levels exert substantial immunosuppressive effects on immune cells, particularly macrophages and lymphocytes, leading to the suppression of innate and adaptive immune responses. The data also highlight the crucial role of cortisol and catecholamines (adrenaline and noradrenaline) in initiating immunosuppressive mechanisms under chronic stress.
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Affiliation(s)
- Evgenii Balakin
- Federal Medical Biophysical Center of Federal Medical Biological Agency, 123098 Moscow, Russia
| | - Ksenia Yurku
- Federal Medical Biophysical Center of Federal Medical Biological Agency, 123098 Moscow, Russia
| | - Mark Ivanov
- Federal Medical Biophysical Center of Federal Medical Biological Agency, 123098 Moscow, Russia
| | - Alexander Izotov
- V.N. Orekhovich Research Institute of Biomedical Chemistry, Pogodinskaya Str. 10, Bldg. 8, 119121 Moscow, Russia
| | - Valeriya Nakhod
- V.N. Orekhovich Research Institute of Biomedical Chemistry, Pogodinskaya Str. 10, Bldg. 8, 119121 Moscow, Russia
| | - Vasiliy Pustovoyt
- Federal Medical Biophysical Center of Federal Medical Biological Agency, 123098 Moscow, Russia
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Werle I, Bertoglio LJ. Psychedelics: A review of their effects on recalled aversive memories and fear/anxiety expression in rodents. Neurosci Biobehav Rev 2024; 167:105899. [PMID: 39305969 DOI: 10.1016/j.neubiorev.2024.105899] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 09/02/2024] [Accepted: 09/16/2024] [Indexed: 09/27/2024]
Abstract
Threatening events and stressful experiences can lead to maladaptive memories and related behaviors. Existing treatments often fail to address these issues linked to anxiety/stress-related disorders effectively. This review identifies dose ranges associated with specific actions across various psychedelics. We examined psilocybin/psilocin, lysergic acid diethylamide (LSD), N,N-dimethyltryptamine (DMT), mescaline, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), serotonin 2 A/2 C agonists (e.g., DOI) and 3,4-methylenedioxymethamphetamine (MDMA) on aversive memory extinction and reconsolidation, learned fear, anxiety, and locomotion in rodents. Nearly 400 studies published since 1957 were reviewed. Psychedelics often show biphasic effects on locomotion at doses that enhance extinction learning/retention, impair memory reconsolidation, or reduce learned fear and anxiety. Emerging evidence suggests a dissociation between their prospective benefits and locomotor effects. Under-explored aspects include sex differences, susceptibility to interference as memories age and generalize, repeated treatments, and immediate vs. delayed changes. Validating findings in traumatic-like memory and maladaptive fear/anxiety models is essential. Understanding how psychedelics modulate threat responses and post-retrieval memory processes in rodents may inform drug development and human studies, improving therapeutic approaches for related psychiatric conditions.
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Affiliation(s)
- Isabel Werle
- Department of Pharmacology, Federal University of Santa Catarina, Florianopolis, SC, Brazil
| | - Leandro J Bertoglio
- Department of Pharmacology, Federal University of Santa Catarina, Florianopolis, SC, Brazil.
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Li Q, Guo Q, Ren L, Zhao S, Luo J, Zhang Y, Zhou W, Xu X, Chen G. Design, synthesis and biological evaluation of arylpropylamine derivatives as potential multi-target antidepressants. Bioorg Med Chem 2024; 114:117935. [PMID: 39393299 DOI: 10.1016/j.bmc.2024.117935] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 09/27/2024] [Accepted: 09/28/2024] [Indexed: 10/13/2024]
Abstract
In this study, a series of novel arylpropylamine derivatives were designed, synthesized and evaluated as potential multi-target antidepressants. Among them, compound (R)-13j displayed unique pharmacological features, exhibiting excellent inhibitory potency against serotonin and noradrenaline transporters (SERT/NET) and high affinity for 5-HT2A/2C receptor, and showing low affinity for histamine H1, adrenergic α1 receptors and hERG channels (to reduce QT interval prolongation). Molecular docking studies provided a rational binding model of (R)-13j in complex with SERT and 5-HT2A/2C receptor. In animal models, compound (R)-13j dose-dependently reduced the immobility time in the tail suspension test (TST) and the forced swimming test (FST) in mice, with higher efficacy when compared to duloxetine, and showed no stimulatory effect on the locomotor activity. Moreover, compound (R)-13j significantly shortened the immobility time in the ACTH-induced rat model of treatment-resistant depression (TRD). Furthermore, compound (R)-13j also exhibited a higher threshold for acute toxicity than duloxetine. In addition, compound (R)-13j possessed a favorable pharmacokinetic profile in mice. Taken together, compound (R)-13j may constitute a novel class of drugs for the treatment of depression.
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Affiliation(s)
- Quxiang Li
- School of Pharmacy, Nanjing Tech University, 30th South Puzhu Road, Nanjing 211816, China
| | - Qiang Guo
- Institute of Pharmaceutical Research, Jiangsu Nhwa Pharmaceutical Co., Ltd. & Jiangsu Key Laboratory of Central Nervous System Drug Research and Development, Xuzhou 221116, China
| | - Lili Ren
- School of Pharmacy, Nanjing Tech University, 30th South Puzhu Road, Nanjing 211816, China
| | - Song Zhao
- Institute of Pharmaceutical Research, Jiangsu Nhwa Pharmaceutical Co., Ltd. & Jiangsu Key Laboratory of Central Nervous System Drug Research and Development, Xuzhou 221116, China
| | - Junyong Luo
- School of Pharmacy, Nanjing Tech University, 30th South Puzhu Road, Nanjing 211816, China
| | - Yi Zhang
- Institute of Pharmaceutical Research, Jiangsu Nhwa Pharmaceutical Co., Ltd. & Jiangsu Key Laboratory of Central Nervous System Drug Research and Development, Xuzhou 221116, China
| | - Wenchao Zhou
- Institute of Pharmaceutical Research, Jiangsu Nhwa Pharmaceutical Co., Ltd. & Jiangsu Key Laboratory of Central Nervous System Drug Research and Development, Xuzhou 221116, China
| | - Xiangqing Xu
- Institute of Pharmaceutical Research, Jiangsu Nhwa Pharmaceutical Co., Ltd. & Jiangsu Key Laboratory of Central Nervous System Drug Research and Development, Xuzhou 221116, China.
| | - Guoguang Chen
- School of Pharmacy, Nanjing Tech University, 30th South Puzhu Road, Nanjing 211816, China.
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Shi HJ, Xue YR, Shao H, Wei C, Liu T, He J, Yang YH, Wang HM, Li N, Ren SQ, Chang L, Wang Z, Zhu LJ. Hippocampal excitation-inhibition balance underlies the 5-HT2C receptor in modulating depressive behaviours. Brain 2024; 147:3764-3779. [PMID: 38701344 DOI: 10.1093/brain/awae143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Revised: 04/02/2024] [Accepted: 04/18/2024] [Indexed: 05/05/2024] Open
Abstract
The implication of 5-hydroxytryptamine 2C receptor (5-HT2CR) activity in depression is a topic of debate, and the underlying mechanisms remain largely unclear. Here, we elucidate how hippocampal excitation-inhibition (E/I) balance underlies the regulatory effects of 5-HT2CR in depression. Molecular biological analyses showed that chronic mild stress (CMS) reduced the expression of 5-HT2CR in hippocampus. We revealed that inhibition of 5-HT2CR induced depressive-like behaviours, reduced GABA release and shifted the E/I balance towards excitation in CA3 pyramidal neurons using behavioural analyses, microdialysis coupled with mass spectrometry and electrophysiological recordings. Moreover, 5-HT2CR modulated the neuronal nitric oxide synthase (nNOS)-carboxy-terminal PDZ ligand of nNOS (CAPON) interaction by influencing intracellular Ca2+ release, as determined by fibre photometry and coimmunoprecipitation. Notably, disruption of nNOS-CAPON with the specific small molecule compound ZLc-002 or AAV-CMV-CAPON-125C-GFP abolished 5-HT2CR inhibition-induced depressive-like behaviours, as well as the impairment in soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex assembly-mediated GABA vesicle release and consequent E/I imbalance. Importantly, optogenetic inhibition of CA3 GABAergic neurons prevented the effects of AAV-CMV-CAPON-125C-GFP on depressive behaviours in the presence of a 5-HT2CR antagonist. Conclusively, our findings disclose the regulatory role of 5-HT2CR in depressive-like behaviours and highlight hippocampal nNOS-CAPON coupling-triggered E/I imbalance as a pivotal cellular event underpinning the behavioural consequences of 5-HT2CR inhibition.
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Affiliation(s)
- Hu-Jiang Shi
- Key Laboratory of Developmental Genes and Human Diseases, MOE, Department of Histology and Embryology, Department of Pharmacy, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 201108, China
| | - Yi-Ren Xue
- Key Laboratory of Developmental Genes and Human Diseases, MOE, Department of Histology and Embryology, Department of Pharmacy, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China
| | - Hua Shao
- Key Laboratory of Developmental Genes and Human Diseases, MOE, Department of Histology and Embryology, Department of Pharmacy, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China
| | - Cheng Wei
- Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Key Laboratory of Mental Health of the Ministry of Education, Guangdong Province Key Laboratory of Psychiatric Disorders, Southern Medical University, Guangzhou 510515, Guangdong, China
| | - Ting Liu
- Key Laboratory of Developmental Genes and Human Diseases, MOE, Department of Histology and Embryology, Department of Pharmacy, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China
| | - Jie He
- Key Laboratory of Developmental Genes and Human Diseases, MOE, Department of Histology and Embryology, Department of Pharmacy, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China
| | - Yu-Hao Yang
- Key Laboratory of Developmental Genes and Human Diseases, MOE, Department of Histology and Embryology, Department of Pharmacy, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China
| | - Hong-Mei Wang
- Key Laboratory of Developmental Genes and Human Diseases, MOE, Department of Histology and Embryology, Department of Pharmacy, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China
| | - Na Li
- Key Laboratory of Developmental Genes and Human Diseases, MOE, Department of Histology and Embryology, Department of Pharmacy, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China
| | - Si-Qiang Ren
- Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Key Laboratory of Mental Health of the Ministry of Education, Guangdong Province Key Laboratory of Psychiatric Disorders, Southern Medical University, Guangzhou 510515, Guangdong, China
| | - Lei Chang
- Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, Jiangsu, 210009, China
| | - Zhen Wang
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 201108, China
| | - Li-Juan Zhu
- Key Laboratory of Developmental Genes and Human Diseases, MOE, Department of Histology and Embryology, Department of Pharmacy, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 201108, China
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10
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Higa GSV, Viana FJC, Francis-Oliveira J, Cruvinel E, Franchin TS, Marcourakis T, Ulrich H, De Pasquale R. Serotonergic neuromodulation of synaptic plasticity. Neuropharmacology 2024; 257:110036. [PMID: 38876308 DOI: 10.1016/j.neuropharm.2024.110036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 05/15/2024] [Accepted: 06/11/2024] [Indexed: 06/16/2024]
Abstract
Synaptic plasticity constitutes a fundamental process in the reorganization of neural networks that underlie memory, cognition, emotional responses, and behavioral planning. At the core of this phenomenon lie Hebbian mechanisms, wherein frequent synaptic stimulation induces long-term potentiation (LTP), while less activation leads to long-term depression (LTD). The synaptic reorganization of neuronal networks is regulated by serotonin (5-HT), a neuromodulator capable of modify synaptic plasticity to appropriately respond to mental and behavioral states, such as alertness, attention, concentration, motivation, and mood. Lately, understanding the serotonergic Neuromodulation of synaptic plasticity has become imperative for unraveling its impact on cognitive, emotional, and behavioral functions. Through a comparative analysis across three main forebrain structures-the hippocampus, amygdala, and prefrontal cortex, this review discusses the actions of 5-HT on synaptic plasticity, offering insights into its role as a neuromodulator involved in emotional and cognitive functions. By distinguishing between plastic and metaplastic effects, we provide a comprehensive overview about the mechanisms of 5-HT neuromodulation of synaptic plasticity and associated functions across different brain regions.
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Affiliation(s)
- Guilherme Shigueto Vilar Higa
- Laboratório de Neurofisiologia, Departamento de Fisiologia e Biofísica, Universidade de São Paulo, Butantã, São Paulo, SP, 05508-000, Brazil; Departamento de Bioquímica, Instituto de Química (USP), Butantã, São Paulo, SP, 05508-900, Brazil
| | - Felipe José Costa Viana
- Laboratório de Neurofisiologia, Departamento de Fisiologia e Biofísica, Universidade de São Paulo, Butantã, São Paulo, SP, 05508-000, Brazil
| | - José Francis-Oliveira
- Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, 35233, USA
| | - Emily Cruvinel
- Laboratório de Neurofisiologia, Departamento de Fisiologia e Biofísica, Universidade de São Paulo, Butantã, São Paulo, SP, 05508-000, Brazil
| | - Thainá Soares Franchin
- Laboratório de Neurofisiologia, Departamento de Fisiologia e Biofísica, Universidade de São Paulo, Butantã, São Paulo, SP, 05508-000, Brazil
| | - Tania Marcourakis
- Departamento de Análises Clínicas e Toxicológicas, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, Butantã, São Paulo, SP, 05508-000, Brazil
| | - Henning Ulrich
- Departamento de Bioquímica, Instituto de Química (USP), Butantã, São Paulo, SP, 05508-900, Brazil
| | - Roberto De Pasquale
- Laboratório de Neurofisiologia, Departamento de Fisiologia e Biofísica, Universidade de São Paulo, Butantã, São Paulo, SP, 05508-000, Brazil.
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11
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Egger K, Aicher HD, Cumming P, Scheidegger M. Neurobiological research on N,N-dimethyltryptamine (DMT) and its potentiation by monoamine oxidase (MAO) inhibition: from ayahuasca to synthetic combinations of DMT and MAO inhibitors. Cell Mol Life Sci 2024; 81:395. [PMID: 39254764 PMCID: PMC11387584 DOI: 10.1007/s00018-024-05353-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 06/19/2024] [Accepted: 07/04/2024] [Indexed: 09/11/2024]
Abstract
The potent hallucinogen N,N-dimethyltryptamine (DMT) has garnered significant interest in recent years due to its profound effects on consciousness and its therapeutic psychopotential. DMT is an integral (but not exclusive) psychoactive alkaloid in the Amazonian plant-based brew ayahuasca, in which admixture of several β-carboline monoamine oxidase A (MAO-A) inhibitors potentiate the activity of oral DMT, while possibly contributing in other respects to the complex psychopharmacology of ayahuasca. Irrespective of the route of administration, DMT alters perception, mood, and cognition, presumably through agonism at serotonin (5-HT) 1A/2A/2C receptors in brain, with additional actions at other receptor types possibly contributing to its overall psychoactive effects. Due to rapid first pass metabolism, DMT is nearly inactive orally, but co-administration with β-carbolines or synthetic MAO-A inhibitors (MAOIs) greatly increase its bioavailability and duration of action. The synergistic effects of DMT and MAOIs in ayahuasca or synthetic formulations may promote neuroplasticity, which presumably underlies their promising therapeutic efficacy in clinical trials for neuropsychiatric disorders, including depression, addiction, and post-traumatic stress disorder. Advances in neuroimaging techniques are elucidating the neural correlates of DMT-induced altered states of consciousness, revealing alterations in brain activity, functional connectivity, and network dynamics. In this comprehensive narrative review, we present a synthesis of current knowledge on the pharmacology and neuroscience of DMT, β-carbolines, and ayahuasca, which should inform future research aiming to harness their full therapeutic potential.
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Affiliation(s)
- Klemens Egger
- Department of Adult Psychiatry and Psychotherapy, Psychiatric University Clinic Zurich and University of Zurich, Zurich, Switzerland.
- Neuroscience Center Zurich, University of Zurich and Swiss Federal Institute of Technology Zurich, Zurich, Switzerland.
- Department of Nuclear Medicine, Bern University Hospital, Bern, Switzerland.
| | - Helena D Aicher
- Department of Adult Psychiatry and Psychotherapy, Psychiatric University Clinic Zurich and University of Zurich, Zurich, Switzerland
- Neuroscience Center Zurich, University of Zurich and Swiss Federal Institute of Technology Zurich, Zurich, Switzerland
- Department of Psychology, University of Zurich, Zurich, Switzerland
| | - Paul Cumming
- Department of Nuclear Medicine, Bern University Hospital, Bern, Switzerland
- School of Psychology and Counselling, Queensland University of Technology, Brisbane, Australia
| | - Milan Scheidegger
- Department of Adult Psychiatry and Psychotherapy, Psychiatric University Clinic Zurich and University of Zurich, Zurich, Switzerland
- Neuroscience Center Zurich, University of Zurich and Swiss Federal Institute of Technology Zurich, Zurich, Switzerland
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12
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Jacobs DS, Bogachuk AP, Le Moing CL, Moghaddam B. Effects of psilocybin on uncertain punishment learning. Neurobiol Learn Mem 2024; 213:107954. [PMID: 38909970 PMCID: PMC11971122 DOI: 10.1016/j.nlm.2024.107954] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Revised: 06/06/2024] [Accepted: 06/20/2024] [Indexed: 06/25/2024]
Abstract
Psilocybin may provide a useful treatment for mood disorders including anxiety and depression but its mechanisms of action for these effects are not well understood. While recent preclinical work has begun to assess psilocybin's role in affective behaviors through innate anxiety or fear conditioning, there is scant evidence for its role in conflict between reward and punishment. The current study was designed to determine the impact of psilocybin on the learning of reward-punishment conflict associations, as well as its effects after learning, in male and female rats. We utilized a chained schedule of reinforcement that involved execution of safe and risky reward-guided actions under uncertain punishment. Different patterns of behavioral suppression by psilocybin emerged during learning versus after learning of risky action-reward associations. Psilocybin increased behavioral suppression in female rats as punishment associations were learned. After learning, psilocybin decreased behavioral suppression in both sexes. Thus, psilocybin produces divergent effects on action suppression during approach-avoidance conflict depending on when the conflict is experienced. This observation may have implications for its therapeutic mechanism of action.
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Affiliation(s)
- David S Jacobs
- Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, USA
| | - Alina P Bogachuk
- Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, USA
| | - Chloé L Le Moing
- Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, USA
| | - Bita Moghaddam
- Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, USA; Department of Psychiatry, Oregon Health & Science University, Portland, OR, USA.
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13
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Liu Y, Yuan J, Dong Y, Jiang S, Zhang M, Zhao X. Interaction between Oligodendrocytes and Interneurons in Brain Development and Related Neuropsychiatric Disorders. Int J Mol Sci 2024; 25:3620. [PMID: 38612430 PMCID: PMC11011273 DOI: 10.3390/ijms25073620] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Revised: 03/17/2024] [Accepted: 03/22/2024] [Indexed: 04/14/2024] Open
Abstract
A variety of neurological and psychiatric disorders have recently been shown to be highly associated with the abnormal development and function of oligodendrocytes (OLs) and interneurons. OLs are the myelin-forming cells in the central nervous system (CNS), while interneurons are important neural types gating the function of excitatory neurons. These two types of cells are of great significance for the establishment and function of neural circuits, and they share similar developmental origins and transcriptional architectures, and interact with each other in multiple ways during development. In this review, we compare the similarities and differences in these two cell types, providing an important reference and further revealing the pathogenesis of related brain disorders.
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Affiliation(s)
| | | | | | | | | | - Xianghui Zhao
- Department of Neuroscience, Air Force Medical University, Xi’an 710032, China
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14
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Oliva V, Possidente C, De Prisco M, Fico G, Anmella G, Hidalgo-Mazzei D, Murru A, Fanelli G, Fabbri C, Fornaro M, de Bartolomeis A, Solmi M, Radua J, Vieta E, Serretti A. Pharmacological treatments for psychotic depression: a systematic review and network meta-analysis. Lancet Psychiatry 2024; 11:210-220. [PMID: 38360024 DOI: 10.1016/s2215-0366(24)00006-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Revised: 12/13/2023] [Accepted: 01/04/2024] [Indexed: 02/17/2024]
Abstract
BACKGROUND There are no recommendations based on the efficacy of specific drugs for the treatment of psychotic depression. To address this evidence gap, we did a network meta-analysis to assess and compare the efficacy and safety of pharmacological treatments for psychotic depression. METHODS In this systematic review and network meta-analysis, we searched ClinicalTrials.gov, CENTRAL, Embase, PsycINFO, PubMed, Scopus, and Web of Science from inception to Nov 23, 2023 for randomised controlled trials published in any language that assessed pharmacological treatments for individuals of any age with a diagnosis of a major depressive episode with psychotic features, in the context of major depressive disorder or bipolar disorder in any setting. We excluded continuation or maintenance trials. We screened the study titles and abstracts identified, and we extracted data from relevant studies after full-text review. If full data were not available, we requested data from study authors twice. We analysed treatments for individual drugs (or drug combinations) and by grouping them on the basis of mechanisms of action. The primary outcomes were response rate (ie, the proportion of participants who responded to treatment) and acceptability (ie, the proportion who discontinued treatment for any reason). We calculated risk ratios and did separate frequentist network meta-analyses by using random-effects models. The risk of bias of individual studies was assessed with the Cochrane risk-of-bias tool and the confidence in the evidence with the Confidence-In-Network-Meta-Analysis (CINeMA). This study was registered with PROSPERO, CRD42023392926. FINDINGS Of 6313 reports identified, 16 randomised controlled trials were included in the systematic review, and 14 were included in the network meta-analyses. The 16 trials included 1161 people with psychotic depression (mean age 50·5 years [SD 11·4]). 516 (44·4%) participants were female and 422 (36·3%) were male; sex data were not available for the other 223 (19·2%). 489 (42·1%) participants were White, 47 (4·0%) were African American, and 12 (1·0%) were Asian; race or ethnicity data were not available for the other 613 (52·8%). Only the combination of fluoxetine plus olanzapine was associated with a higher proportion of participants with a treatment response compared with placebo (risk ratio 1·91 [95% CI 1·27-2·85]), with no differences in terms of safety outcomes compared with placebo. When treatments were grouped by mechanism of action, the combination of a selective serotonin reuptake inhibitor with a second-generation antipsychotic was associated with a higher proportion of treatment responses than was placebo (1·89 [1·17-3·04]), with no differences in terms of safety outcomes. In head-to-head comparisons of active treatments, a significantly higher proportion of participants had a response to amitriptyline plus perphenazine (3·61 [1·23-10·56]) and amoxapine (3·14 [1·01-9·80]) than to perphenazine, and to fluoxetine plus olanzapine compared with olanzapine alone (1·60 [1·09-2·34]). Venlafaxine, venlafaxine plus quetiapine (2·25 [1·09-4·63]), and imipramine (1·95 [1·01-3·79]) were also associated with a higher proportion of treatment responses overall. In head-to-head comparisons grouped by mechanism of action, antipsychotic plus antidepressant combinations consistently outperformed monotherapies from either drug class in terms of the proportion of participants with treatment responses. Heterogeneity was low. No high-risk instances were identified in the bias assessment for our primary outcomes. INTERPRETATION According to the available evidence, the combination of a selective serotonin reuptake inhibitor and a second-generation antipsychotic-and particularly of fluoxetine and olanzapine-could be the optimal treatment choice for psychotic depression. These findings should be taken into account in the development of clinical practice guidelines. However, these conclusions should be interpreted cautiously in view of the low number of included studies and the limitations of these studies. FUNDING None.
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Affiliation(s)
- Vincenzo Oliva
- Departament de Medicina, Facultat de Medicina i Ciències de la Salut, Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain; Bipolar and Depressive Disorders Unit, Hospìtal Clinic de Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - Chiara Possidente
- Departament de Medicina, Facultat de Medicina i Ciències de la Salut, Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain; Bipolar and Depressive Disorders Unit, Hospìtal Clinic de Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - Michele De Prisco
- Departament de Medicina, Facultat de Medicina i Ciències de la Salut, Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain; Bipolar and Depressive Disorders Unit, Hospìtal Clinic de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental, Instituto de Salud Carlos III, Madrid, Spain
| | - Giovanna Fico
- Departament de Medicina, Facultat de Medicina i Ciències de la Salut, Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain; Bipolar and Depressive Disorders Unit, Hospìtal Clinic de Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
| | - Gerard Anmella
- Departament de Medicina, Facultat de Medicina i Ciències de la Salut, Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain; Bipolar and Depressive Disorders Unit, Hospìtal Clinic de Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental, Instituto de Salud Carlos III, Madrid, Spain
| | - Diego Hidalgo-Mazzei
- Departament de Medicina, Facultat de Medicina i Ciències de la Salut, Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain; Bipolar and Depressive Disorders Unit, Hospìtal Clinic de Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
| | - Andrea Murru
- Departament de Medicina, Facultat de Medicina i Ciències de la Salut, Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain; Bipolar and Depressive Disorders Unit, Hospìtal Clinic de Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
| | - Giuseppe Fanelli
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy; Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, Netherlands
| | - Chiara Fabbri
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy; Social, Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
| | - Michele Fornaro
- Section of Psychiatry, Department of Neuroscience, Reproductive Science and Odontostomatology, Federico II University of Naples, Naples, Italy
| | - Andrea de Bartolomeis
- Section of Psychiatry, Department of Neuroscience, Reproductive Science and Odontostomatology, Federico II University of Naples, Naples, Italy
| | - Marco Solmi
- Department of Psychiatry and Ottawa Hospital Research Institute Clinical Epidemiology Program, University of Ottawa, Ottawa, ON, Canada; Regional Centre for the Treatment of Eating Disorders and On Track: The Champlain First Episode Psychosis Program, Department of Mental Health, The Ottawa Hospital, Ottawa, ON, Canada; Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin, Berlin, Germany
| | - Joaquim Radua
- Departament de Medicina, Facultat de Medicina i Ciències de la Salut, Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental, Instituto de Salud Carlos III, Madrid, Spain
| | - Eduard Vieta
- Departament de Medicina, Facultat de Medicina i Ciències de la Salut, Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain; Bipolar and Depressive Disorders Unit, Hospìtal Clinic de Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental, Instituto de Salud Carlos III, Madrid, Spain.
| | - Alessandro Serretti
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy; Department of Medicine and Surgery, Kore University of Enna, Enna, Italy
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15
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Sathe PK, Ramdasi GR, Giammatteo K, Beauzile H, Wang S, Zhang H, Kulkarni P, Booth RG, Ferris C. Effects of (-)-MBP, a novel 5-HT 2C agonist and 5-HT 2A/2B antagonist/inverse agonist on brain activity: A phMRI study on awake mice. Pharmacol Res Perspect 2023; 11:e01144. [PMID: 37837184 PMCID: PMC10576165 DOI: 10.1002/prp2.1144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 09/10/2023] [Accepted: 09/14/2023] [Indexed: 10/15/2023] Open
Abstract
A novel serotonin ligand (-)-MBP was developed for the treatment of schizophrenia that has 5-HT2A/2B antagonist activity together with 5-HT2C agonist activity. The multi-functional activity of this novel drug candidate was characterized using pharmacological magnetic resonance imaging. It was hypothesized (-)-MBP would affect activity in brain areas associated with sensory perception. Adult male mice were given one of three doses of (-)-MBP (3.0, 10, 18 mg/kg) or vehicle while fully awake during the MRI scanning session and imaged for 15 min post I.P. injection. BOLD functional imaging was used to follow changes in global brain activity. Data for each treatment were registered to a 3D MRI mouse brain atlas providing site-specific information on 132 different brain areas. There was a dose-dependent decrease in positive BOLD signal in numerous brain regions, especially thalamus, cerebrum, and limbic cortex. The 3.0 mg/kg dose had the greatest effect on positive BOLD while the 18 mg/kg dose was less effective. Conversely, the 18 mg/kg dose showed the greatest negative BOLD response while the 3.0 mg/kg showed the least. The prominent activation of the thalamus and cerebrum included the neural circuitry associated with Papez circuit of emotional experience. When compared to vehicle, the 3.0 mg dose affected all sensory modalities, for example, olfactory, somatosensory, motor, and auditory except for the visual cortex. These findings show that (-)-MBP, a ligand with both 5-HT2A/2B antagonist and 5-HT2C agonist activities, interacts with thalamocortical circuitry and impacts areas involved in sensory perception.
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Affiliation(s)
- Preeti K. Sathe
- Department Pharmaceutical SciencesNortheastern UniversityBostonMassachusettsUSA
| | - Gargi R. Ramdasi
- Department Pharmaceutical SciencesNortheastern UniversityBostonMassachusettsUSA
| | - Kaylie Giammatteo
- Department Pharmaceutical SciencesNortheastern UniversityBostonMassachusettsUSA
| | - Harvens Beauzile
- Department Pharmaceutical SciencesNortheastern UniversityBostonMassachusettsUSA
| | - Shuyue Wang
- Department Pharmaceutical SciencesNortheastern UniversityBostonMassachusettsUSA
| | - Heng Zhang
- Department Pharmaceutical SciencesNortheastern UniversityBostonMassachusettsUSA
| | - Praveen Kulkarni
- Center for Translational NeuroscienceNortheastern UniversityBostonMassachusettsUSA
| | - Raymond G. Booth
- Department Pharmaceutical SciencesNortheastern UniversityBostonMassachusettsUSA
| | - Craig F. Ferris
- Department Pharmaceutical SciencesNortheastern UniversityBostonMassachusettsUSA
- Center for Translational NeuroscienceNortheastern UniversityBostonMassachusettsUSA
- Department PsychologyNortheastern UniversityBostonMassachusettsUSA
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16
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Zeng X, Tan Z, Wang W, Li W, Li S, Zhang D, Tan Q. Long-term Impact of Prenatal Famine on Differential DNA Methylation of Genes in the Serotonin Receptor Signalling Pathway in Adults. Neuroscience 2023; 529:107-115. [PMID: 37598834 DOI: 10.1016/j.neuroscience.2023.08.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 08/01/2023] [Accepted: 08/04/2023] [Indexed: 08/22/2023]
Abstract
The correlation of early life adversity with adulthood psychopathology has already been revealed by epidemiological studies. To find the biological mechanisms underlying the cross-talk between prenatal adversity and mental health, molecular genetic studies have been performed using animal models of prenatal undernutrition and stress, reporting altered expression of serotonin receptors which modulate the release of many neurotransmitters that regulate a broad range of physiological functions including psychopathology. Unfortunately, no such study has been possible on humans due to ethical reasons. Using the Chinese Famine of 1959-1961 as a natural experiment, we investigated DNA methylation patterns in genes of the serotonin receptor signaling pathway in the whole blood of adults born during the famine. A significant pattern of reduced DNA methylation was observed in sex combined samples (p value, 0.022). In a sex-stratified analysis, the pattern was only significant in females (p-value, 0.019) but not in males. We further tested the DNA methylation patterns specifically in HTR1A, HTR2A and the X-linked HTR2C and found reduced DNA methylation in females for HTR2A (p-value 0.033) and HTR2C (p-value 0.014) but not in males. Overall, this study reveals altered epigenetic regulation of the serotonin receptor signaling pathway in association with prenatal adversity in humans providing novel epigenetic evidence in support of neurodevelopmental origin of psychiatric disorders.
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Affiliation(s)
- Xin Zeng
- The Second People's Hospital of Lishui, Zhejiang, China.
| | - Zhen Tan
- The Second People's Hospital of Lishui, Zhejiang, China.
| | - Weijing Wang
- Qingdao University School of Public Health, Qingdao, China.
| | - Weilong Li
- Unit of Demography, Faculty of Social Science, University of Helsinki, Helsinki, Finland.
| | - Shuxia Li
- Epidemiology and Biostatistics, Department of Public Health, University of Southern Denmark, Odense, Denmark.
| | - Dongfeng Zhang
- Qingdao University School of Public Health, Qingdao, China.
| | - Qihua Tan
- Epidemiology and Biostatistics, Department of Public Health, University of Southern Denmark, Odense, Denmark.
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17
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Chen J, Garcia EJ, Merritt CR, Zamora JC, Bolinger AA, Pazdrak K, Stafford SJ, Mifflin RC, Wold EA, Wild CT, Chen H, Anastasio NC, Cunningham KA, Zhou J. Discovery of Novel Oleamide Analogues as Brain-Penetrant Positive Allosteric Serotonin 5-HT 2C Receptor and Dual 5-HT 2C/5-HT 2A Receptor Modulators. J Med Chem 2023; 66:9992-10009. [PMID: 37462530 PMCID: PMC10853020 DOI: 10.1021/acs.jmedchem.3c00908] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/28/2023]
Abstract
The serotonin 5-HT2A receptor (5-HT2AR) and 5-HT2CR localize to the brain and share overlapping signal transduction facets that contribute to their roles in cognition, mood, learning, and memory. Achieving selective targeting of these receptors is challenged by the similarity in their 5-HT orthosteric binding pockets. A fragment-based discovery approach was employed to design and synthesize novel oleamide analogues as selective 5-HT2CR or dual 5-HT2CR/5-HT2AR positive allosteric modulators (PAMs). Compound 13 (JPC0323) exhibited on-target properties, acceptable plasma exposure and brain penetration, as well as negligible displacement to orthosteric sites of ∼50 GPCRs and transporters. Furthermore, compound 13 suppressed novelty-induced locomotor activity in a 5-HT2CR-dependent manner, suggesting 5-HT2CR PAM, but not 5-HT2AR, activity at the level of the whole organism at the employed doses of 13. We discovered new selective 5-HT2CR PAMs and first-in-class 5-HT2CR/5-HT2AR dual PAMs that broaden the pharmacological toolbox to explore the biology of these vital receptors.
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Affiliation(s)
- Jianping Chen
- Center for Addiction Sciences and Therapeutics and Chemical Biology Program and Department of Pharmacology and Toxicology, University of Texas Medical Branch (UTMB), Galveston, Texas 77555, United States
| | - Erik J. Garcia
- Center for Addiction Sciences and Therapeutics, University of Texas Medical Branch (UTMB), Galveston, Texas 77555, United States
| | - Christina R. Merritt
- Center for Addiction Sciences and Therapeutics, University of Texas Medical Branch (UTMB), Galveston, Texas 77555, United States
| | - Joshua C. Zamora
- Center for Addiction Sciences and Therapeutics, University of Texas Medical Branch (UTMB), Galveston, Texas 77555, United States
| | - Andrew A. Bolinger
- Center for Addiction Sciences and Therapeutics and Chemical Biology Program and Department of Pharmacology and Toxicology, University of Texas Medical Branch (UTMB), Galveston, Texas 77555, United States
| | - Konrad Pazdrak
- Center for Addiction Sciences and Therapeutics, University of Texas Medical Branch (UTMB), Galveston, Texas 77555, United States
| | - Susan J. Stafford
- Center for Addiction Sciences and Therapeutics, University of Texas Medical Branch (UTMB), Galveston, Texas 77555, United States
| | - Randy C. Mifflin
- Center for Addiction Sciences and Therapeutics, University of Texas Medical Branch (UTMB), Galveston, Texas 77555, United States
| | - Eric A. Wold
- Center for Addiction Sciences and Therapeutics and Chemical Biology Program and Department of Pharmacology and Toxicology, University of Texas Medical Branch (UTMB), Galveston, Texas 77555, United States
| | - Christopher T. Wild
- Center for Addiction Sciences and Therapeutics and Chemical Biology Program and Department of Pharmacology and Toxicology, University of Texas Medical Branch (UTMB), Galveston, Texas 77555, United States
| | - Haiying Chen
- Center for Addiction Sciences and Therapeutics and Chemical Biology Program and Department of Pharmacology and Toxicology, University of Texas Medical Branch (UTMB), Galveston, Texas 77555, United States
| | - Noelle C. Anastasio
- Center for Addiction Sciences and Therapeutics and Chemical Biology Program and Department of Pharmacology and Toxicology, University of Texas Medical Branch (UTMB), Galveston, Texas 77555, United States
| | - Kathryn A. Cunningham
- Center for Addiction Sciences and Therapeutics and Chemical Biology Program and Department of Pharmacology and Toxicology, University of Texas Medical Branch (UTMB), Galveston, Texas 77555, United States
| | - Jia Zhou
- Center for Addiction Sciences and Therapeutics and Chemical Biology Program and Department of Pharmacology and Toxicology, University of Texas Medical Branch (UTMB), Galveston, Texas 77555, United States
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Presa MH, Rocha MJD, Pires CS, Ledebuhr KNB, Costa GPD, Alves D, Bortolatto CF, Brüning CA. Antidepressant-like Effect of 1-(2-(4-(4-Ethylphenyl)-1 H-1,2,3-triazol-1-yl)phenyl)ethan-1-one in Mice: Evidence of the Contribution of the Serotonergic System. ACS Chem Neurosci 2023. [PMID: 37294690 DOI: 10.1021/acschemneuro.3c00108] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/11/2023] Open
Abstract
Major depressive disorder (MDD) is a psychiatric disorder that affects a large portion of the population, with dysregulation of the serotonergic system, which is deeply involved in both the pathophysiology of MDD and mechanism of action of many antidepressants. Current pharmacological therapies do not meet the neurobiological needs of all depressed individuals, making the development of new antidepressants necessary. In recent decades, compounds containing triazoles have become promising due to their range of biological activities, including antidepressant activity. In this study, we evaluated the antidepressant-like effect of a hybrid containing triazole and acetophenone, 1-(2-(4-(4-ethylphenyl)-1H-1,2,3-triazol-1-yl)phenyl)ethan-1-one (ETAP) (0.5-5 mg/kg), in the forced swimming test (FST) and tail suspension test (TST) in mice, as well as the involvement of the serotonergic system in this effect. Our findings demonstrated that ETAP exhibited an antidepressant-like effect from the dose of 1 mg/kg and that this effect is modulated by 5-HT2A/2C and 5-HT4 receptors. We also demonstrated that this effect may be related to inhibition of monoamine oxidase A activity in the hippocampus. Additionally, we evaluated the in silico pharmacokinetic profile of ETAP, which predicted its penetration into the central nervous system. ETAP exhibited a low potential for toxicity at a high dose, making this molecule interesting for the development of a new therapeutic strategy for MDD.
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Affiliation(s)
- Marcelo Heinemann Presa
- Laboratory of Biochemistry and Molecular Neuropharmacology (LABIONEM), Postgraduate Program in Biochemistry and Bioprospecting (PPGBBio), Chemical, Pharmaceutical and Food Sciences Center (CCQFA), Federal University of Pelotas (UFPel), P.O. Box 354, 96010-900 Pelotas, Rio Grande do Sul, Brazil
| | - Marcia Juciele da Rocha
- Laboratory of Biochemistry and Molecular Neuropharmacology (LABIONEM), Postgraduate Program in Biochemistry and Bioprospecting (PPGBBio), Chemical, Pharmaceutical and Food Sciences Center (CCQFA), Federal University of Pelotas (UFPel), P.O. Box 354, 96010-900 Pelotas, Rio Grande do Sul, Brazil
| | - Camila Simões Pires
- Laboratory of Biochemistry and Molecular Neuropharmacology (LABIONEM), Postgraduate Program in Biochemistry and Bioprospecting (PPGBBio), Chemical, Pharmaceutical and Food Sciences Center (CCQFA), Federal University of Pelotas (UFPel), P.O. Box 354, 96010-900 Pelotas, Rio Grande do Sul, Brazil
| | - Kauane Nayara Bahr Ledebuhr
- Laboratory of Biochemistry and Molecular Neuropharmacology (LABIONEM), Postgraduate Program in Biochemistry and Bioprospecting (PPGBBio), Chemical, Pharmaceutical and Food Sciences Center (CCQFA), Federal University of Pelotas (UFPel), P.O. Box 354, 96010-900 Pelotas, Rio Grande do Sul, Brazil
| | - Gabriel Pereira da Costa
- Laboratory of Clean Organic Synthesis (LASOL), Chemical, Pharmaceutical and Food Sciences Center (CCQFA), Federal University of Pelotas (UFPel), P.O. Box 354, 96010-900 Pelotas, Rio Grande do Sul, Brazil
| | - Diego Alves
- Laboratory of Clean Organic Synthesis (LASOL), Chemical, Pharmaceutical and Food Sciences Center (CCQFA), Federal University of Pelotas (UFPel), P.O. Box 354, 96010-900 Pelotas, Rio Grande do Sul, Brazil
| | - Cristiani Folharini Bortolatto
- Laboratory of Biochemistry and Molecular Neuropharmacology (LABIONEM), Postgraduate Program in Biochemistry and Bioprospecting (PPGBBio), Chemical, Pharmaceutical and Food Sciences Center (CCQFA), Federal University of Pelotas (UFPel), P.O. Box 354, 96010-900 Pelotas, Rio Grande do Sul, Brazil
| | - César Augusto Brüning
- Laboratory of Biochemistry and Molecular Neuropharmacology (LABIONEM), Postgraduate Program in Biochemistry and Bioprospecting (PPGBBio), Chemical, Pharmaceutical and Food Sciences Center (CCQFA), Federal University of Pelotas (UFPel), P.O. Box 354, 96010-900 Pelotas, Rio Grande do Sul, Brazil
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19
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da Rocha MJ, Pires CS, Presa MH, Besckow EM, Nunes GD, Gomes CS, Penteado F, Lenardão EJ, Bortolatto CF, Brüning CA. Involvement of the serotonergic system in the antidepressant-like effect of 1-(phenylselanyl)-2-(p-tolyl)indolizine in mice. Psychopharmacology (Berl) 2023; 240:373-389. [PMID: 36645465 DOI: 10.1007/s00213-023-06313-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 01/05/2023] [Indexed: 01/17/2023]
Abstract
RATIONALE Depression is a mental disorder that affects approximately 280 million people worldwide. In the search for new treatments for mood disorders, compounds containing selenium and indolizine derivatives show promising results. OBJECTIVES AND METHODS To evaluate the antidepressant-like effect of 1-(phenylselanyl)-2-(p-tolyl)indolizine (MeSeI) (0.5-50 mg/kg, intragastric-i.g.) on the tail suspension test (TST) and the forced swim test (FST) in adult male Swiss mice and to elucidate the role of the serotonergic system in this effect through pharmacological and in silico approaches, as well to evaluate acute oral toxicity at a high dose (300 mg/kg). RESULTS MeSeI administered 30 min before the FST and the TST reduced immobility time at doses from 1 mg/kg and at 50 mg/kg and increased the latency time for the first episode of immobility, demonstrating an antidepressant-like effect. In the open field test (OFT), MeSeI did not change the locomotor activity. The antidepressant-like effect of MeSeI (50 mg/kg, i.g.) was prevented by the pre-treatment with p-chlorophenylalanine (p-CPA), a selective tryptophan hydroxylase inhibitor (100 mg/kg, intraperitoneally-i.p. for 4 days), with ketanserin, a 5-HT2A/2C receptor antagonist (1 mg/kg, i.p.), and with GR113808, a 5-HT4 receptor antagonist (0.1 mg/kg, i.p.), but not with WAY100635, a selective 5-HT1A receptor antagonist (0.1 mg/kg, subcutaneous-s.c.) and ondansetron, a 5-HT3 receptor antagonist (1 mg/kg, i.p.). MeSeI showed a binding affinity with 5-HT2A, 5 -HT2C, and 5-HT4 receptors by molecular docking. MeSeI (300 mg/kg, i.g.) demonstrated low potential to cause acute toxicity in adult female Swiss mice. CONCLUSION In summary, MeSeI exhibits an antidepressant-like effect mediated by the serotonergic system and could be considered for the development of new treatment strategies for depression.
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Affiliation(s)
- Marcia Juciele da Rocha
- Laboratory of Biochemistry and Molecular Neuropharmacology (LABIONEM), Postgraduate Program in Biochemistry and Bioprospecting (PPGBBio), Center of Chemical, Pharmaceutical and Food Sciences (CCQFA), Federal University of Pelotas (UFPel), Capão Do Leão Campus, Pelotas, RS, 96010-900, Brazil
| | - Camila Simões Pires
- Laboratory of Biochemistry and Molecular Neuropharmacology (LABIONEM), Postgraduate Program in Biochemistry and Bioprospecting (PPGBBio), Center of Chemical, Pharmaceutical and Food Sciences (CCQFA), Federal University of Pelotas (UFPel), Capão Do Leão Campus, Pelotas, RS, 96010-900, Brazil
| | - Marcelo Heinemann Presa
- Laboratory of Biochemistry and Molecular Neuropharmacology (LABIONEM), Postgraduate Program in Biochemistry and Bioprospecting (PPGBBio), Center of Chemical, Pharmaceutical and Food Sciences (CCQFA), Federal University of Pelotas (UFPel), Capão Do Leão Campus, Pelotas, RS, 96010-900, Brazil
| | - Evelyn Mianes Besckow
- Laboratory of Biochemistry and Molecular Neuropharmacology (LABIONEM), Postgraduate Program in Biochemistry and Bioprospecting (PPGBBio), Center of Chemical, Pharmaceutical and Food Sciences (CCQFA), Federal University of Pelotas (UFPel), Capão Do Leão Campus, Pelotas, RS, 96010-900, Brazil
| | - Gustavo D'Avila Nunes
- Laboratory of Biochemistry and Molecular Neuropharmacology (LABIONEM), Postgraduate Program in Biochemistry and Bioprospecting (PPGBBio), Center of Chemical, Pharmaceutical and Food Sciences (CCQFA), Federal University of Pelotas (UFPel), Capão Do Leão Campus, Pelotas, RS, 96010-900, Brazil
| | - Caroline Signorini Gomes
- Clean Organic Synthesis Laboratory (LASOL), Postgraduate Program in Chemistry (PPGQ), Center of Chemical, Pharmaceutical and Food Sciences (CCQFA), Federal University of Pelotas (UFPel), Capão Do Leão Campus, Pelotas, RS, 96010-900, Brazil
| | - Filipe Penteado
- Clean Organic Synthesis Laboratory (LASOL), Postgraduate Program in Chemistry (PPGQ), Center of Chemical, Pharmaceutical and Food Sciences (CCQFA), Federal University of Pelotas (UFPel), Capão Do Leão Campus, Pelotas, RS, 96010-900, Brazil
| | - Eder João Lenardão
- Clean Organic Synthesis Laboratory (LASOL), Postgraduate Program in Chemistry (PPGQ), Center of Chemical, Pharmaceutical and Food Sciences (CCQFA), Federal University of Pelotas (UFPel), Capão Do Leão Campus, Pelotas, RS, 96010-900, Brazil
| | - Cristiani Folharini Bortolatto
- Laboratory of Biochemistry and Molecular Neuropharmacology (LABIONEM), Postgraduate Program in Biochemistry and Bioprospecting (PPGBBio), Center of Chemical, Pharmaceutical and Food Sciences (CCQFA), Federal University of Pelotas (UFPel), Capão Do Leão Campus, Pelotas, RS, 96010-900, Brazil.
| | - César Augusto Brüning
- Laboratory of Biochemistry and Molecular Neuropharmacology (LABIONEM), Postgraduate Program in Biochemistry and Bioprospecting (PPGBBio), Center of Chemical, Pharmaceutical and Food Sciences (CCQFA), Federal University of Pelotas (UFPel), Capão Do Leão Campus, Pelotas, RS, 96010-900, Brazil.
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20
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Qi JS, Su Q, Li T, Liu GW, Zhang YL, Guo JH, Wang ZJ, Wu MN. Agomelatine: a potential novel approach for the treatment of memory disorder in neurodegenerative disease. Neural Regen Res 2023; 18:727-733. [DOI: 10.4103/1673-5374.353479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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21
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Süß ST, Olbricht LM, Herlitze S, Spoida K. Constitutive 5-HT2C receptor knock-out facilitates fear extinction through altered activity of a dorsal raphe-bed nucleus of the stria terminalis pathway. Transl Psychiatry 2022; 12:487. [PMID: 36402746 PMCID: PMC9675804 DOI: 10.1038/s41398-022-02252-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 10/24/2022] [Accepted: 11/07/2022] [Indexed: 11/21/2022] Open
Abstract
Serotonin 2C receptors (5-HT2CRs) are widely distributed throughout the brain and are strongly implicated in the pathophysiology of anxiety disorders such as post-traumatic stress disorder (PTSD). Although in recent years, a considerable amount of evidence supports 5-HT2CRs facilitating effect on anxiety behavior, the involvement in learned fear responses and fear extinction is rather unexplored. Here, we used a 5-HT2CR knock-out mouse line (2CKO) to gain new insights into the involvement of 5-HT2CRs in the neuronal fear circuitry. Using a cued fear conditioning paradigm, our results revealed that global loss of 5-HT2CRs exclusively accelerates fear extinction, without affecting fear acquisition and fear expression. To investigate the neuronal substrates underlying the extinction enhancing effect, we mapped the immediate-early gene product cFos, a marker for neuronal activity, in the dorsal raphe nucleus (DRN), amygdala and bed nucleus of the stria terminalis (BNST). Surprisingly, besides extinction-associated changes, our results revealed alterations in neuronal activity even under basal home cage conditions in specific subregions of the DRN and the BNST in 2CKO mice. Neuronal activity in the dorsal BNST was shifted in an extinction-supporting direction due to 5-HT2CR knock-out. Finally, the assessment of DRN-BNST connectivity using antero- and retrograde tracing techniques uncovered a discrete serotonergic pathway projecting from the most caudal subregion of the DRN (DRC) to the anterodorsal portion of the BNST (BNSTad). This serotonergic DRC-BNSTad pathway showed increased neuronal activity in 2CKO mice. Thus, our results provide new insights for the fear extinction network by revealing a specific serotonergic DRC-BNSTad pathway underlying a 5-HT2CR-sensitive mechanism with high significance in the treatment of PTSD.
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Affiliation(s)
- Sandra T Süß
- Department of General Zoology and Neurobiology, ND7/31, Ruhr-University Bochum, Universitätsstr. 150, D-44780, Bochum, Germany.
| | - Linda M Olbricht
- Department of General Zoology and Neurobiology, ND7/31, Ruhr-University Bochum, Universitätsstr. 150, D-44780, Bochum, Germany
| | - Stefan Herlitze
- Department of General Zoology and Neurobiology, ND7/31, Ruhr-University Bochum, Universitätsstr. 150, D-44780, Bochum, Germany
| | - Katharina Spoida
- Department of General Zoology and Neurobiology, ND7/31, Ruhr-University Bochum, Universitätsstr. 150, D-44780, Bochum, Germany.
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22
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Lu K, Hong Y, Tao M, Shen L, Zheng Z, Fang K, Yuan F, Xu M, Wang C, Zhu D, Guo X, Liu Y. Depressive patient-derived GABA interneurons reveal abnormal neural activity associated with HTR2C. EMBO Mol Med 2022; 15:e16364. [PMID: 36373384 PMCID: PMC9832822 DOI: 10.15252/emmm.202216364] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 10/20/2022] [Accepted: 10/21/2022] [Indexed: 11/16/2022] Open
Abstract
Major depressive disorder with suicide behavior (sMDD) is a server mood disorder, bringing tremendous burden to family and society. Although reduced gamma amino butyric acid (GABA) level has been observed in postmortem tissues of sMDD patients, the molecular mechanism by which GABA levels are altered remains elusive. In this study, we generated induced pluripotent stem cells (iPSC) from five sMDD patients and differentiated the iPSCs to GABAergic interneurons (GINs) and ventral forebrain organoids. sMDD GINs exhibited altered neuronal morphology and increased neural firing, as well as weakened calcium signaling propagation, compared with controls. Transcriptomic sequencing revealed that a decreased expression of serotoninergic receptor 2C (5-HT2C) may cause the defected neuronal activity in sMDD. Furthermore, targeting 5-HT2C receptor, using a small molecule agonist or genetic approach, restored neuronal activity deficits in sMDD GINs. Our findings provide a human cellular model for studying the molecular mechanisms and drug discoveries for sMDD.
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Affiliation(s)
- Kaiqin Lu
- Institute for Stem Cell and Neural Regeneration, State Key Laboratory of Reproductive MedicineSchool of PharmacyNanjing Medical UniversityNanjingChina
| | - Yuan Hong
- Institute for Stem Cell and Neural Regeneration, State Key Laboratory of Reproductive MedicineSchool of PharmacyNanjing Medical UniversityNanjingChina
| | - Mengdan Tao
- Institute for Stem Cell and Neural Regeneration, State Key Laboratory of Reproductive MedicineSchool of PharmacyNanjing Medical UniversityNanjingChina
| | - Luping Shen
- Institute for Stem Cell and Neural Regeneration, State Key Laboratory of Reproductive MedicineSchool of PharmacyNanjing Medical UniversityNanjingChina
| | - Zhilong Zheng
- Department of NeurobiologyKey Laboratory of Human Functional Genomics of Jiangsu ProvinceNanjing Medical UniversityNanjingChina
| | - Kaiheng Fang
- Institute for Stem Cell and Neural Regeneration, State Key Laboratory of Reproductive MedicineSchool of PharmacyNanjing Medical UniversityNanjingChina
| | - Fang Yuan
- Institute for Stem Cell and Neural Regeneration, State Key Laboratory of Reproductive MedicineSchool of PharmacyNanjing Medical UniversityNanjingChina
| | - Min Xu
- Institute for Stem Cell and Neural Regeneration, State Key Laboratory of Reproductive MedicineSchool of PharmacyNanjing Medical UniversityNanjingChina
| | - Chun Wang
- Nanjing Brain Hospital Affiliated to Nanjing Medical UniversityNanjingChina
| | - Dongya Zhu
- Institute for Stem Cell and Neural Regeneration, State Key Laboratory of Reproductive MedicineSchool of PharmacyNanjing Medical UniversityNanjingChina
| | - Xing Guo
- Department of NeurobiologyKey Laboratory of Human Functional Genomics of Jiangsu ProvinceNanjing Medical UniversityNanjingChina,Co‐innovation Center of NeuroregenerationNantong UniversityJiangsuChina
| | - Yan Liu
- Institute for Stem Cell and Neural Regeneration, State Key Laboratory of Reproductive MedicineSchool of PharmacyNanjing Medical UniversityNanjingChina
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Rossi GN, Guerra LTL, Baker GB, Dursun SM, Saiz JCB, Hallak JEC, dos Santos RG. Molecular Pathways of the Therapeutic Effects of Ayahuasca, a Botanical Psychedelic and Potential Rapid-Acting Antidepressant. Biomolecules 2022; 12:1618. [PMID: 36358968 PMCID: PMC9687782 DOI: 10.3390/biom12111618] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 10/27/2022] [Accepted: 10/29/2022] [Indexed: 03/30/2025] Open
Abstract
Ayahuasca is a psychoactive brew traditionally used in indigenous and religious rituals and ceremonies in South America for its therapeutic, psychedelic, and entheogenic effects. It is usually prepared by lengthy boiling of the leaves of the bush Psychotria viridis and the mashed stalks of the vine Banisteriopsis caapi in water. The former contains the classical psychedelic N,N-dimethyltryptamine (DMT), which is thought to be the main psychoactive alkaloid present in the brew. The latter serves as a source for β-carbolines, known for their monoamine oxidase-inhibiting (MAOI) properties. Recent preliminary research has provided encouraging results investigating ayahuasca's therapeutic potential, especially regarding its antidepressant effects. On a molecular level, pre-clinical and clinical evidence points to a complex pharmacological profile conveyed by the brew, including modulation of serotoninergic, glutamatergic, dopaminergic, and endocannabinoid systems. Its substances also interact with the vesicular monoamine transporter (VMAT), trace amine-associated receptor 1 (TAAR1), and sigma-1 receptors. Furthermore, ayahuasca's components also seem to modulate levels of inflammatory and neurotrophic factors beneficially. On a biological level, this translates into neuroprotective and neuroplastic effects. Here we review the current knowledge regarding these molecular interactions and how they relate to the possible antidepressant effects ayahuasca seems to produce.
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Affiliation(s)
- Giordano Novak Rossi
- Department of Neurosciences and Behavior, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14040-900, Brazil
| | - Lorena T. L. Guerra
- Department of Neurosciences and Behavior, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14040-900, Brazil
| | - Glen B. Baker
- National Institute of Science and Technology—Translational Medicine, Ribeirão Preto 3900, Brazil
- Department of Psychiatry (Neurochemical Research Unit) and Neuroscience & Mental Health Institute, University of Alberta, Edmonton, AB T6G 2G3, Canada
| | - Serdar M. Dursun
- National Institute of Science and Technology—Translational Medicine, Ribeirão Preto 3900, Brazil
- Department of Psychiatry (Neurochemical Research Unit) and Neuroscience & Mental Health Institute, University of Alberta, Edmonton, AB T6G 2G3, Canada
| | - José Carlos Bouso Saiz
- Department of Neurosciences and Behavior, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14040-900, Brazil
- ICEERS Foundation, International Center for Ethnobotanical Education, Research and Services, 08015 Barcelona, Spain
- Medical Anthropology Research Center (MARC), Universitat Rovira i Virgili, 43001 Tarragona, Spain
| | - Jaime E. C. Hallak
- Department of Neurosciences and Behavior, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14040-900, Brazil
- National Institute of Science and Technology—Translational Medicine, Ribeirão Preto 3900, Brazil
- Department of Psychiatry (Neurochemical Research Unit) and Neuroscience & Mental Health Institute, University of Alberta, Edmonton, AB T6G 2G3, Canada
| | - Rafael G. dos Santos
- Department of Neurosciences and Behavior, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14040-900, Brazil
- National Institute of Science and Technology—Translational Medicine, Ribeirão Preto 3900, Brazil
- ICEERS Foundation, International Center for Ethnobotanical Education, Research and Services, 08015 Barcelona, Spain
- Departamento de Neurociências e Ciências do Comportamento, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Hospital das Clínicas, Terceiro Andar, Av. Bandeirantes, Ribeirão Preto 3900, Brazil
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Popova NK, Tsybko AS, Naumenko VS. The Implication of 5-HT Receptor Family Members in Aggression, Depression and Suicide: Similarity and Difference. Int J Mol Sci 2022; 23:ijms23158814. [PMID: 35955946 PMCID: PMC9369404 DOI: 10.3390/ijms23158814] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Revised: 07/21/2022] [Accepted: 08/06/2022] [Indexed: 11/16/2022] Open
Abstract
Being different multifactorial forms of psychopathology, aggression, depression and suicidal behavior, which is considered to be violent aggression directed against the self, have principal neurobiological links: preclinical and clinical evidence associates depression, aggression and suicidal behavior with dysregulation in central serotonergic (5-HT) neurotransmission. The implication of different types of 5-HT receptors in the genetic and epigenetic mechanisms of aggression, depression and suicidality has been well recognized. In this review, we consider and compare the orchestra of 5-HT receptors involved in these severe psychopathologies. Specifically, it concentrates on the role of 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3 and 5-HT7 receptors in the mechanisms underlying the predisposition to aggression, depression and suicidal behavior. The review provides converging lines of evidence that: (1) depression-related 5-HT receptors include those receptors with pro-depressive properties (5-HT2A, 5-HT3 and 5-HT7) as well as those providing an antidepressant effect (5-HT1A, 5-HT1B, 5-HT2C subtypes). (2) Aggression-related 5-HT receptors are identical to depression-related 5-HT receptors with the exception of 5-HT7 receptors. Activation of 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C receptors attenuate aggressiveness, whereas agonists of 5-HT3 intensify aggressive behavior.
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Barbee BR, Gourley SL. Brain systems in cocaine abstinence-induced anxiety-like behavior in rodents: A review. ADDICTION NEUROSCIENCE 2022; 2:100012. [PMID: 37485439 PMCID: PMC10361393 DOI: 10.1016/j.addicn.2022.100012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/25/2023]
Abstract
Cocaine use disorder (CUD) is a significant public health issue that generates substantial personal, familial, and economic burdens. Still, there are no FDA-approved pharmacotherapies for CUD. Cocaine-dependent individuals report anxiety during withdrawal, and alleviation of anxiety and other negative affective states may be critical for maintaining drug abstinence. However, the neurobiological mechanisms underlying abstinence-related anxiety in humans or anxiety-like behavior in rodents are not fully understood. This review summarizes investigations regarding anxiety-like behavior in mice and rats undergoing cocaine abstinence, as assessed using four of the most common anxiety-related assays: the elevated plus (or its derivative, the elevated zero) maze, open field test, light-dark transition test, and defensive burying task. We first summarize available evidence that cocaine abstinence generates anxiety-like behavior that persists throughout protracted abstinence. Then, we examine investigations concerning neuropeptide, neurotransmitter, and neuromodulator systems in cocaine abstinence-induced anxiety-like behavior. Throughout, we discuss how differences in sex, rodent strain, cocaine dose and dosing strategy and abstinence duration interact to generate anxiety-like behavior.
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Affiliation(s)
- Britton R. Barbee
- Graduate Program in Molecular and Systems Pharmacology,
Emory University
- Department of Pediatrics, Emory University School of
Medicine; Yerkes National Primate Research Center
| | - Shannon L. Gourley
- Graduate Program in Molecular and Systems Pharmacology,
Emory University
- Department of Pediatrics, Emory University School of
Medicine; Yerkes National Primate Research Center
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Lan T, Wu Y, Zhang Y, Li S, Zhu Z, Wang L, Mao X, Li Y, Fan C, Wang W, Yu SY. Agomelatine rescues lipopolysaccharide-induced neural injury and depression-like behaviors via suppression of the Gαi-2-PKA-ASK1 signaling pathway. J Neuroinflammation 2022; 19:117. [PMID: 35610704 PMCID: PMC9131561 DOI: 10.1186/s12974-022-02479-x] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 05/15/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Agomelatine has been shown to be effective in the treatment of depression, but the molecular mechanisms underlying its antidepressant effects have yet to be elucidated. Identification of these molecular mechanisms would not only offer new insights into the basis for depression but also provide the foundation for the development of novel treatments for this disorder. METHODS Intraperitoneal injection of LPS was used to induce depression-like behaviors in rats. The interactions of the 5-HT2C reporter and Gαi-2 were verified by immunoprecipitation or immunofluorescence assay. Inflammatory related proteins, autophagy related proteins and apoptosis markers were verified by immunoblotting or immunofluorescence assay. Finally, electron microscopy analysis was used to observe the synapse and ultrastructural pathology. RESULTS Here, we found that the capacity for agomelatine to ameliorate depression and anxiety in a lipopolysaccharide (LPS)-induced rat model of depression was associated with an alleviation of neuroinflammation, abnormal autophagy and neuronal apoptosis as well as the promotion of neurogenesis in the hippocampal dentate gyrus (DG) region of these rats. We also found that the 5-HT2C receptor is coupled with G alphai (2) (Gαi-2) protein within hippocampal neurons and, agomelatine, acting as a 5-HT2C receptor antagonist, can up-regulate activity of the Gαi-2-cAMP-PKA pathway. Such events then suppress activation of the apoptosis signal-regulating kinase 1 (ASK1) pathway, a member of the mitogen-activated protein kinase (MAPK) family involved in pathological processes of many diseases. CONCLUSION Taken together, these results suggest that agomelatine plays a neuroprotective role in regulating neuroinflammation, autophagy disorder and apoptosis in this LPS-induced rat model of depression, effects which are associated with the display of antidepressant behaviors. These findings provide evidence for some of the potential mechanisms for the antidepressant effects of agomelatine.
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Affiliation(s)
- Tian Lan
- Department of Physiology, School of Basic Medical Sciences, Shandong University, 44 Wenhuaxilu Road, Jinan, Shandong Province, 250012, People's Republic of China
| | - Yuhan Wu
- Department of Physiology, School of Basic Medical Sciences, Shandong University, 44 Wenhuaxilu Road, Jinan, Shandong Province, 250012, People's Republic of China
| | - Yulei Zhang
- Jinan International Travel Healthcare Center, Wenhuadonglu Road 62#, Jinan, Shandong Province, 250012, People's Republic of China
| | - Shuhan Li
- Department of Physiology, School of Basic Medical Sciences, Shandong University, 44 Wenhuaxilu Road, Jinan, Shandong Province, 250012, People's Republic of China
| | - Zhanpeng Zhu
- Department of Physiology, School of Basic Medical Sciences, Shandong University, 44 Wenhuaxilu Road, Jinan, Shandong Province, 250012, People's Republic of China
| | - Liyan Wang
- Morphological Experimental Center, School of Basic Medical Sciences, Shandong University, 44 Wenhuaxilu Road, Jinan, Shandong Province, 250012, People's Republic of China
| | - Xueqin Mao
- Department of Psychology, Qilu Hospital of Shandong University, 107 Wenhuaxilu Road, Jinan, Shandong Province, 250012, People's Republic of China
| | - Ye Li
- Department of Physiology, School of Basic Medical Sciences, Shandong University, 44 Wenhuaxilu Road, Jinan, Shandong Province, 250012, People's Republic of China
| | - Cuiqin Fan
- Department of Physiology, School of Basic Medical Sciences, Shandong University, 44 Wenhuaxilu Road, Jinan, Shandong Province, 250012, People's Republic of China
| | - Wenjing Wang
- Department of Physiology, School of Basic Medical Sciences, Shandong University, 44 Wenhuaxilu Road, Jinan, Shandong Province, 250012, People's Republic of China
| | - Shu Yan Yu
- Department of Physiology, School of Basic Medical Sciences, Shandong University, 44 Wenhuaxilu Road, Jinan, Shandong Province, 250012, People's Republic of China. .,Shandong Provincial Key Laboratory of Mental Disorders, School of Basic Medical Sciences, 44 Wenhuaxilu Road, Jinan, Shandong Province, 250012, People's Republic of China.
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Isoindolone derivatives as novel potential anti-Alzheimer’s candidates: synthesis, in silico, and AChE inhibitory activity evaluation. Med Chem Res 2022. [DOI: 10.1007/s00044-022-02884-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
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28
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Mao Q, Zhang B, Tian S, Qin W, Chen J, Huang XP, Xin Y, Yang H, Zhen XC, Shui W, Ye N. Structural optimizations and bioevaluation of N-H aporphine analogues as Gq-biased and selective serotonin 5-HT2C receptor agonists. Bioorg Chem 2022; 123:105795. [DOI: 10.1016/j.bioorg.2022.105795] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 03/31/2022] [Accepted: 04/05/2022] [Indexed: 11/29/2022]
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Guo G, Tang J, Shi M, Yang C, Ou H, Chen W. MK212, a 5-hydroxytryptamine 2C receptor agonist, reverses prepulse inhibition deficits in the medial prefrontal cortex and ventral hippocampus. Prog Neuropsychopharmacol Biol Psychiatry 2022; 113:110441. [PMID: 34560172 DOI: 10.1016/j.pnpbp.2021.110441] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 08/31/2021] [Accepted: 09/16/2021] [Indexed: 10/20/2022]
Abstract
Prepulse inhibition (PPI) is disrupted in many neuropsychiatric diseases. Molecules such as 5-HT2C receptor agonists alleviate PPI deficits in rodents; however, the precise mechanisms and critical regions of the brain responsible for the reversal effect of these agonists remain inconclusive. The present study aimed to investigate the areas of the brain critical for the reversal effect of 5-HT2C receptor agonists on PPI deficits in mice. The results showed that systemic administration of the 5-HT2C receptor agonist MK212 did not affect normal PPI behavior, but reversed the PPI deficits induced by the N-methyl d-aspartate receptor antagonist MK801 in mice. In addition, the 5-HT2C receptor antagonist SB242084 had no effect on PPI behavior despite MK801 treatment. Moreover, local infusion of MK212 into the medial prefrontal cortex and ventral hippocampus, excluding the nucleus accumbens or ventral tegmental area, rescued the PPI deficits induced by MK801. These data suggest that the medial prefrontal cortex and ventral hippocampus are critical brain areas responsible for the reversal of 5-HT2C agonists on PPI deficits. The results will contribute to our current knowledge on the molecular and neural mechanisms underlying the antipsychotic effects of 5-HT2C receptor agonists, especially the neural circuits modulated by 5-HT2C receptor activity.
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Affiliation(s)
- Guanlong Guo
- Key Laboratory of Cognition and Personality (Southwest University), Ministry of Education, Chongqing, China; Faculty of Psychology, Southwest University, Chongqing, China
| | - Jiaxin Tang
- Key Laboratory of Cognition and Personality (Southwest University), Ministry of Education, Chongqing, China; Faculty of Psychology, Southwest University, Chongqing, China
| | - Mengwen Shi
- Key Laboratory of Cognition and Personality (Southwest University), Ministry of Education, Chongqing, China; Faculty of Psychology, Southwest University, Chongqing, China
| | - Chengmei Yang
- Key Laboratory of Cognition and Personality (Southwest University), Ministry of Education, Chongqing, China; Faculty of Psychology, Southwest University, Chongqing, China
| | - Huaxing Ou
- Key Laboratory of Cognition and Personality (Southwest University), Ministry of Education, Chongqing, China; Faculty of Psychology, Southwest University, Chongqing, China
| | - Weihai Chen
- Key Laboratory of Cognition and Personality (Southwest University), Ministry of Education, Chongqing, China; Faculty of Psychology, Southwest University, Chongqing, China.
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Millan MJ. Agomelatine for the treatment of generalized anxiety disorder: focus on its distinctive mechanism of action. Ther Adv Psychopharmacol 2022; 12:20451253221105128. [PMID: 35795687 PMCID: PMC9251978 DOI: 10.1177/20451253221105128] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 03/04/2022] [Indexed: 11/16/2022] Open
Abstract
UNLABELLED Generalized anxiety disorder (GAD), the most frequently diagnosed form of anxiety, is usually treated by cognitive-behavioural approaches or medication; in particular, benzodiazepines (acutely) and serotonin or serotonin/noradrenaline reuptake inhibitors (long term). Efficacy, compliance, and acceptability are, however, far from ideal, reinforcing interest in alternative options. Agomelatine, clinically employed in the treatment of major depression, expresses anxiolytic properties in rodents and was effective in the treatment of GAD (including severely ill patients) in several double-blind, short-term (12 weeks) and relapse-prevention (6 months) studies. At active doses, the incidence of adverse effects was no higher than for placebo. Agomelatine possesses a unique binding profile, behaving as a melatonin (MT1/MT2) receptor agonist and 5-HT2C receptor antagonist, yet recognizing neither monoamine transporters nor GABAA receptors. Extensive evidence supports a role for 5-HT2C receptors in the induction of anxious states, and their blockade likely plays a primary role in mediating the anxiolytic actions of agomelatine, including populations in the amygdala and bed nucleus of stria terminalis, as well as the hippocampus. Recruitment of MT receptors in the suprachiasmatic nucleus, thalamic reticular nucleus, and hippocampus appears to fulfil a complimentary role. Downstream of 5-HT2C and MT receptors, modulation of stress-sensitive glutamatergic circuits and altered release of the anxiogenic neuropeptides, corticotrophin-releasing factor, and vasopressin, may be implicated in the actions of agomelatine. To summarize, agomelatine exerts its anxiolytic actions by mechanisms clearly distinct from those of other agents currently employed for the management of GAD. PLAIN LANGUAGE SUMMARY How agomelatine helps in the treatment of anxiety disorders. INTRODUCTION • Anxiety disorders have a significant negative impact on quality of life.• The most common type of anxiety disorder, called generalized anxiety disorder (GAD), is associated with nervousness and excessive worry.• These symptoms can lead to additional symptoms like tiredness, sleeplessness, irritability, and poor attention.• GAD is generally treated through either cognitive-behavioural therapy or medication. However, widely used drugs like benzodiazepines and serotonin reuptake inhibitors have adverse effects.• Agomelatine, a well-established antidepressant drug, has shown anxiety-lowering ('anxiolytic') properties in rats and has been shown to effectively treat GAD with minimal side effects.• However, exactly how it acts on the brain to manage GAD is not yet clear.• Thus, this review aims to shed light on agomelatine's mechanism of action in treating GAD. METHODS • The authors reviewed studies on how agomelatine treats anxiety in animals.• They also looked at clinical studies on the effects of agomelatine in people with GAD. RESULTS • The study showed that agomelatine 'blocks' a receptor in nerve cells, which plays a role in causing anxiety, called the 5-HT2C receptor.• Blocking this receptor, especially in specific brain regions such as nerve cells of the amygdala, bed nucleus of stria terminalis, and hippocampus, produced the anxiety reduction seen during agomelatine treatment.• Agomelatine also activates the melatonin (MT) receptor, which is known to keep anxiety in check, promote sleep, and maintain the sleep cycle.• Agomelatine should thus tackle sleep disturbances commonly seen in patients with GAD.• Beyond 5-HT2C and MT receptors, signalling molecules in nerve cells that are known to be involved in anxiety disorders (called 'neurotransmitters' and 'neuropeptides') are also affected by agomelatine. CONCLUSION • Agomelatine's anxiolytic effects are caused by mechanisms that are distinct from those of other medications currently used to treat GAD.• This explains its therapeutic success and minimal adverse side effects.
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Affiliation(s)
- Mark J Millan
- Institute of Neuroscience and Psychology, College of Medicine, Vet and Life Sciences, Glasgow University, 28 Hillhead Street, Glasgow G12 8QB, UK
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31
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John Jayakumar JAK, Panicker MM. The roles of serotonin in cell adhesion and migration, and cytoskeletal remodeling. Cell Adh Migr 2021; 15:261-271. [PMID: 34494935 PMCID: PMC8437456 DOI: 10.1080/19336918.2021.1963574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 07/04/2021] [Accepted: 07/29/2021] [Indexed: 11/22/2022] Open
Abstract
Serotonin is well known as a neurotransmitter. Its roles in neuronal processes such as learning, memory or cognition are well established, and also in disorders such as depression, schizophrenia, bipolar disorder, and dementia. However, its effects on adhesion and cytoskeletal remodelling which are strongly affected by 5-HT receptors, are not as well studied with some exceptions for e.g. platelet aggregation. Neuronal function is strongly dependent on cell-cell contacts and adhesion-related processes. Therefore the role played by serotonin in psychiatric illness, as well as in the positive and negative effects of neuropsychiatric drugs through cell-related adhesion can be of great significance. In this review, we explore the role of serotonin in some of these aspects based on recent findings.
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Affiliation(s)
- Joe Anand Kumar John Jayakumar
- Manipal Academy of Higher Education, Manipal, India
- National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bengaluru, India
| | - Mitradas M. Panicker
- National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bengaluru, India
- Present Address - Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, USA
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32
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Casey AB, Mukherjee M, McGlynn RP, Cui M, Kohut SJ, Booth RG. A new class of serotonin 5-HT 2A /5-HT 2C receptor inverse agonists: Synthesis, molecular modeling, in vitro and in vivo pharmacology of novel 2-aminotetralins. Br J Pharmacol 2021; 179:2610-2630. [PMID: 34837227 DOI: 10.1111/bph.15756] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 10/27/2021] [Accepted: 10/29/2021] [Indexed: 11/28/2022] Open
Abstract
BACKGROUND AND PURPOSE The 5-HT receptor (5-HTR) subtypes 5-HT2A and 5-HT2C are important neurotherapeutic targets, though, obtaining selectivity over 5-HT2B and closely related histamine H1 Rs is challenging. Here, we delineated molecular determinants of selective binding to 5-HT2A and 5-HT2C Rs for novel 4-phenyl-2-dimethylaminotetralins (4-PATs). EXPERIMENTAL APPROACH We synthesized 42 novel 4-PATs with halogen or aryl moieties at the C(4)-phenyl meta position. Affinity, function, molecular modeling, and 5-HT2A R mutagenesis studies were undertaken to understand structure-activity relationships at 5-HT2 -type and H1 Rs. Lead 4-PAT-type selective 5-HT2A /5-HT2C R inverse agonists were compared to pimavanserin, a selective 5-HT2A /5-HT2C R inverse agonist approved to treat psychoses, in the mouse head twitch response, and locomotor activity assays, as models relevant to antipsychotic drug development. KEY RESULTS Most 4-PAT diastereomers in the (2S,4R)-configuration bound non-selectively to 5-HT2A , 5-HT2C, and H1 Rs, with >100-fold selectivity over 5-HT2B Rs, whereas, diastereomers in the (2R,4R)-configuration bound preferentially to 5-HT2A over 5-HT2C Rs and had >100-fold selectivity over 5-HT2B and H1 Rs. Results suggest that G2385.42 and V2355.39 in 5-HT2A Rs (conserved in 5-HT2C Rs) are important for high affinity binding, whereas, interactions with T1945.42 and W1584.56 determine H1 R affinity. The 4-PAT (2S,4R)-2k, a potent and selective 5-HT2A /5-HT2C R inverse agonist, had activity like pimavanserin in the mouse head-twitch response assay, but was distinct in not suppressing locomotor activity. CONCLUSIONS AND IMPLICATIONS We provide evidence that the novel 4-PAT chemotype can yield selective 5-HT2A /5-HT2C R inverse agonists for antipsychotic drug development by optimizing ligand-receptor interactions in transmembrane domain 5. We also show that chirality can be exploited to attain selectivity over H1 Rs which may circumvent sedative effects.
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Affiliation(s)
- Austen B Casey
- Center for Drug Discovery, Northeastern University, Boston, Massachusetts, United States.,Department of Pharmaceutical Sciences, Northeastern University, Boston, Massachusetts, United States.,Department of Chemistry & Chemical Biology, Northeastern University, Boston, Massachusetts, United States
| | - Munmun Mukherjee
- Center for Drug Discovery, Northeastern University, Boston, Massachusetts, United States.,Department of Pharmaceutical Sciences, Northeastern University, Boston, Massachusetts, United States.,Department of Chemistry & Chemical Biology, Northeastern University, Boston, Massachusetts, United States
| | - Ryan P McGlynn
- Center for Drug Discovery, Northeastern University, Boston, Massachusetts, United States.,Department of Pharmaceutical Sciences, Northeastern University, Boston, Massachusetts, United States.,Department of Chemistry & Chemical Biology, Northeastern University, Boston, Massachusetts, United States
| | - Meng Cui
- Center for Drug Discovery, Northeastern University, Boston, Massachusetts, United States.,Department of Pharmaceutical Sciences, Northeastern University, Boston, Massachusetts, United States
| | - Stephen J Kohut
- Center for Drug Discovery, Northeastern University, Boston, Massachusetts, United States.,Department of Pharmaceutical Sciences, Northeastern University, Boston, Massachusetts, United States.,Behavioral Neuroimaging Laboratory, McLean Hospital and Department of Psychiatry, Harvard Medical School, Belmont, Massachusetts, United States
| | - Raymond G Booth
- Center for Drug Discovery, Northeastern University, Boston, Massachusetts, United States.,Department of Pharmaceutical Sciences, Northeastern University, Boston, Massachusetts, United States.,Department of Chemistry & Chemical Biology, Northeastern University, Boston, Massachusetts, United States
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Xie KY, Chien SJ, Tan BCM, Chen YW. RNA editing of 5-HT 2C R impairs insulin secretion of pancreatic beta cells via altered store-operated calcium entry. FASEB J 2021; 35:e21929. [PMID: 34553421 DOI: 10.1096/fj.202100265rr] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 08/20/2021] [Accepted: 08/31/2021] [Indexed: 11/11/2022]
Abstract
Recent studies emphasize the importance of 5-HT2C receptor (5-HT2C R) signaling in the regulation of energy homeostasis. The 5-HT2C R is the only G-protein-coupled receptor known to undergo post-transcriptional adenosine to inosine (A-to-I) editing by adenosine deaminase acting on RNA (ADAR). 5-HT2C R has emerged as an important role in the modulation of pancreatic β cell functions. This study investigated mechanisms behind the effects of palmitic acid (PA) on insulin secretion in different overexpressed 5-HT2C R edited isoforms in pancreatic MIN6 β cells. Results showed that the expressions of 5HT2C R and ADAR2 were upregulated in the pancreatic islets of mice fed with high-fat diet (HFD) compared to control mice. PA treatment significantly induced the expressions of 5-HT2C R and ADAR2 in pancreatic MIN6 β cells. PA treatment significantly induced the editing of 5-HT2C R in pancreatic MIN6 β cells. There was no significant difference in cell viability between naïve cells and three overexpressed 5-HT2C R edited isoforms in pancreatic MIN6 β cells. Overexpressed 5-HT2C R edited isoforms showed reduced glucose-stimulated insulin secretion (GSIS) compared with green fluorescent protein (GFP) expressed cells. Moreover, 5-HT2C R edited isoforms displayed reduced endoplasmic reticulum (ER) calcium release and store-operated calcium entry (SOCE) activation, probably through inhibition of stromal interaction molecule 1 trafficking under PA treatment. Altogether, our results show that PA-mediated editing of 5-HT2C R modulates GSIS through alteration of ER calcium release and SOCE activation in pancreatic MIN6 β cells.
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Affiliation(s)
- Ke-Yun Xie
- Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Shao-Ju Chien
- Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Bertrand Chin-Ming Tan
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.,Department of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.,Department of Neurosurgery, Linkou Medical Center, Chang Gung Memorial Hospital, Linkou, Taiwan.,Research Center for Emerging Viral Infections, Chang Gung University, Taoyuan, Taiwan
| | - Yun-Wen Chen
- Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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Li Y, Wang L, Liu X, Huang Y, Li X, He H, Xu X, Guo Y, Li Q, Zhu D, Wang X, Wang H, Li W, Li D, Xie P. Nucleoprotein (P40) Binding to 5HT2C Receptors (5HT2CR) is the Key Point in the Pathogenesis of BoDV-1-Infected Hosts. Neurochem Res 2021; 46:2427-2438. [PMID: 34165668 DOI: 10.1007/s11064-021-03385-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 06/16/2021] [Accepted: 06/17/2021] [Indexed: 10/21/2022]
Abstract
Nucleoprotein (P40) is one of the most important proteins of Borna disease virus 1 (BoDV-1), but which proteins it would bind to in the pathogenesis of BoDV-1-infected hosts is unknown. We used lentivirus LV5-P40 overexpressing P40 to infect primary hippocampal neurons and characterized the interactome of P40 with co-immunoprecipitation (Co-IP) followed by mass spectrometry (MS) analysis. These interacting protein partners revealed the pathogenesis of BoDV-1-infected hosts. We also show for the first time that P40 interacts with 5HT2CR in rat neurons, which may be the molecular basis leading to neuropsychiatric diseases such as anxiety disorders and behavioral abnormalities after BoDV-1 infection of hosts.
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Affiliation(s)
- Yuanxin Li
- Faculty of Basic Medicine, Department of Pathology, Chongqing Medical University, 1 Yixueyuan Road, Yuzhong, Chongqing, 400016, China
- NHC Key Laboratory of Diagnosis and Treatment On Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, 1 Yixueyuan Road, Yuzhong, Chongqing, 400016, China
| | - Lixin Wang
- Faculty of Basic Medicine, Department of Pathology, Chongqing Medical University, 1 Yixueyuan Road, Yuzhong, Chongqing, 400016, China
- NHC Key Laboratory of Diagnosis and Treatment On Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, 1 Yixueyuan Road, Yuzhong, Chongqing, 400016, China
| | - Xueni Liu
- Faculty of Basic Medicine, Department of Pathology, Chongqing Medical University, 1 Yixueyuan Road, Yuzhong, Chongqing, 400016, China
- NHC Key Laboratory of Diagnosis and Treatment On Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, 1 Yixueyuan Road, Yuzhong, Chongqing, 400016, China
| | - Ying Huang
- Faculty of Basic Medicine, Department of Pathology, Chongqing Medical University, 1 Yixueyuan Road, Yuzhong, Chongqing, 400016, China
- NHC Key Laboratory of Diagnosis and Treatment On Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, 1 Yixueyuan Road, Yuzhong, Chongqing, 400016, China
| | - Xiaomei Li
- Faculty of Basic Medicine, Department of Pathology, Chongqing Medical University, 1 Yixueyuan Road, Yuzhong, Chongqing, 400016, China
- NHC Key Laboratory of Diagnosis and Treatment On Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, 1 Yixueyuan Road, Yuzhong, Chongqing, 400016, China
| | - Hong He
- NHC Key Laboratory of Diagnosis and Treatment On Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, 1 Yixueyuan Road, Yuzhong, Chongqing, 400016, China
- Department of Neurology, The First Branch, The First Affiliated Hospital, Chongqing Medical University, Chongqing, 400016, China
| | - Xiaoyan Xu
- NHC Key Laboratory of Diagnosis and Treatment On Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, 1 Yixueyuan Road, Yuzhong, Chongqing, 400016, China
| | - Yujie Guo
- NHC Key Laboratory of Diagnosis and Treatment On Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, 1 Yixueyuan Road, Yuzhong, Chongqing, 400016, China
| | - Qi Li
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Dan Zhu
- Department of Physical Examination, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Road, Yuzhong District, Chongqing, 400016, China
| | - Xingyu Wang
- Faculty of Basic Medicine, Department of Pathology, Chongqing Medical University, 1 Yixueyuan Road, Yuzhong, Chongqing, 400016, China
- NHC Key Laboratory of Diagnosis and Treatment On Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, 1 Yixueyuan Road, Yuzhong, Chongqing, 400016, China
| | - Haiyang Wang
- NHC Key Laboratory of Diagnosis and Treatment On Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, 1 Yixueyuan Road, Yuzhong, Chongqing, 400016, China
| | - Wenwen Li
- Faculty of Basic Medicine, Department of Pathology, Chongqing Medical University, 1 Yixueyuan Road, Yuzhong, Chongqing, 400016, China
- NHC Key Laboratory of Diagnosis and Treatment On Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, 1 Yixueyuan Road, Yuzhong, Chongqing, 400016, China
| | - Dan Li
- Faculty of Basic Medicine, Department of Pathology, Chongqing Medical University, 1 Yixueyuan Road, Yuzhong, Chongqing, 400016, China.
- NHC Key Laboratory of Diagnosis and Treatment On Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, 1 Yixueyuan Road, Yuzhong, Chongqing, 400016, China.
| | - Peng Xie
- NHC Key Laboratory of Diagnosis and Treatment On Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, 1 Yixueyuan Road, Yuzhong, Chongqing, 400016, China.
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Bönisch H, Fink KB, Malinowska B, Molderings GJ, Schlicker E. Serotonin and beyond-a tribute to Manfred Göthert (1939-2019). NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2021; 394:1829-1867. [PMID: 33991216 PMCID: PMC8376721 DOI: 10.1007/s00210-021-02083-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Accepted: 03/29/2021] [Indexed: 01/13/2023]
Abstract
Manfred Göthert, who had served Naunyn-Schmiedeberg's Arch Pharmacol as Managing Editor from 1998 to 2005, deceased in June 2019. His scientific oeuvre encompasses more than 20 types of presynaptic receptors, mostly on serotoninergic and noradrenergic neurones. He was the first to identify presynaptic receptors for somatostatin and ACTH and described many presynaptic receptors, known from animal preparations, also in human tissue. In particular, he elucidated the pharmacology of presynaptic 5-HT receptors. A second field of interest included ligand-gated and voltage-dependent channels. The negative allosteric effect of anesthetics at peripheral nACh receptors is relevant for the peripheral clinical effects of these drugs and modified the Meyer-Overton hypothesis. The negative allosteric effect of ethanol at NMDA receptors in human brain tissue occurred at concentrations found in the range of clinical ethanol intoxication. Moreover, the inhibitory effect of gabapentinoids on P/Q Ca2+ channels and the subsequent decrease in AMPA-induced noradrenaline release may contribute to their clinical effect. Another ligand-gated ion channel, the 5-HT3 receptor, attracted the interest of Manfred Göthert from the whole animal via isolated preparations down to the cellular level. He contributed to that molecular study in which 5-HT3 receptor subtypes were disclosed. Finally, he found altered pharmacological properties of 5-HT receptor variants like the Arg219Leu 5-HT1A receptor (which was also shown to be associated with major depression) and the Phe124Cys 5-HT1B receptor (which may be related to sumatriptan-induced vasospasm). Manfred Göthert was a brilliant scientist and his papers have a major impact on today's pharmacology.
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Affiliation(s)
- H Bönisch
- Institute of Pharmacology and Toxicology, University of Bonn, Venusberg-Campus 1, 53105, Bonn, Germany
| | - K B Fink
- Merz Pharmaceuticals, Frankfurt/Main, Germany
| | - B Malinowska
- Department of Physiology and Pathophysiology, Medical University of Białystok, Białystok, Poland
| | - G J Molderings
- Institute of Human Genetics, University of Bonn, Bonn, Germany
| | - E Schlicker
- Institute of Pharmacology and Toxicology, University of Bonn, Venusberg-Campus 1, 53105, Bonn, Germany.
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Gawlińska K, Gawliński D, Filip M, Przegaliński E. Maternal feeding patterns affect the offspring's brain: focus on serotonin 5-HT 2C and 5-HT 2A receptors. Pharmacol Rep 2021; 73:1170-1178. [PMID: 34146338 PMCID: PMC8413174 DOI: 10.1007/s43440-021-00298-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 06/02/2021] [Accepted: 06/10/2021] [Indexed: 12/01/2022]
Abstract
BACKGROUND Recent studies have shown a relationship between the composition of the maternal diet and acquiring a risk of mental illnesses through changes in the offspring's brain. This study assessed the role of a modified maternal diet on the levels of serotonin (5-HT)2C and 5-HT2A receptors in the offspring brain. METHODS Wistar rat dams during gestation and lactation were maintained either on a standard (SD) or special diets: high-fat (HFD), high-carbohydrate (rich in sucrose, HCD) or mixed (MD). Offspring were weaned to SD after lactation, and at postnatal days (PNDs) 28 and 63 changes in the 5-HT2C and 5-HT2A receptor levels were evaluated in their prefrontal cortex (PFCx), nucleus accumbens (NAc), dorsal striatum (DSTR) and hippocampus (HIP). RESULTS Maternal HFD reduced the expression of 5-HT2C receptors in male rats at PND 28 in the PFCx, NAc, and DSTR but increased it at PND 63 in male animals in the NAc and DSTR. HCD induced a decrease in the expression of 5-HT2C receptors in male offspring at PND 28 but increased it in female rats at PND 63 in the PFCx. MD reduced 5-HT2C receptor expression in males at PND 28 in the PFCx and increased it in male and female offspring at PND 28 in the HIP. Moreover, maternal HFD reduced 5-HT2A receptor levels within the PFCx in adolescent male offspring. CONCLUSION Our findings indicate that a modified maternal diet induces age- and sex-specific adaptive changes mainly in 5-HT2C receptors, which may contribute to disturbances in the offspring brain.
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Affiliation(s)
- Kinga Gawlińska
- Department of Drug Addiction Pharmacology, Maj Institute of Pharmacology Polish Academy of Sciences, Smętna Street 12, 31-343, Kraków, Poland.
| | - Dawid Gawliński
- Department of Drug Addiction Pharmacology, Maj Institute of Pharmacology Polish Academy of Sciences, Smętna Street 12, 31-343, Kraków, Poland
| | - Małgorzata Filip
- Department of Drug Addiction Pharmacology, Maj Institute of Pharmacology Polish Academy of Sciences, Smętna Street 12, 31-343, Kraków, Poland
| | - Edmund Przegaliński
- Department of Drug Addiction Pharmacology, Maj Institute of Pharmacology Polish Academy of Sciences, Smętna Street 12, 31-343, Kraków, Poland
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da Silva AW, Ferreira MKA, Rebouças EL, Mendes FRS, Dos S Moura AL, de Menezes JESA, Marinho MM, Marinho ES, Santos HS, Teixeira AMR. Anxiolytic-like effect of natural product 2-hydroxy-3,4,6-trimethoxyacetophenone isolated from Croton anisodontus in adult zebrafish via serotonergic neuromodulation involvement of the 5-HT system. Naunyn Schmiedebergs Arch Pharmacol 2021; 394:2023-2032. [PMID: 34251503 DOI: 10.1007/s00210-021-02116-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Accepted: 06/22/2021] [Indexed: 10/20/2022]
Abstract
Benzodiazepines are highly effective in combating anxiety; however, they have considerable adverse effects, so it is important to discover new safe anxiolytic agents. This study was designed to investigate the effect of the natural product 2-hydroxy-3,4,6-trimethoxyacetophenone (HTMCX) on anxiety and seizure behavior in adult zebrafish and its possible mechanisms of action. The acute toxicity of 96 h of HTMCX was analyzed, and the open and light/dark field tests (n = 6 animals/group) were used to assess the anxiety behavior of animals treated with HTMCX. In addition, the mechanisms of action were investigated with antagonists of the GABAA, 5-HT receptors, and molecular anchorage study. Pentylenetetrazole (PTZ) was used to induce seizure by immersion. As a result, acetophenone HTMCX (1, 3 and 10 mg/kg; v.o.) was non-toxic and affected locomotor activity. The higher doses (3 and 10 mg/kg; v.o.) produced signs of anxiolytic action in the light/dark test, and this effect was reversed by the pizotifen (antagonist 5HTR1 and 5HTR2A/2C), having the potential to form a complex with 5HTR1B. However, the anxiolytic effect of HTMCX has not been abolished by flumazenil (antagonist GABAA), cyproheptadine (antagonist 5HTR2A), and granisetron (antagonist 5HTR3A/3B). Therefore, HTMCX demonstrated an anxiolytic effect, suggesting that the 5HTR1 and 5HTR2C receptors may be involved in the pharmacological performance of this acetophenone in the central nervous system.
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Affiliation(s)
- Antonio Wlisses da Silva
- Graduate Program in Biotechnology, Northeast Biotechnology Network, State University of Ceará, Fortaleza, CE, Brazil
| | - Maria Kueirislene A Ferreira
- Graduate Program in Natural Sciences, Natural Products Chemistry Laboratory, State University of Ceará, Fortaleza, CE, Brazil
| | - Emanuela L Rebouças
- Graduate Program in Biotechnology, Northeast Biotechnology Network, State University of Ceará, Fortaleza, CE, Brazil
| | - Francisco Rogenio S Mendes
- Graduate Program in Biological Chemistry, Department of Biological Chemistry, Regional University of Cariri, Crato, CE, Brasil
| | - Atilano Lucas Dos S Moura
- Graduate Program in Natural Sciences, Natural Products Chemistry Laboratory, State University of Ceará, Fortaleza, CE, Brazil
| | - Jane Eire S A de Menezes
- Graduate Program in Natural Sciences, Natural Products Chemistry Laboratory, State University of Ceará, Fortaleza, CE, Brazil
| | - Márcia Machado Marinho
- Faculty of Philosophy Dom Aureliano Matos, State University of Ceará, Limoeiro do Norte, CE, Brazil
| | - Emmanuel Silva Marinho
- Faculty of Philosophy Dom Aureliano Matos, State University of Ceará, Limoeiro do Norte, CE, Brazil
| | - Hélcio S Santos
- Graduate Program in Biotechnology, Northeast Biotechnology Network, State University of Ceará, Fortaleza, CE, Brazil.,Graduate Program in Natural Sciences, Natural Products Chemistry Laboratory, State University of Ceará, Fortaleza, CE, Brazil.,Graduate Program in Biological Chemistry, Department of Biological Chemistry, Regional University of Cariri, Crato, CE, Brasil.,Science and Technology Centre, Course of Chemistry, State University Vale do Acaraú, Sobral, CE, Brazil
| | - Alexandre M R Teixeira
- Graduate Program in Biotechnology, Northeast Biotechnology Network, State University of Ceará, Fortaleza, CE, Brazil. .,Graduate Program in Biological Chemistry, Department of Biological Chemistry, Regional University of Cariri, Crato, CE, Brasil.
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Exercise and fluoxetine treatment during adolescence protect against early life stress-induced behavioral abnormalities in adult rats. Pharmacol Biochem Behav 2021; 205:173190. [PMID: 33865889 DOI: 10.1016/j.pbb.2021.173190] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 04/10/2021] [Accepted: 04/12/2021] [Indexed: 12/13/2022]
Abstract
Depression is a psychiatric disorder with several comorbidities that has a complicated pathophysiology. Multiple mechanisms such as abnormal hypothalamic-pituitary adrenal (HPA) axis activity, neurotransmission (namely serotonin), and immune-inflammatory responses are involved in the pathophysiology of disease. In this study, we hypothesized that applying exercise (running wheel (RW) and treadmill (TM)) or fluoxetine (FLX) during adolescence could protect adult rats against the negative impact of early-life stress. To do this, we applied maternal separation stress (MS) to neonatal rats from postnatal day (PND) 2 to 14 and at PND 28, rats were divided into 8 experimental groups and were subjected to TM or RW or FLX treatment. After four weeks of physical activity or FLX treatment, at PND 64, behaviors were assessed by applying forced swimming test, sucrose preference test, open-field test, and elevated plus maze test. Serum cortiscosterone (CORT) levels and expression of genes associated with inflammatory factors (Il1β, Hmgb1, and Il6) and serotonergic systems (5-ht2c and 5-ht3a) were studies in the hippocampus (HIPP) and prefrontal cortex (PFC). Our results revealed that RW and FLX treatment during adolescence are capable of attenuating MS-induced depressive- and anxiety-like disorders in adult male rats. These effects were accompanied by the normalization of both serum CORT and the expression of genes in the HIPP and PFC. TM exercise in adolescence showed anxiolytic effects but failed to produce antidepressant-like effects. Results of this study suggest that voluntary physical activity during adolescence can reduce the negative effects of early-life stress through different mechanisms.
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Kummerfeld DM, Raabe CA, Brosius J, Mo D, Skryabin BV, Rozhdestvensky TS. A Comprehensive Review of Genetically Engineered Mouse Models for Prader-Willi Syndrome Research. Int J Mol Sci 2021; 22:3613. [PMID: 33807162 PMCID: PMC8037846 DOI: 10.3390/ijms22073613] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 03/26/2021] [Accepted: 03/28/2021] [Indexed: 02/05/2023] Open
Abstract
Prader-Willi syndrome (PWS) is a neurogenetic multifactorial disorder caused by the deletion or inactivation of paternally imprinted genes on human chromosome 15q11-q13. The affected homologous locus is on mouse chromosome 7C. The positional conservation and organization of genes including the imprinting pattern between mice and men implies similar physiological functions of this locus. Therefore, considerable efforts to recreate the pathogenesis of PWS have been accomplished in mouse models. We provide a summary of different mouse models that were generated for the analysis of PWS and discuss their impact on our current understanding of corresponding genes, their putative functions and the pathogenesis of PWS. Murine models of PWS unveiled the contribution of each affected gene to this multi-facetted disease, and also enabled the establishment of the minimal critical genomic region (PWScr) responsible for core symptoms, highlighting the importance of non-protein coding genes in the PWS locus. Although the underlying disease-causing mechanisms of PWS remain widely unresolved and existing mouse models do not fully capture the entire spectrum of the human PWS disorder, continuous improvements of genetically engineered mouse models have proven to be very powerful and valuable tools in PWS research.
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Affiliation(s)
- Delf-Magnus Kummerfeld
- Medical Faculty, Core Facility Transgenic Animal and Genetic Engineering Models (TRAM), University of Muenster, Von-Esmarch-Str. 56, D-48149 Muenster, Germany;
| | - Carsten A. Raabe
- Research Group Regulatory Mechanisms of Inflammation, Institute of Medical Biochemistry (ZMBE), University of Muenster, Von-Esmarch-Str. 56, D-48149 Muenster, Germany;
- Institute of Experimental Pathology (ZMBE), University of Muenster, Von-Esmarch-Str. 56, D-48149 Muenster, Germany;
| | - Juergen Brosius
- Institute of Experimental Pathology (ZMBE), University of Muenster, Von-Esmarch-Str. 56, D-48149 Muenster, Germany;
- Institutes for Systems Genetics, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Dingding Mo
- School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen 518055, China;
| | - Boris V. Skryabin
- Medical Faculty, Core Facility Transgenic Animal and Genetic Engineering Models (TRAM), University of Muenster, Von-Esmarch-Str. 56, D-48149 Muenster, Germany;
| | - Timofey S. Rozhdestvensky
- Medical Faculty, Core Facility Transgenic Animal and Genetic Engineering Models (TRAM), University of Muenster, Von-Esmarch-Str. 56, D-48149 Muenster, Germany;
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40
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Villas-Boas GR, Lavorato SN, Paes MM, de Carvalho PMG, Rescia VC, Cunha MS, de Magalhães-Filho MF, Ponsoni LF, de Carvalho AAV, de Lacerda RB, da S. Leite L, da S. Tavares-Henriques M, Lopes LAF, Oliveira LGR, Silva-Filho SE, da Silveira APS, Cuman RKN, de S. Silva-Comar FM, Comar JF, do A. Brasileiro L, dos Santos JN, de Freitas WR, Leão KV, da Silva JG, Klein RC, Klein MHF, da S. Ramos BH, Fernandes CKC, de L. Ribas DG, Oesterreich SA. Modulation of the Serotonergic Receptosome in the Treatment of Anxiety and Depression: A Narrative Review of the Experimental Evidence. Pharmaceuticals (Basel) 2021; 14:ph14020148. [PMID: 33673205 PMCID: PMC7918669 DOI: 10.3390/ph14020148] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 02/05/2021] [Accepted: 02/09/2021] [Indexed: 02/07/2023] Open
Abstract
Serotonin (5-HT) receptors are found throughout central and peripheral nervous systems, mainly in brain regions involved in the neurobiology of anxiety and depression. 5-HT receptors are currently promising targets for discovering new drugs for treating disorders ranging from migraine to neuropsychiatric upsets, such as anxiety and depression. It is well described in the current literature that the brain expresses seven types of 5-HT receptors comprising eighteen distinct subtypes. In this article, we comprehensively reviewed 5-HT1-7 receptors. Of the eighteen 5-HT receptors known today, thirteen are G protein-coupled receptors (GPCRs) and represent targets for approximately 40% of drugs used in humans. Signaling pathways related to these receptors play a crucial role in neurodevelopment and can be modulated to develop effective therapies to treat anxiety and depression. This review presents the experimental evidence of the modulation of the “serotonergic receptosome” in the treatment of anxiety and depression, as well as demonstrating state-of-the-art research related to phytochemicals and these disorders. In addition, detailed aspects of the pharmacological mechanism of action of all currently known 5-HT receptor families were reviewed. From this review, it will be possible to direct the rational design of drugs towards new therapies that involve signaling via 5-HT receptors.
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Affiliation(s)
- Gustavo R. Villas-Boas
- Research Group on Development of Pharmaceutical Products (P & DProFar), Center for Biological and Health Sciences, Federal University of Western Bahia, Rua Bertioga, 892, Morada Nobre II, Barreiras CEP 47810-059, BA, Brazil; (S.N.L.); (M.M.P.); (P.M.G.d.C.); (V.C.R.); (M.S.C.); (M.F.d.M.-F.); (L.F.P.); (A.A.V.d.C.)
- Correspondence: ; Tel.: +55-(77)-3614-3152
| | - Stefânia N. Lavorato
- Research Group on Development of Pharmaceutical Products (P & DProFar), Center for Biological and Health Sciences, Federal University of Western Bahia, Rua Bertioga, 892, Morada Nobre II, Barreiras CEP 47810-059, BA, Brazil; (S.N.L.); (M.M.P.); (P.M.G.d.C.); (V.C.R.); (M.S.C.); (M.F.d.M.-F.); (L.F.P.); (A.A.V.d.C.)
| | - Marina M. Paes
- Research Group on Development of Pharmaceutical Products (P & DProFar), Center for Biological and Health Sciences, Federal University of Western Bahia, Rua Bertioga, 892, Morada Nobre II, Barreiras CEP 47810-059, BA, Brazil; (S.N.L.); (M.M.P.); (P.M.G.d.C.); (V.C.R.); (M.S.C.); (M.F.d.M.-F.); (L.F.P.); (A.A.V.d.C.)
| | - Pablinny M. G. de Carvalho
- Research Group on Development of Pharmaceutical Products (P & DProFar), Center for Biological and Health Sciences, Federal University of Western Bahia, Rua Bertioga, 892, Morada Nobre II, Barreiras CEP 47810-059, BA, Brazil; (S.N.L.); (M.M.P.); (P.M.G.d.C.); (V.C.R.); (M.S.C.); (M.F.d.M.-F.); (L.F.P.); (A.A.V.d.C.)
| | - Vanessa C. Rescia
- Research Group on Development of Pharmaceutical Products (P & DProFar), Center for Biological and Health Sciences, Federal University of Western Bahia, Rua Bertioga, 892, Morada Nobre II, Barreiras CEP 47810-059, BA, Brazil; (S.N.L.); (M.M.P.); (P.M.G.d.C.); (V.C.R.); (M.S.C.); (M.F.d.M.-F.); (L.F.P.); (A.A.V.d.C.)
| | - Mila S. Cunha
- Research Group on Development of Pharmaceutical Products (P & DProFar), Center for Biological and Health Sciences, Federal University of Western Bahia, Rua Bertioga, 892, Morada Nobre II, Barreiras CEP 47810-059, BA, Brazil; (S.N.L.); (M.M.P.); (P.M.G.d.C.); (V.C.R.); (M.S.C.); (M.F.d.M.-F.); (L.F.P.); (A.A.V.d.C.)
| | - Manoel F. de Magalhães-Filho
- Research Group on Development of Pharmaceutical Products (P & DProFar), Center for Biological and Health Sciences, Federal University of Western Bahia, Rua Bertioga, 892, Morada Nobre II, Barreiras CEP 47810-059, BA, Brazil; (S.N.L.); (M.M.P.); (P.M.G.d.C.); (V.C.R.); (M.S.C.); (M.F.d.M.-F.); (L.F.P.); (A.A.V.d.C.)
| | - Luis F. Ponsoni
- Research Group on Development of Pharmaceutical Products (P & DProFar), Center for Biological and Health Sciences, Federal University of Western Bahia, Rua Bertioga, 892, Morada Nobre II, Barreiras CEP 47810-059, BA, Brazil; (S.N.L.); (M.M.P.); (P.M.G.d.C.); (V.C.R.); (M.S.C.); (M.F.d.M.-F.); (L.F.P.); (A.A.V.d.C.)
| | - Adryano Augustto Valladao de Carvalho
- Research Group on Development of Pharmaceutical Products (P & DProFar), Center for Biological and Health Sciences, Federal University of Western Bahia, Rua Bertioga, 892, Morada Nobre II, Barreiras CEP 47810-059, BA, Brazil; (S.N.L.); (M.M.P.); (P.M.G.d.C.); (V.C.R.); (M.S.C.); (M.F.d.M.-F.); (L.F.P.); (A.A.V.d.C.)
| | - Roseli B. de Lacerda
- Department of Pharmacology, Center for Biological Sciences, Federal University of Paraná, Jardim das Américas, Caixa. postal 19031, Curitiba CEP 81531-990, PR, Brazil;
| | - Lais da S. Leite
- Collegiate Biomedicine, SulAmérica College, Rua Gláuber Rocha, 66, Jardim Paraíso, Luís Eduardo Magalhães CEP 47850-000, BA, Brazil;
| | - Matheus da S. Tavares-Henriques
- Laboratory of Pharmacology of Toxins (LabTox), Graduate Program in Pharmacology and Medicinal Chemistry (PPGFQM), Institute of Biomedical Sciences (ICB) Federal Universityof Rio de Janeiro (UFRJ), Avenida Carlos Chagas Filho, 373, Cidade Universitária, Rio de Janeiro CEP 21941-590, RJ, Brazil;
| | - Luiz A. F. Lopes
- Teaching and Research Manager at the University Hospital—Federal University of Grande Dourados (HU/EBSERH-UFGD), Federal University of Grande Dourados, Rua Ivo Alves da Rocha, 558, Altos do Indaiá, Dourados CEP 79823-501, MS, Brazil;
| | - Luiz G. R. Oliveira
- Nucleus of Studies on Infectious Agents and Vectors (Naive), Federal University of Western Bahia, Rua Bertioga, 892, Morada Nobre II, Barreiras CEP 47810-059, BA, Brazil;
| | - Saulo E. Silva-Filho
- Pharmaceutical Sciences, Food and Nutrition College, Federal University of Mato Grosso do Sul, Avenida Costa e Silva, s/n°, Bairro Universitário, Campo Grande CEP 79070-900, MS, Brazil;
| | - Ana P. S. da Silveira
- Faculty of Biological and Health Sciences, Unigran Capital University Center, RuaBalbina de Matos, 2121, Jarddim Universitário, Dourados CEP 79.824-900, MS, Brazil;
| | - Roberto K. N. Cuman
- Department of Pharmacology and Therapeutics, State University of Maringá, Avenida Colombo, n° 5790, Jardim Universitário, Maringá CEP 87020-900, PR, Brazil; (R.K.N.C.); (F.M.d.S.S.-C.)
| | - Francielli M. de S. Silva-Comar
- Department of Pharmacology and Therapeutics, State University of Maringá, Avenida Colombo, n° 5790, Jardim Universitário, Maringá CEP 87020-900, PR, Brazil; (R.K.N.C.); (F.M.d.S.S.-C.)
| | - Jurandir F. Comar
- Department of Biochemistry, State Universityof Maringá, Avenida Colombo, n° 5790, Jardim Universitário, Maringá CEP 87020-900, PR, Brazil;
| | - Luana do A. Brasileiro
- Nacional Cancer Institute (INCA), Rua Visconde de Santa Isabel, 274, Rio de Janeiro CEP 20560-121, RJ, Brazil;
| | | | - William R. de Freitas
- Research Group on Biodiversity and Health (BIOSA), Center for Training in Health Sciences, Federal University of Southern Bahia, Praça Joana Angélica, 58, São José, Teixeira de Freitas CEP 45988-058, BA, Brazil;
| | - Katyuscya V. Leão
- Pharmacy Department, Federal University of Western Bahia, Rua Bertioga, 892, Morada Nobre II, Barreiras CEP 47810-059, BA, Brazil; (K.V.L.); (J.G.d.S.); (R.C.K.); (M.H.F.K.)
| | - Jonatas G. da Silva
- Pharmacy Department, Federal University of Western Bahia, Rua Bertioga, 892, Morada Nobre II, Barreiras CEP 47810-059, BA, Brazil; (K.V.L.); (J.G.d.S.); (R.C.K.); (M.H.F.K.)
| | - Raphael C. Klein
- Pharmacy Department, Federal University of Western Bahia, Rua Bertioga, 892, Morada Nobre II, Barreiras CEP 47810-059, BA, Brazil; (K.V.L.); (J.G.d.S.); (R.C.K.); (M.H.F.K.)
| | - Mary H. F. Klein
- Pharmacy Department, Federal University of Western Bahia, Rua Bertioga, 892, Morada Nobre II, Barreiras CEP 47810-059, BA, Brazil; (K.V.L.); (J.G.d.S.); (R.C.K.); (M.H.F.K.)
| | - Bruno H. da S. Ramos
- Institute of the Spine and Pain Clinic, Rua Dr. Renato Gonçalves, 108, Renato Gonçalves, Barreiras CEP 47806-021, BA, Brazil;
| | - Cristiane K. C. Fernandes
- University Center of Montes Belos, Av. Hermógenes Coelho s/n, Setor Universitário, São Luís de Montes Belos CEP 76100-000, GO, Brazil;
| | - Dayane G. de L. Ribas
- Gaus College and Course, Rua Severino Vieira, 60, Centro, Barreiras CEP 47800-160, BA, Brazil;
| | - Silvia A. Oesterreich
- Faculty of Health Sciences, Federal University of Grande Dourados, Dourados Rodovia Dourados, Itahum Km 12, Cidade Universitaria, Caixa postal 364, Dourados CEP 79804-970, MS, Brazil;
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Cortical influences of serotonin and glutamate on layer V pyramidal neurons. PROGRESS IN BRAIN RESEARCH 2021; 261:341-378. [PMID: 33785135 DOI: 10.1016/bs.pbr.2020.11.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Layer V pyramidal neurons constitute principle output neurons of the medial prefrontal cortex (mPFC)/neocortex to subcortical regions including the intralaminar/midline thalamic nuclei, amygdala, basal ganglia, brainstem nuclei and the spinal cord. The effects of 5-hydroxytryptamine (5-HT) on layer V pyramidal cells primarily reflect a range of excitatory influences through 5-HT2A receptors and inhibitory influences through non-5-HT2A receptors, including 5-HT1A receptors. While the 5-HT2A receptor is primarily a postsynaptic receptor on throughout the apical dendritic field of 5-HT2A receptors, activation of a minority of 5-HT2A receptors also appears to increase spontaneous excitatory postsynaptic currents/potentials (EPSCs/EPSPs) via a presynaptic effect on thalamocortical terminals arising from the midline and intralaminar thalamic nuclei. Activation of 5-HT2A receptors by the phenethylamine hallucinogen also appears to increase asynchronous release of glutamate upon the layer V pyramidal dendritic field, an effect that is suppressed by 5-HT itself through non-5-HT2A receptors. Serotonergic hallucinogens acting on 5-HT2A receptors also appears to increase gene expression of immediate early genes (iEG) and other receptors appearing to induce an iEG-like response like BDNF. Psychedelic hallucinogens acting on 5-HT2A receptors also induce head twitches in rodents that appear related to induction of glutamate release. These electrophysiological, biochemical and behavioral effects of serotonergic hallucinogens appear to be related to modulating glutamatergic thalamocortical neurotransmission and/or shifting the balance toward 5-HT2A receptor activation and away from non-5-HT2A receptor activation. These 5-HT2A receptor induced responses are modulated by feedback homeostatic mechanisms through mGlu2, mGlu4, and mGlu8 presynaptic receptors on thalamocortical terminals. These 5-HT2A receptor and glutamatergic interactions also appear to play a role on higher cortical functions of the mPFC such as motoric impulsivity and antidepressant-like behavioral responses on the differential-reinforcement-of low rate 72-s (DRL 72-s schedule). These mutually opposing effects between 5-HT2A receptor and mGlu autoreceptor activation (e.g., blocking 5-HT2A receptors and enhancing activity at mGlu2 receptors) may play a clinical role with respect to currently prescribed or novel antidepressant drugs. Thus, there is an important balance between 5-HT2A receptor activation and activation of mGlu autoreceptors on prefrontal cortical layer V pyramidal cells with respect to the electrophysiological, biochemical and behavioral effects serotonergic hallucinogenic drugs.
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Yang Y, Okada S, Sakurai M. Adenosine-to-inosine RNA editing in neurological development and disease. RNA Biol 2021; 18:999-1013. [PMID: 33393416 DOI: 10.1080/15476286.2020.1867797] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Adenosine-to-inosine (A-to-I) editing is one of the most prevalent post-transcriptional RNA modifications in metazoan. This reaction is catalysed by enzymes called adenosine deaminases acting on RNA (ADARs). RNA editing is involved in the regulation of protein function and gene expression. The numerous A-to-I editing sites have been identified in both coding and non-coding RNA transcripts. These editing sites are also found in various genes expressed in the central nervous system (CNS) and play an important role in neurological development and brain function. Aberrant regulation of RNA editing has been associated with the pathogenesis of neurological and psychiatric disorders, suggesting the physiological significance of RNA editing in the CNS. In this review, we discuss the current knowledge of editing on neurological disease and development.
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Affiliation(s)
- Yuxi Yang
- Research Institute for Biomedical Sciences, Tokyo University of Science, Noda-shi, Chiba, Japan
| | - Shunpei Okada
- Research Institute for Biomedical Sciences, Tokyo University of Science, Noda-shi, Chiba, Japan
| | - Masayuki Sakurai
- Research Institute for Biomedical Sciences, Tokyo University of Science, Noda-shi, Chiba, Japan
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Xiao X, Bi M, Jiao Q, Chen X, Du X, Jiang H. A new understanding of GHSR1a--independent of ghrelin activation. Ageing Res Rev 2020; 64:101187. [PMID: 33007437 DOI: 10.1016/j.arr.2020.101187] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 09/13/2020] [Accepted: 09/21/2020] [Indexed: 12/13/2022]
Abstract
Growth hormone secretagogue receptor 1a (GHSR1a), a member of the G protein-coupled receptor (GPCR) family, is a functional receptor of ghrelin. The expression levels and activities of GHSR1a are affected by various factors. In past years, it has been found that the ghrelin-GHSR1a system can perform biological functions such as anti-inflammation, anti-apoptosis, and anti-oxidative stress. In addition to mediating the effect of ghrelin, GHSR1a also has abnormally high constitutive activity; that is, it can still transmit intracellular signals without activation of the ghrelin ligand. This constitutive activity affects brain functions, growth and development of the body; therefore, it has profound impacts on neurodegenerative diseases and some other age-related diseases. In addition, GHSR1a can also form homodimers or heterodimers with other GPCRs, affecting the release of neurotransmitters, appetite regulation, cell proliferation and insulin release. Therefore, further understanding of the constitutive activities and dimerization of GHSR1a will enable us to better clarify the characteristics of GHSR1a and provide more therapeutic targets for drug development. Here, we focus on the roles of GHSR1a in various biological functions and provide a comprehensive summary of the current research on GHSR1a to provide broader therapeutic prospects for age-related disease treatment.
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Affiliation(s)
- Xue Xiao
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, School of Basic Medicine, Qingdao University, Qingdao, China
| | - Mingxia Bi
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, School of Basic Medicine, Qingdao University, Qingdao, China
| | - Qian Jiao
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, School of Basic Medicine, Qingdao University, Qingdao, China
| | - Xi Chen
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, School of Basic Medicine, Qingdao University, Qingdao, China
| | - Xixun Du
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, School of Basic Medicine, Qingdao University, Qingdao, China.
| | - Hong Jiang
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, School of Basic Medicine, Qingdao University, Qingdao, China.
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De Deurwaerdère P, Chagraoui A, Cunningham KA. Editorial: Contemporary Perspective on 5-HT 2C Receptor Function and Its Pharmacological Targeting. Front Pharmacol 2020; 11:606414. [PMID: 33324228 PMCID: PMC7724505 DOI: 10.3389/fphar.2020.606414] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Accepted: 10/05/2020] [Indexed: 12/18/2022] Open
Affiliation(s)
- Philippe De Deurwaerdère
- Institut des Neurosciences Cognitives et Integratives d'Aquitaine, CNRS UMR 5287, Bordeaux, France
| | - Abdeslam Chagraoui
- Neuronal and Neuroendocrine Differentiation and Communication Laboratory, Institute for Research and Innovation in Biomedicine of Normandy (IRIB), Normandie University, UNIROUEN, INSERM, U1239, Rouen, France.,CHU Rouen, Rouen, France
| | - Kathryn A Cunningham
- Center for Addiction Research and Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, United States
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Trujillo V, Valentim-Lima E, Mencalha R, Carbalan QSR, Dos-Santos RC, Felintro V, Girardi CEN, Rorato R, Lustrino D, Reis LC, Mecawi AS. Neonatal Serotonin Depletion Induces Hyperactivity and Anxiolytic-like Sex-Dependent Effects in Adult Rats. Mol Neurobiol 2020; 58:1036-1051. [PMID: 33083963 DOI: 10.1007/s12035-020-02181-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Accepted: 10/14/2020] [Indexed: 12/16/2022]
Abstract
The serotoninergic system plays an important role in the ontogeny of the mammalian central nervous system, and changes in serotonin production during development may lead to permanent changes in brain cytoarchitecture and function. The present study investigated the programming effects of neonatal serotonin depletion on behavior and molecular components of the serotoninergic system in adult male and female rats. Subcutaneous para-chlorophenylalanine (pCPA) administration (100 mg kg-1) was performed daily on postnatal days 8-16 to deplete brain serotonin content. During adulthood, elevated plus-maze, open field, social interaction, forced swimming, and food, saline, and sucrose intake tests were performed. Relative expression of serotonin neurotransmission components in several brain areas was determined by qPCR. Additionally, serotonin immunofluorescence and neuropeptide mRNA expression were assessed in dorsal raphe (DRN) and paraventricular (PVN) nuclei, respectively. Rat performance in behavioral tests demonstrated a general increase in locomotor activity and active escape behavior as well as decreased anxiety-like behavior after neonatal brain serotonin depletion. The behavioral programming effects due to neonatal serotonin depletion were more pronounced in females than males. At the gene expression level, the mRNA of Tph1 and Tph2 were lower in DRN while Htr2c was higher in the amygdala of pCPA-treated males, while Htr1a, Htr2c, Oxt, Avp, Crh, and Trh were not different in any treatments or sex in PVN. The results indicate that neonatal serotonin depletion has long-term consequences on locomotion and anxiety-like behavior associated with long-lasting molecular changes in the brain serotoninergic system in adult rats.
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Affiliation(s)
- Verónica Trujillo
- Laboratory of Neuroendocrinology, Department of Biophysics, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), Rua Botucatu, 862, Edifício de Ciências Biomédicas, 7° andar, Vila Clementino, São Paulo, CEP 04023-062, Brasil
- Departament of Physiology, Facultad de Ciencias Exactas, Físicas y Naturales, Universidad Nacional de Córdoba, Córdoba, Argentina
| | - Evandro Valentim-Lima
- Laboratory of Neuroendocrinology, Department of Biophysics, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), Rua Botucatu, 862, Edifício de Ciências Biomédicas, 7° andar, Vila Clementino, São Paulo, CEP 04023-062, Brasil
| | - Rodrigo Mencalha
- Department of Natural Sciences, Universidade Federal do Acre, Rio Branco, Brazil
| | - Quézia S R Carbalan
- Department of Physiological Sciences, Instituto de Ciências Biológicas e da Saúde, Universidade Federal Rural do Rio de Janeiro, Seropédica, Brazil
| | - Raoni C Dos-Santos
- Department of Physiological Sciences, Instituto de Ciências Biológicas e da Saúde, Universidade Federal Rural do Rio de Janeiro, Seropédica, Brazil
| | - Viviane Felintro
- Department of Physiological Sciences, Instituto de Ciências Biológicas e da Saúde, Universidade Federal Rural do Rio de Janeiro, Seropédica, Brazil
| | - Carlos E N Girardi
- Department of Psychobiology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Rodrigo Rorato
- Laboratory of Neuroendocrinology, Department of Biophysics, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), Rua Botucatu, 862, Edifício de Ciências Biomédicas, 7° andar, Vila Clementino, São Paulo, CEP 04023-062, Brasil
| | - Danilo Lustrino
- Department of Physiology, Centro de Ciências Biológicas e da Saúde, Universidade Federal de Sergipe, São Cristóvão, Brazil
| | - Luis C Reis
- Department of Physiological Sciences, Instituto de Ciências Biológicas e da Saúde, Universidade Federal Rural do Rio de Janeiro, Seropédica, Brazil
| | - André S Mecawi
- Laboratory of Neuroendocrinology, Department of Biophysics, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), Rua Botucatu, 862, Edifício de Ciências Biomédicas, 7° andar, Vila Clementino, São Paulo, CEP 04023-062, Brasil.
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Hebras J, Marty V, Personnaz J, Mercier P, Krogh N, Nielsen H, Aguirrebengoa M, Seitz H, Pradere JP, Guiard BP, Cavaille J. Reassessment of the involvement of Snord115 in the serotonin 2c receptor pathway in a genetically relevant mouse model. eLife 2020; 9:60862. [PMID: 33016258 PMCID: PMC7673782 DOI: 10.7554/elife.60862] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Accepted: 09/22/2020] [Indexed: 12/12/2022] Open
Abstract
SNORD115 has been proposed to promote the activity of serotonin (HTR2C) receptor via its ability to base pair with its pre-mRNA and regulate alternative RNA splicing and/or A-to-I RNA editing. Because SNORD115 genes are deleted in most patients with the Prader-Willi syndrome (PWS), diminished HTR2C receptor activity could contribute to the impaired emotional response and/or compulsive overeating characteristic of this disease. In order to test this appealing but never demonstrated hypothesis in vivo, we created a CRISPR/Cas9-mediated Snord115 knockout mouse. Surprisingly, we uncovered only modest region-specific alterations in Htr2c RNA editing profiles, while Htr2c alternative RNA splicing was unchanged. These subtle changes, whose functional relevance remains uncertain, were not accompanied by any discernible defects in anxio-depressive-like phenotypes. Energy balance and eating behavior were also normal, even after exposure to high-fat diet. Our study raises questions concerning the physiological role of SNORD115, notably its involvement in behavioural disturbance associated with PWS.
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Affiliation(s)
- Jade Hebras
- Laboratoire de Biologie Moléculaire Eucaryote, Centre de Biologie Intégrative, Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Virginie Marty
- Laboratoire de Biologie Moléculaire Eucaryote, Centre de Biologie Intégrative, Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Jean Personnaz
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institut National de la Santé et de la Recherche Médicale (INSERM), France Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université de Toulouse Université Paul Sabatier, Toulouse, France
| | - Pascale Mercier
- Institut de Pharmacologie et de Biologie Structurale (IPBS), Centre National de la Recherche Scientifique UMR5089, Toulouse, France
| | - Nicolai Krogh
- Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Henrik Nielsen
- Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Marion Aguirrebengoa
- LBCMCP, Centre de Biologie Intégrative (CBI), CNRS, Université de Toulouse, Toulouse, France
| | - Hervé Seitz
- IGH (CNRS and University of Montpellier), Montpellier, France
| | - Jean-Phillipe Pradere
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institut National de la Santé et de la Recherche Médicale (INSERM), France Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université de Toulouse Université Paul Sabatier, Toulouse, France
| | - Bruno P Guiard
- Centre de Recherches sur la Cognition Animale (CRCA), Centre de Biologie Intégrative (CBI), Centre National de la Recherche Scientifique, Université de Toulouse, Toulouse, France
| | - Jérôme Cavaille
- Laboratoire de Biologie Moléculaire Eucaryote, Centre de Biologie Intégrative, Université de Toulouse, CNRS, UPS, Toulouse, France
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Levchenko A, Vyalova NM, Nurgaliev T, Pozhidaev IV, Simutkin GG, Bokhan NA, Ivanova SA. NRG1, PIP4K2A, and HTR2C as Potential Candidate Biomarker Genes for Several Clinical Subphenotypes of Depression and Bipolar Disorder. Front Genet 2020; 11:936. [PMID: 33193575 PMCID: PMC7478333 DOI: 10.3389/fgene.2020.00936] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Accepted: 07/27/2020] [Indexed: 12/20/2022] Open
Abstract
GSK3B, BDNF, NGF, NRG1, HTR2C, and PIP4K2A play important roles in molecular mechanisms of psychiatric disorders. GSK3B occupies a central position in these molecular mechanisms and is also modulated by psychotropic drugs. BDNF regulates a number of key aspects in neurodevelopment and synaptic plasticity. NGF exerts a trophic action and is implicated in cerebral alterations associated with psychiatric disorders. NRG1 is active in neural development, synaptic plasticity, and neurotransmission. HTR2C is another important psychopharmacological target. PIP4K2A catalyzes the phosphorylation of PI5P to form PIP2, the latter being implicated in various aspects of neuronal signal transduction. In the present study, the six genes were sequenced in a cohort of 19 patients with bipolar affective disorder, 41 patients with recurrent depressive disorder, and 55 patients with depressive episode. The study revealed a number of genetic variants associated with antidepressant treatment response, time to recurrence of episodes, and depression severity. Namely, alleles of rs35641374 and rs10508649 (NRG1 and PIP4K2A) may be prognostic biomarkers of time to recurrence of depressive and manic/mixed episodes among patients with bipolar affective disorder. Alleles of NC_000008.11:g.32614509_32614510del, rs61731109, and rs10508649 (also NRG1 and PIP4K2A) seem to be predictive biomarkers of response to pharmacological antidepressant treatment on the 28th day assessed by the HDRS-17 or CGI-I scale. In particular, the allele G of rs10508649 (PIP4K2A) may increase resistance to antidepressant treatment and be at the same time protective against recurrent manic/mixed episodes. These results support previous data indicating a biological link between resistance to antidepressant treatment and mania. Bioinformatic functional annotation of associated variants revealed possible impact for transcriptional regulation of PIP4K2A. In addition, the allele A of rs2248440 (HTR2C) may be a prognostic biomarker of depression severity. This allele decreases expression of the neighboring immune system gene IL13RA2 in the putamen according to the GTEx portal. The variant rs2248440 is near rs6318 (previously associated with depression and effects of psychotropic drugs) that is an eQTL for the same gene and tissue. Finally, the study points to several protein interactions relevant in the pathogenesis of mood disorders. Functional studies using cellular or animal models are warranted to support these results.
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Affiliation(s)
- Anastasia Levchenko
- Theodosius Dobzhansky Center for Genome Bioinformatics, Saint Petersburg State University, Saint Petersburg, Russia
| | - Natalia M Vyalova
- Tomsk National Research Medical Center, Mental Health Research Institute, Russian Academy of Sciences, Tomsk, Russia
| | - Timur Nurgaliev
- Institute of Translational Biomedicine, Saint Petersburg State University, Saint Petersburg, Russia
| | - Ivan V Pozhidaev
- Tomsk National Research Medical Center, Mental Health Research Institute, Russian Academy of Sciences, Tomsk, Russia
| | - German G Simutkin
- Tomsk National Research Medical Center, Mental Health Research Institute, Russian Academy of Sciences, Tomsk, Russia
| | - Nikolay A Bokhan
- Tomsk National Research Medical Center, Mental Health Research Institute, Russian Academy of Sciences, Tomsk, Russia.,National Research Tomsk State University, Tomsk, Russia.,Siberian State Medical University, Tomsk, Russia
| | - Svetlana A Ivanova
- Tomsk National Research Medical Center, Mental Health Research Institute, Russian Academy of Sciences, Tomsk, Russia.,Siberian State Medical University, Tomsk, Russia.,National Research Tomsk Polytechnic University, Tomsk, Russia
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Wang D, Tian HL, Cui X, Wang Q, Guo F, Zhang W, Tang QS. Effects of Jian-Pi-Zhi-Dong Decoction on the Expression of 5-HT and Its Receptor in a Rat Model of Tourette Syndrome and Comorbid Anxiety. Med Sci Monit 2020; 26:e924658. [PMID: 32738135 PMCID: PMC7416613 DOI: 10.12659/msm.924658] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2020] [Accepted: 05/13/2020] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND Anxiety is one of the common comorbidities of Tourette syndrome (TS). The serotonin (5-HT) system is involved in both TS and anxiety. Jian-pi-zhi-dong decoction (JPZDD) is widely used. However, the mechanism remains unknown. In this study, a rat model of TS and comorbid anxiety was used to evaluate the effect of JPZDD on 5-HT and its receptor. MATERIAL AND METHODS 48 rats were divided into 4 groups randomly (n=12). The model was established by empty water bottle stimulation plus iminodipropionitrile injection for 3 weeks. Then the control and model groups were gavaged with saline, while the treatment groups were gavaged with fluoxetine hydrochloride (Flx) or JPZDD. Body weights were measured, and behavioral tests were evaluated with stereotypy and elevated plus maze. The morphologic characters were observed by hematoxylin and eosin staining. The content of 5-HT was detected by enzyme-linked immunosorbent assay and high-performance liquid chromatography. The expression of 5-HT2C receptor was detected by western blot and quantitative polymerase chain reaction. RESULTS The stereotypy score was lower and the time spent in the open arm was longer in the JPZDD group compared with the model group. After the treatment of Flx or JPZDD, the structure of neurons became gradually normal and the cells were arranged neatly. The contents of 5-HT in the treatment groups were higher compared with the model group in the striatum. The expression of 5-HT2C mRNA in the striatum of JPZDD and Flx groups decreased compared with the model group, and the JPZDD group was lower than the Flx group. CONCLUSIONS JPZDD alleviated both tic and anxiety symptoms and the mechanism may be via reducing the expression of 5-HT2C mRNA in the striatum, increasing the concentration of 5-HT, and enhancing the activity of the 5-HT system, which in turn exerts neuro-inhibition.
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Affiliation(s)
- Dan Wang
- Department of Encephalopathy, The Third Affiliated Hospital of Beijing University of Chinese Medicine, Beijing, P.R. China
| | - Hui-ling Tian
- Acupuncture-Moxibustion and Tuina Institute, Beijing University of Chinese Medicine, Beijing, P.R. China
| | - Xia Cui
- Department of Pediatrics, The Third Affiliated Hospital of Beijing University of Chinese Medicine, Beijing, P.R. China
| | - Qian Wang
- Department of Pediatrics, The Third Affiliated Hospital of Beijing University of Chinese Medicine, Beijing, P.R. China
| | - Fan Guo
- Department of Pediatrics, The Third Affiliated Hospital of Beijing University of Chinese Medicine, Beijing, P.R. China
| | - Wen Zhang
- Department of Pediatrics, The Third Affiliated Hospital of Beijing University of Chinese Medicine, Beijing, P.R. China
| | - Qi-sheng Tang
- Department of Encephalopathy, The Third Affiliated Hospital of Beijing University of Chinese Medicine, Beijing, P.R. China
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De Deurwaerdère P, Bharatiya R, Chagraoui A, Di Giovanni G. Constitutive activity of 5-HT receptors: Factual analysis. Neuropharmacology 2020; 168:107967. [DOI: 10.1016/j.neuropharm.2020.107967] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 12/26/2019] [Accepted: 01/12/2020] [Indexed: 12/16/2022]
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50
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Gonçalves NGG, de Araújo JIF, Magalhães FEA, Mendes FRS, Lobo MDP, Moreira ACDOM, Moreira RDA. Protein fraction from Artocarpus altilis pulp exhibits antioxidant properties and reverses anxiety behavior in adult zebrafish via the serotoninergic system. J Funct Foods 2020. [DOI: 10.1016/j.jff.2019.103772] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
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