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McFarland MH, Morrow AL, Robinson DL. Allopregnanolone Regulation of Phasic Dopamine Release and Motivated Behavior. ACS Chem Neurosci 2025; 16:1860-1871. [PMID: 40343867 DOI: 10.1021/acschemneuro.4c00774] [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] [Indexed: 05/11/2025] Open
Abstract
Allopregnanolone, an endogenous neurosteroid that is a potent, positive allosteric modulator of γ-aminobutyric acid type A (GABAA) receptors, has emerged as a compound with considerable potential in the treatment of psychiatric disorders, including substance use disorders and postpartum depression. We previously demonstrated that allopregnanolone dose- and sex-dependently reduced electrically evoked dopamine release in the nucleus accumbens (NAc) of anesthetized male and female rats, which could indicate negative effects on motivation and reward processing. The present study investigated the effects of allopregnanolone on dopamine release and motivated behaviors in awake rats. Using fast-scan cyclic voltammetry, we found that 15 mg/kg allopregnanolone (IP) reduced the frequency of spontaneous dopamine transients in the NAc of freely moving male and female rats. Next, we observed that allopregnanolone (15 mg/kg, IP) produced a robust conditioned place preference in males and females, indicating that allopregnanolone's effects are not aversive despite fewer dopamine transients. Finally, using a sucrose self-administration task, we found that allopregnanolone (7.5 and 15 mg/kg, IP) did not significantly alter response rate, intertrial and interpress intervals, or trial latency in either sex, suggesting that allopregnanolone does not alter motivation or fast motor actions. These results clarify the regulation of dopamine neurotransmission and motivated behavior by allopregnanolone, which has clinical implications for its use as a therapeutic agent to treat various psychiatric disorders.
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Affiliation(s)
- Minna H McFarland
- Bowles Center for Alcohol Studies, Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
| | - A Leslie Morrow
- Bowles Center for Alcohol Studies, Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
| | - Donita L Robinson
- Bowles Center for Alcohol Studies, Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
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Zhou L, Saltoun K, Carrier J, Storch KF, Dunbar RIM, Bzdok D. Multimodal population study reveals the neurobiological underpinnings of chronotype. Nat Hum Behav 2025:10.1038/s41562-025-02182-w. [PMID: 40246996 DOI: 10.1038/s41562-025-02182-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Accepted: 03/14/2025] [Indexed: 04/19/2025]
Abstract
The rapid shifts in society have altered human behavioural patterns, with increased evening activities, increased screen time and changed sleep schedules. As an explicit manifestation of circadian rhythms, chronotype is closely intertwined with physical and mental health. Night owls often exhibit unhealthier lifestyle habits, are more susceptible to mood disorders and have poorer physical fitness compared with early risers. Although individual differences in chronotype yield varying consequences, their neurobiological underpinnings remain elusive. Here we conducted a pattern-learning analysis with three brain-imaging modalities (grey matter volume, white-matter integrity and functional connectivity) and capitalized on 976 phenotypes in 27,030 UK Biobank participants. The resulting multilevel analysis reveals convergence on the basal ganglia, limbic system, hippocampus and cerebellum. The pattern derived from modelling actigraphy wearables data of daily movement further highlighted these key brain features. Overall, our population-level study comprehensively investigates chronotype, emphasizing its close connections with habit formation, reward processing and emotional regulation.
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Affiliation(s)
- Le Zhou
- TheNeuro - Montreal Neurological Institute (MNI), Department of Biomedical Engineering, McGill University, Montreal, Quebec, Canada
- Mila - Quebec Artificial Intelligence Institute, Montreal, Quebec, Canada
| | - Karin Saltoun
- TheNeuro - Montreal Neurological Institute (MNI), Department of Biomedical Engineering, McGill University, Montreal, Quebec, Canada
- Mila - Quebec Artificial Intelligence Institute, Montreal, Quebec, Canada
| | - Julie Carrier
- Department of Psychology, Université de Montréal, Montreal, Quebec, Canada
- Center for Advanced Research in Sleep Medicine, Research center of the Centre intégré universitaire de santé et de services sociaux du Nord de l'Île-de-Montréal, Montreal, Quebec, Canada
| | - Kai-Florian Storch
- Department of Psychiatry, McGill University, Montreal, Quebec, Canada
- Douglas Mental Health University Institute, McGill University, Montreal, Quebec, Canada
| | - Robin I M Dunbar
- Department of Experimental Psychology, University of Oxford, Oxford, UK
| | - Danilo Bzdok
- TheNeuro - Montreal Neurological Institute (MNI), Department of Biomedical Engineering, McGill University, Montreal, Quebec, Canada.
- Mila - Quebec Artificial Intelligence Institute, Montreal, Quebec, Canada.
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3
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Shi Z, Wen K, Sammudin NH, LoRocco N, Zhuang X. Erasing "bad memories": reversing aberrant synaptic plasticity as therapy for neurological and psychiatric disorders. Mol Psychiatry 2025:10.1038/s41380-025-03013-0. [PMID: 40210977 DOI: 10.1038/s41380-025-03013-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Revised: 02/24/2025] [Accepted: 04/02/2025] [Indexed: 04/12/2025]
Abstract
Dopamine modulates corticostriatal plasticity in both the direct and indirect pathways of the cortico-striato-thalamo-cortical (CSTC) loops. These gradual changes in corticostriatal synaptic strengths produce long-lasting changes in behavioral responses. Under normal conditions, these mechanisms enable the selection of the most appropriate responses while inhibiting others. However, under dysregulated dopamine conditions, including a lack of dopamine release or dopamine signaling, these mechanisms could lead to the selection of maladaptive responses and/or the inhibition of appropriate responses in an experience-dependent and task-specific manner. In this review, we propose that preventing or reversing such maladaptive synaptic strengths and erasing such aberrant "memories" could be a disease-modifying therapeutic strategy for many neurological and psychiatric disorders. We review evidence from Parkinson's disease, drug-induced parkinsonism, L-DOPA-induced dyskinesia, obsessive-compulsive disorder, substance use disorders, and depression as well as research findings on animal disease models. Altogether, these studies allude to an emerging theme in translational neuroscience and promising new directions for therapy development. Specifically, we propose that combining pharmacotherapy with behavioral therapy or with deep brain stimulation (DBS) could potentially cause desired changes in specific neural circuits. If successful, one important advantage of correcting aberrant synaptic plasticity is long-lasting therapeutic effects even after treatment has ended. We will also discuss the potential molecular targets for these therapeutic approaches, including the cAMP pathway, proteins involved in synaptic plasticity as well as pathways involved in new protein synthesis. We place special emphasis on RNA binding proteins and epitranscriptomic mechanisms, as they represent a new frontier with the distinct advantage of rapidly and simultaneously altering the synthesis of many proteins locally.
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Affiliation(s)
- Zhuoyue Shi
- The Committee on Genetics, Genomics and Systems Biology, The University of Chicago, Chicago, IL, 60637, USA
| | - Kailong Wen
- The Committee on Neurobiology, The University of Chicago, Chicago, IL, 60637, USA
| | - Nabilah H Sammudin
- The Committee on Neurobiology, The University of Chicago, Chicago, IL, 60637, USA
| | - Nicholas LoRocco
- The Interdisciplinary Scientist Training Program, The University of Chicago, Chicago, IL, 60637, USA
| | - Xiaoxi Zhuang
- The Department of Neurobiology, The University of Chicago, Chicago, IL, 60637, USA.
- The Neuroscience Institute, The University of Chicago, Chicago, IL, 60637, USA.
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Zhao ZW, Wang YC, Chen PC, Tzeng SF, Chen PS, Kuo YM. Dopamine D1 receptor agonist alleviates post-weaning isolation-induced neuroinflammation and depression-like behaviors in female mice. BEHAVIORAL AND BRAIN FUNCTIONS : BBF 2025; 21:6. [PMID: 40065395 PMCID: PMC11895232 DOI: 10.1186/s12993-025-00269-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Accepted: 02/24/2025] [Indexed: 03/14/2025]
Abstract
BACKGROUND Major depressive disorder is a significant global cause of disability, particularly among adolescents. The dopamine system and nearby neuroinflammation, crucial for regulating mood and processing rewards, are central to the frontostriatal circuit, which is linked to depression. This study aimed to investigate the effect of post-weaning isolation (PWI) on depression in adolescent mice, with a focus on exploring the involvement of microglia and dopamine D1 receptor (D1R) in the frontostriatal circuit due to their known links with mood disorders. RESULTS Adolescent mice underwent 8 weeks of PWI before evaluating their depression-like behaviors and the activation status of microglia in the frontostriatal regions. Selective D1-like dopamine receptor agonist SKF-81,297 was administered into the medial prefrontal cortex (mPFC) of PWI mice to assess its antidepressant and anti-microglial activation properties. The effects of SKF-81,297 on inflammatory signaling pathways were examined in BV2 microglial cells. After 8 weeks of PWI, female mice exhibited more severe depression-like behaviors than males, with greater microglial activation in the frontostriatal regions. Microglial activation in mPFC was the most prominent among the three frontostriatal regions examined, and it was positively correlated with the severity of depression-like behaviors. Female PWI mice exhibited increased expression of dopamine D2 receptors (D2R). SKF-81,297 treatment alleviated depression-like behaviors and local microglial activation induced by PWI; however, SKF-81,297 induced these alterations in naïve mice. In vitro, SKF-81,297 decreased pro-inflammatory cytokine release and phosphorylations of JNK and ERK induced by lipopolysaccharide, while in untreated BV2 cells, SKF-81,297 elicited inflammation. CONCLUSIONS This study highlights a sex-specific susceptibility to PWI-induced neuroinflammation and depression. While targeting the D1R shows potential in alleviating PWI-induced changes, further investigation is required to evaluate potential adverse effects under normal conditions.
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Affiliation(s)
- Zi-Wei Zhao
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan
| | - Yun-Chen Wang
- Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan
| | - Pei-Chun Chen
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan
- Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan
| | - Shun-Fen Tzeng
- Department of Life Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, 70101, Taiwan
| | - Po-See Chen
- Department of Psychiatry, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, 70101, Taiwan
- Institute of Behavioral Medicine, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan
| | - Yu-Min Kuo
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan.
- Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan.
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Jalilian-Khave L, Kitaneh R, Ysrayl BB, Borelli A, Funaro MC, Potenza MN, Angarita GA. Potential roles for vitamin D in preventing and treating impulse control disorders, behavioral addictions, and substance use disorders: A scoping review. ADDICTION NEUROSCIENCE 2025; 14:100190. [PMID: 40083958 PMCID: PMC11902922 DOI: 10.1016/j.addicn.2024.100190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/16/2025]
Abstract
Vitamin D deficiency is a problem of endemic proportions. Vitamin D is a major regulator of dopaminergic and serotonergic circuits, pathways implicated in addictive disorders. This scoping review (OSF registered as 67yhb) examines preclinical and clinical studies exploring relationships between vitamin D in impulse control disorders, behavioral addictions, and substance use disorders. We searched Ovid MEDLINE, Embase, APA PsycInfo, Cochrane Library, Web of Science, and Scopus databases. We extracted and summarized quantitative and qualitative data through a narrative synthesis and assessed the quality of studies using the Joanna Briggs Institute (JBI) and SYRCLE (Systematic Review Centre for Laboratory Animal Experimentation) criteria. Of 5,442 initial records identified, 28 preclinical and clinical studies were included. For most conditions, we found a negative relationship between vitamin D levels and symptom presence and/or severity. While data suggest a potential beneficial effect of vitamin D on preventing or treating these conditions, there were significant limitations identified by the JBI and SYRCLE assessments. Future studies should include impulse control disorders and other under-explored conditions, address heterogeneity regarding forms, doses, and duration of exposures to vitamin D, and explore vitamin D's potential therapeutic mechanisms.
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Affiliation(s)
- Laya Jalilian-Khave
- Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA
- Department of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, CT, 06520, USA
| | - Razi Kitaneh
- Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA
- Clinical Neuroscience Research Unit, Connecticut Mental Health Center, 34 Park Street, New Haven, CT, 06519, USA
- Connecticut Mental Health Center, 34 Park Street, New Haven, CT, 06519, USA
| | - Binah Baht Ysrayl
- Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA
- Department of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, CT, 06520, USA
- Clinical Neuroscience Research Unit, Connecticut Mental Health Center, 34 Park Street, New Haven, CT, 06519, USA
- Connecticut Mental Health Center, 34 Park Street, New Haven, CT, 06519, USA
| | - Anna Borelli
- Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA
- Clinical Neuroscience Research Unit, Connecticut Mental Health Center, 34 Park Street, New Haven, CT, 06519, USA
- Connecticut Mental Health Center, 34 Park Street, New Haven, CT, 06519, USA
| | - Melissa C. Funaro
- Harvey Cushing/John Hay Whitney Medical Library, Yale University, New Haven, CT, USA
| | - Marc N. Potenza
- Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA
- Clinical Neuroscience Research Unit, Connecticut Mental Health Center, 34 Park Street, New Haven, CT, 06519, USA
- Child Study Center, Yale University School of Medicine, New Haven, CT, 06510, USA
- Department of Neuroscience, Yale University, New Haven, CT, 06510, USA
- Connecticut Council On Problem Gambling, Wethersfield, CT, 06109, USA
- Wu Tsai Institute, Yale University, New Haven, CT, 06510, USA
| | - Gustavo A. Angarita
- Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA
- Clinical Neuroscience Research Unit, Connecticut Mental Health Center, 34 Park Street, New Haven, CT, 06519, USA
- Connecticut Mental Health Center, 34 Park Street, New Haven, CT, 06519, USA
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Slifstein M, Qu W, Gil R, Weinstein JJ, Perlman G, Jaworski-Calara T, Meng J, Hu B, Moeller SJ, Horga G, Abi-Dargham A. Kappa opioid receptor availability predicts severity of anhedonia in schizophrenia. Neuropsychopharmacology 2024; 49:2087-2093. [PMID: 39217267 PMCID: PMC11480413 DOI: 10.1038/s41386-024-01975-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Revised: 07/31/2024] [Accepted: 08/20/2024] [Indexed: 09/04/2024]
Abstract
The kappa opioid receptor (KOR) and its endogenous agonist dynorphin have been implicated in multiple psychiatric conditions including psychotic disorders. We tested the hypotheses that kappa expression is elevated and associated with psychotic symptoms in schizophrenia. We measured kappa expression in unmedicated patients with schizophrenia (7 female, 6 male) and matched controls (7 female, 6 male) with positron emission tomography (PET). We also acquired a measurement of cumulative dopamine activity over the life span in the same subjects using neuromelanin sensitive MRI. We hypothesized that neuromelanin accumulation would be higher in patients than controls and that in patients there would be a positive association between KOR availability and neuromelanin accumulation. Fourteen patients and thirteen controls were enrolled. Whole brain dynamic PET imaging data using the KOR selective tracer [18F]LY245998 were acquired. Distribution volume (VT) was measured with region of interest analysis in 14 brain regions. Neuromelanin accumulation in midbrain dopaminergic nuclei was assessed in the same subjects. Positive and negative symptoms were measured by a clinical psychologist. We did not observe group level differences in KOR expression, neuromelanin accumulation or relationships of these to positive symptoms. Unexpectedly, we did observe strong positive associations between KOR expression and symptoms of anhedonia in the patients (Pearson r > 0.7, uncorrected p < 0.01 in 8 cortical brain regions). We also observed moderate associations between KOR expression and neuromelanin levels in patients. In conclusion, we did not observe a relationship between kappa and symptoms of psychosis but the observed relationship to the negative symptom of anhedonia is in line with recent work testing kappa antagonism as a therapy for anhedonia in depression.
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Affiliation(s)
- Mark Slifstein
- Renaissance School of Medicine, Stony Brook University, Stony Brook, New York, USA.
| | - Wenchao Qu
- Renaissance School of Medicine, Stony Brook University, Stony Brook, New York, USA
| | - Roberto Gil
- Renaissance School of Medicine, Stony Brook University, Stony Brook, New York, USA
| | - Jodi J Weinstein
- Renaissance School of Medicine, Stony Brook University, Stony Brook, New York, USA
| | - Greg Perlman
- Renaissance School of Medicine, Stony Brook University, Stony Brook, New York, USA
| | | | - Jiayan Meng
- Renaissance School of Medicine, Stony Brook University, Stony Brook, New York, USA
| | - Bao Hu
- Renaissance School of Medicine, Stony Brook University, Stony Brook, New York, USA
| | - Scott J Moeller
- Renaissance School of Medicine, Stony Brook University, Stony Brook, New York, USA
| | - Guillermo Horga
- Vagelos College of Physicians and Surgeons, Columbia University, Stony Brook, New York, USA
- New York State Psychiatric Institute, Stony Brook, New York, USA
| | - Anissa Abi-Dargham
- Renaissance School of Medicine, Stony Brook University, Stony Brook, New York, USA
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7
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Mao Q, Wang J, Yang Z, Ding R, Lv S, Ji X. The Pathologic Roles and Therapeutic Implications of Ghrelin/GHSR System in Mental Disorders. Depress Anxiety 2024; 2024:5537319. [PMID: 40226675 PMCID: PMC11919235 DOI: 10.1155/2024/5537319] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Revised: 10/16/2024] [Accepted: 10/21/2024] [Indexed: 04/15/2025] Open
Abstract
Ghrelin is a hormone consisting of 28 amino acids. Growth hormone secretagogue receptor (GHSR) is a receptor for ghrelin, which is expressed in the brain, pituitary gland, and adrenal glands, especially in the hypothalamus. The binding of ghrelin to the receptor 1a subtype mediates most of the biological effects of ghrelin. Ghrelin has a close relationship with the onset of psychosis. Ghrelin can affect the onset of psychosis by regulating neurotransmitters such as dopamine, γ-aminobutyric acid (GABA), and 5-hydroxytryptamine (5-HT) through the hypothalamus-pituitary-adrenal (HPA) axis, brain-gut axis, the mesolimbic dopamine system, and other ways. Ghrelin activates neuropeptide Y (NPY) in the hypothalamic arcuate nucleus (ARC) through the GHSR. Ghrelin binds to neurons in the ventral tegmental area (VTA), where it promotes the activity of dopamine neurons in the nucleus accumbens (NAcs) in a GHSR-dependent way, increasing dopamine levels and the reward system. This article summarized the recent research progress of ghrelin in depression, anxiety, schizophrenia, anorexia nervosa (AN), and bulimia nervosa (BN), and emphasized its potential application for psychiatric disorders treatment.
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Affiliation(s)
- Qianshuo Mao
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng 475004, Henan, China
| | - Jinjia Wang
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng 475004, Henan, China
| | - Zihan Yang
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng 475004, Henan, China
| | - Ruidong Ding
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng 475004, Henan, China
| | - Shuangyu Lv
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng 475004, Henan, China
- Department of Neurosurgery, The First Affiliated Hospital of Henan University, Henan University, Kaifeng 475001, Henan, China
| | - Xinying Ji
- Faculty of Basic Medical Subjects, Shu-Qing Medical College of Zhengzhou, 6 Gong-Ming Road, Mazhai Town, Erqi District, Zhengzhou 450064, Henan, China
- Department of Medicine, Huaxian County People's Hospital, Huaxian 456400, Henan, China
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D'Aquila PS. Licking microstructure in response to novel rewards, reward devaluation and dopamine antagonists: Possible role of D1 and D2 medium spiny neurons in the nucleus accumbens. Neurosci Biobehav Rev 2024; 165:105861. [PMID: 39159734 DOI: 10.1016/j.neubiorev.2024.105861] [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: 06/03/2024] [Revised: 07/29/2024] [Accepted: 08/16/2024] [Indexed: 08/21/2024]
Abstract
Evidence on the effect of dopamine D1 and D2-like antagonists and of manipulations of reward value on licking microstructure is reanalysed considering recent findings on the role of nucleus accumbens (NAc) medium spiny neurons (MSNs) in the control of sugar intake. The results of this analysis suggest that D1 MSN activation, which is involved in the emission of licking bursts, might play a crucial role in response to novel rewards. D2 MSN activation, which results in reduction of burst size and suppression of licking, might mediate the response to reward devaluation. Elucidating the neural mechanisms underlying the licking response might lead to a better definition of its microstructural measures in behaviourally and psychologically meaningful functional terms. This could further support its use as a behavioural substrate in the study of the neural mechanisms of ingestive behaviour and motivation, as well as in animal models of pathological conditions such as eating disorders and obesity.
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Affiliation(s)
- Paolo S D'Aquila
- Dipartimento di Scienze Biomediche, Università di Sassari, Viale S. Pietro 43/b, Sassari 07100, Italy.
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9
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Steiner AM, Roscoe RF, Booze RM, Mactutus CF. Motivational dysregulation with melanocortin 4 receptor haploinsufficiency. NEUROIMMUNE PHARMACOLOGY AND THERAPEUTICS 2024; 3:237-250. [PMID: 39741559 PMCID: PMC11683877 DOI: 10.1515/nipt-2024-0011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/19/2024] [Accepted: 10/18/2024] [Indexed: 01/03/2025]
Abstract
Obesity, by any standard, is a global health crisis. Both genetic and dietary contributions to the development and maintenance of obesity were integral factors of our experimental design. As mutations of the melanocortin 4 receptors (MC4R) are the leading monogenetic cause of obesity, MC4R haploinsufficient rats were fed a range of dietary fat (0-12 %) in a longitudinal design. Physiological and motivational assessments were performed using a locomotor task, a 5-choice sucrose preference task, an operant task with fixed and progressive ratios, as well as a distraction operant task. Dendritic spine morphology of medium spiny neurons (MSNs) of the nucleus accumbens (NAc), cells with ample D1 and D2 receptors, was also assessed. The percentage of lipid deposits in the liver of each rat was also analyzed using the Area Fraction Fractionator probe for stereological measurements. MC4R haploinsufficiency resulted in a phenotypic resemblance for adult-onset obesity that was exacerbated by the consumption of a high-fat diet. Results from the operant tasks indicate that motivational deficits due to MC4R haploinsufficiency were apparent prior to the onset of obesity and exacerbated by dietary fat consumption after obesity was well established. Moreover, MSN morphology shifted to longer spines with smaller head diameters for the MC4R+/- animals under the high-fat diet, suggesting a potential mechanism for the dysregulation of motivation to work for food. Increasing our knowledge of the neural circuitry/mechanisms responsible for the rewarding properties of food has significant implications for understanding energy balance and the development of obesity.
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Affiliation(s)
- Alex M. Steiner
- Cognitive and Neural Science Program, Department of Psychology, Barnwell College, University of South Carolina, Columbia, SC, USA
| | - Robert F. Roscoe
- Cognitive and Neural Science Program, Department of Psychology, Barnwell College, University of South Carolina, Columbia, SC, USA
| | - Rosemarie M. Booze
- Cognitive and Neural Science Program, Department of Psychology, Barnwell College, University of South Carolina, Columbia, SC, USA
| | - Charles F. Mactutus
- Cognitive and Neural Science Program, Department of Psychology, Barnwell College, University of South Carolina, Columbia, SC, USA
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10
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Bruns Vi N, Tressler EH, Vendruscolo LF, Leggio L, Farokhnia M. IUPHAR review - Glucagon-like peptide-1 (GLP-1) and substance use disorders: An emerging pharmacotherapeutic target. Pharmacol Res 2024; 207:107312. [PMID: 39032839 PMCID: PMC11467891 DOI: 10.1016/j.phrs.2024.107312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Revised: 07/10/2024] [Accepted: 07/15/2024] [Indexed: 07/23/2024]
Abstract
Addiction is a chronic relapsing disease with high morbidity and mortality. Treatments for addiction include pharmacological and psychosocial interventions; however, currently available medications are limited in number and efficacy. The glucagon-like-peptide-1 (GLP-1) system is emerging as a potential novel pharmacotherapeutic target for alcohol and other substance use disorders (ASUDs). In this review, we summarize and discuss the wealth of available evidence from testing GLP-1 receptor (GLP-1R) agonist medications in preclinical models and humans with ASUDs, possible mechanisms underlying the impact of GLP-1R agonists on alcohol/substance use, gaps in knowledge, and future directions. Most of the research with GLP-1R agonists has been conducted in relation to alcohol use; psychostimulants, opioids, and nicotine have also been investigated. Preclinical evidence suggests that GLP-1R agonists reduce alcohol/substance use and other related outcomes. The main proposed mechanisms are related to reward processing, stress, and cognitive function, as well as broader mechanisms related to satiety, changes in gastric motility, and glucose homeostasis. More in-depth mechanistic studies are warranted. Clinical studies have been limited and their findings have been less conclusive; however, most support the safety and potential efficacy of GLP-1R agonists in ASUD treatment. Identifying preferred compounds, as well as possible subgroups who are most responsive to GLP-1R agonists are some of the key research questions to translate the promising preclinical data into clinical settings. Several clinical trials are underway to test GLP-1R agonists in people with ASUDs.
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Affiliation(s)
- Nicolaus Bruns Vi
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, National Institutes of Health, Baltimore, MD, USA; Neurobiology of Addiction Section, Integrative Neuroscience Research Branch, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, MD, USA; Stress & Addiction Neuroscience Unit, Integrative Neuroscience Research Branch, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, National Institutes of Health, Baltimore, MD, USA
| | - Elizabeth H Tressler
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, National Institutes of Health, Baltimore, MD, USA; Neurobiology of Addiction Section, Integrative Neuroscience Research Branch, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, MD, USA; Stress & Addiction Neuroscience Unit, Integrative Neuroscience Research Branch, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, National Institutes of Health, Baltimore, MD, USA
| | - Leandro F Vendruscolo
- Stress & Addiction Neuroscience Unit, Integrative Neuroscience Research Branch, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, National Institutes of Health, Baltimore, MD, USA
| | - Lorenzo Leggio
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, National Institutes of Health, Baltimore, MD, USA.
| | - Mehdi Farokhnia
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, National Institutes of Health, Baltimore, MD, USA.
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11
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Nelson CA, Brundage JN, Williams BM, Baldridge JK, Stockard AL, Bassett CH, Burger BJ, Gunter BT, Payne AJ, Yorgason JT, Steffensen SC, Bills KB. Voluntary Exercise Ameliorates Chronic Ethanol Withdrawal-Induced Adaptations of Opioid Receptor Expression in the Nucleus Accumbens, Dopamine Release, and Ethanol Consumption. Biomedicines 2024; 12:1593. [PMID: 39062166 PMCID: PMC11274624 DOI: 10.3390/biomedicines12071593] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 07/05/2024] [Accepted: 07/14/2024] [Indexed: 07/28/2024] Open
Abstract
Exercise has increasingly been recognized as an adjunctive therapy for alcohol-use disorder (AUD), yet our understanding of its underlying neurological mechanisms remains limited. This knowledge gap impedes the development of evidence-based exercise guidelines for AUD treatment. Chronic ethanol (EtOH) exposure has been shown to upregulate and sensitize kappa opioid receptors (KORs) in the nucleus accumbens (NAc), which is innervated by dopamine (DA) neurons in the midbrain ventral tegmental area (VTA), which may contribute to AUD-related behaviors. In this study, we investigated the impact of voluntary exercise in EtOH-dependent mice on EtOH consumption, KOR and delta opioid receptor (DOR) expression in the NAc and VTA, and functional effects on EtOH-induced alterations in DA release in the NAc. Our findings reveal that voluntary exercise reduces EtOH consumption, reduces KOR and enhances DOR expression in the NAc, and modifies EtOH-induced adaptations in DA release, suggesting a competitive interaction between exercise-induced and EtOH-induced alterations in KOR expression. We also found changes to DOR expression in the NAc and VTA with voluntary exercise but no significant changes to DA release. These findings elucidate the complex interplay of AUD-related neurobiological processes, highlighting the potential for exercise as a therapeutic intervention for AUD.
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Affiliation(s)
- Christina A. Nelson
- Department of Biomedical Sciences, Noorda College of Osteopathic Medicine, Provo, UT 84606, USA; (C.A.N.); (K.B.B.)
| | - James N. Brundage
- Department of Psychology/Neuroscience, Brigham Young University, Provo, UT 84602, USA (J.K.B.); (A.L.S.)
| | - Benjamin M. Williams
- Department of Psychology/Neuroscience, Brigham Young University, Provo, UT 84602, USA (J.K.B.); (A.L.S.)
| | - Jared K. Baldridge
- Department of Psychology/Neuroscience, Brigham Young University, Provo, UT 84602, USA (J.K.B.); (A.L.S.)
| | - Alyssa L. Stockard
- Department of Psychology/Neuroscience, Brigham Young University, Provo, UT 84602, USA (J.K.B.); (A.L.S.)
| | - Charlton H. Bassett
- Department of Psychology/Neuroscience, Brigham Young University, Provo, UT 84602, USA (J.K.B.); (A.L.S.)
| | - Brandon J. Burger
- Department of Biomedical Sciences, Noorda College of Osteopathic Medicine, Provo, UT 84606, USA; (C.A.N.); (K.B.B.)
| | - Bridger T. Gunter
- Department of Biomedical Sciences, Noorda College of Osteopathic Medicine, Provo, UT 84606, USA; (C.A.N.); (K.B.B.)
| | - Andrew J. Payne
- Department of Biomedical Sciences, Noorda College of Osteopathic Medicine, Provo, UT 84606, USA; (C.A.N.); (K.B.B.)
| | - Jordan T. Yorgason
- Department of Psychology/Neuroscience, Brigham Young University, Provo, UT 84602, USA (J.K.B.); (A.L.S.)
| | - Scott C. Steffensen
- Department of Biomedical Sciences, Noorda College of Osteopathic Medicine, Provo, UT 84606, USA; (C.A.N.); (K.B.B.)
- Department of Psychology/Neuroscience, Brigham Young University, Provo, UT 84602, USA (J.K.B.); (A.L.S.)
| | - Kyle B. Bills
- Department of Biomedical Sciences, Noorda College of Osteopathic Medicine, Provo, UT 84606, USA; (C.A.N.); (K.B.B.)
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12
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D'Aquila PS. Dopamine, activation of ingestion and evaluation of response efficacy: a focus on the within-session time-course of licking burst number. Psychopharmacology (Berl) 2024; 241:1111-1124. [PMID: 38702473 PMCID: PMC11106101 DOI: 10.1007/s00213-024-06600-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Accepted: 04/24/2024] [Indexed: 05/06/2024]
Abstract
RATIONALE Evidence on the effect of dopamine D1-like and D2-like receptor antagonists on licking microstructure and the forced swimming response led us to suggest that (i) dopamine on D1-like receptors plays a role in activating reward-directed responses and (ii) the level of response activation is reboosted based on a process of evaluation of response efficacy requiring dopamine on D2-like receptors. A main piece of evidence in support of this hypothesis is the observation that the dopamine D2-like receptor antagonist raclopride induces a within-session decrement of burst number occurring after the contact with the reward. The few published studies with a detailed analysis of the time-course of this measure were conducted in our laboratory. OBJECTIVES The aim of this review is to recapitulate and discuss the evidence in support of the analysis of the within-session burst number as a behavioural substrate for the study of the mechanisms governing ingestion, behavioural activation and the related evaluation processes, and its relevance in the analysis of drug effects on ingestion. CONCLUSIONS The evidence gathered so far suggests that the analysis of the within-session time-course of burst number provides an important behavioural substrate for the study of the mechanisms governing ingestion, behavioural activation and the related evaluation processes, and might provide decisive evidence in the analysis of the effects of drugs on ingestion. However, further evidence from independent sources is necessary to validate the use and the proposed interpretation of this measure.
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Affiliation(s)
- Paolo S D'Aquila
- Dipartimento di Scienze Biomediche, Università di Sassari, Viale S. Pietro 43/b, Sassari, 07100, Italy.
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13
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Liu C, Filbey FM. Unlocking the age-old secrets of reward and substance use. Pharmacol Biochem Behav 2024; 239:173766. [PMID: 38604456 DOI: 10.1016/j.pbb.2024.173766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 03/25/2024] [Accepted: 04/08/2024] [Indexed: 04/13/2024]
Abstract
Although substance use is widespread across the lifespan from early adolescence to older adulthood, the prevalence of substance use disorder (SUD) differs between age groups. These age differences in SUD rates necessitate an investigation into how age moderates reward sensitivity, and consequently influences the risks and consequences related to substance use. This theoretical review integrates evidence from the literature to address the dynamic interplay between age and reward in the context of substance use. Overall, increasing evidence demonstrates that age moderates reward sensitivity and underlying reward system neurobiology. Reward sensitivity undergoes a non-linear trajectory across the lifespan. Low levels of reward sensitivity are associated with childhood and late adulthood. In contrast, high levels are associated with early to late adolescence, followed by a decline in the twenties. These fluctuations in reward sensitivity across the lifespan contribute to complex associations with substance use. This lends support to adolescence and young adulthood as vulnerable periods for the risk of subsequent SUD. More empirical research is needed to investigate reward sensitivity during SUD maintenance and recovery. Future research should also involve larger sample sizes and encompass a broader range of age groups, including older adults.
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Affiliation(s)
- Che Liu
- School of Behavioral and Brain Sciences, The University of Texas at Dallas, Dallas, TX 75235, United States of America.
| | - Francesca M Filbey
- School of Behavioral and Brain Sciences, The University of Texas at Dallas, Dallas, TX 75235, United States of America
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14
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Adam AS, LaMalfa KS, Razavi Y, Kohut SJ, Kangas BD. A Multimodal Preclinical Assessment of MDMA in Female and Male Rats: Prohedonic, Cognition Disruptive, and Prosocial Effects. PSYCHEDELIC MEDICINE (NEW ROCHELLE, N.Y.) 2024; 2:96-108. [PMID: 39149579 PMCID: PMC11324000 DOI: 10.1089/psymed.2023.0049] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/17/2024]
Abstract
Background Frontline antidepressants such as selective serotonin reuptake inhibitors (SSRIs) leave many patients with unmet treatment needs. Moreover, even when SSRIs reduce depressive symptoms, anhedonia, the loss of pleasure to previously rewarding activities, often remains unabated. This state of affairs is disheartening and calls for the development of medications to more directly treat anhedonia. The atypical psychedelic 3,4-methylenedioxymethamphetamine (MDMA) might have promise as a prohedonic medication given its efficacious applications for treatment-resistant post-traumatic stress disorder and comorbid depression. However, in addition to its prosocial effects as an entactogen, MDMA is also associated with neurotoxic cognitive deficits. The present studies were designed to examine the relative potency of MDMA in female and male rats across three distinct behavioral domains to assist in defining a preclinical profile of MDMA as a candidate prohedonic therapeutic. Methods First, signal detection metrics of reward responsivity were examined using the touchscreen probabilistic reward task (PRT), a reverse-translated assay used to objectively quantify anhedonic phenotypes in humans. Second, to probe potential cognitive deficits, touchscreen-based assays of psychomotor vigilance and delayed matching-to-position were used to examine attentional processes and short-term spatial memory, respectively. Finally, MDMA's entactogenic effects were studied via pairwise assessments of social interaction facilitated by machine-learning analyses. Results Findings show (1) dose-dependent increases in reward responsivity as quantified by the PRT, (2) dose-dependent deficits in attention and short-term memory, and (3) dose-dependent increases in aspects of prosocial interaction in male but not female subjects. Neither the desirable (prohedonic) nor undesirable (cognition disruptive) effects of MDMA persisted beyond 24 h. Conclusions The present results characterize MDMA as a promising prohedonic treatment, notwithstanding some liability for short-lived cognitive impairment following acute administration.
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Affiliation(s)
- Abshir S. Adam
- Harvard Medical School, McLean Hospital, Belmont, Massachusetts, USA
| | | | - Yasaman Razavi
- Harvard Medical School, McLean Hospital, Belmont, Massachusetts, USA
| | - Stephen J. Kohut
- Harvard Medical School, McLean Hospital, Belmont, Massachusetts, USA
| | - Brian D. Kangas
- Harvard Medical School, McLean Hospital, Belmont, Massachusetts, USA
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15
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Yu R, Kong DL, Liao C, Yu YJ, He ZW, Wang Y. Natural products as the therapeutic strategies for addiction. Biomed Pharmacother 2024; 175:116687. [PMID: 38701568 DOI: 10.1016/j.biopha.2024.116687] [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: 01/29/2024] [Revised: 04/25/2024] [Accepted: 04/29/2024] [Indexed: 05/05/2024] Open
Abstract
World Drug Report 2023 concluded that 296 million people abused drugs, 39.5 million became addiction and 494,000 died as a direct or indirect result of addiction. Addiction has become a growing problem that affects individuals, their families, societies, countries and even the world. However, treatment for addiction is only limited to some developed countries because of the high cost, difficult implementation, and time consuming. Therefore, there is an urgent need to develop a low-cost, effective drug for the development of addiction treatment in more countries, which is essential for the stability and sustainable development of the world. In this review, it provided an overview of the abuse of common addictive drugs, related disorders, and current therapeutic regimen worldwide, and summarized the mechanisms of drug addiction as reward circuits, neuroadaptation and plasticity, cognitive decision-making, genetics, and environment. According to their chemical structure, 43 natural products and 5 herbal combinations with potential to treat addiction were classified, and their sources, pharmacological effects and clinical trials were introduced. It was also found that mitragine, ibogine, L-tetrahydropalmatine and crocin had greater potential for anti-addiction.
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Affiliation(s)
- Rui Yu
- Department of Clinical Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning, China
| | - De-Lei Kong
- Department of Respiratory and Critical Care Medicine, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Cai Liao
- Department of Clinical Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning, China
| | - Ya-Jie Yu
- Department of Clinical Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning, China
| | - Zhen-Wei He
- Department of Neurology, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China.
| | - Yun Wang
- Department of Clinical Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning, China.
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16
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Murata K, Maegawa A, Imoto Y, Fujieda S, Fukazawa Y. Endogenous opioids in the olfactory tubercle and their roles in olfaction and quality of life. Front Neural Circuits 2024; 18:1408189. [PMID: 38872907 PMCID: PMC11170707 DOI: 10.3389/fncir.2024.1408189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Accepted: 05/06/2024] [Indexed: 06/15/2024] Open
Abstract
Olfactory dysfunctions decrease daily quality of life (QOL) in part by reducing the pleasure of eating. Olfaction plays an essential role in flavor sensation and palatability. The decreased QOL due to olfactory dysfunction is speculated to result from abnormal neural activities in the olfactory and limbic areas of the brain, as well as peripheral odorant receptor dysfunctions. However, the specific underlying neurobiological mechanisms remain unclear. As the olfactory tubercle (OT) is one of the brain's regions with high expression of endogenous opioids, we hypothesize that the mechanism underlying the decrease in QOL due to olfactory dysfunction involves the reduction of neural activity in the OT and subsequent endogenous opioid release in specialized subregions. In this review, we provide an overview and recent updates on the OT, the endogenous opioid system, and the pleasure systems in the brain and then discuss our hypothesis. To facilitate the effective treatment of olfactory dysfunctions and decreased QOL, elucidation of the neurobiological mechanisms underlying the pleasure of eating through flavor sensation is crucial.
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Affiliation(s)
- Koshi Murata
- Division of Brain Structure and Function, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
- Life Science Innovation Center, University of Fukui, Fukui, Japan
| | - Ayako Maegawa
- Division of Brain Structure and Function, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
- Life Science Innovation Center, University of Fukui, Fukui, Japan
- Department of Otorhinolaryngology-Head and Neck Surgery, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Yoshimasa Imoto
- Life Science Innovation Center, University of Fukui, Fukui, Japan
- Department of Otorhinolaryngology-Head and Neck Surgery, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Shigeharu Fujieda
- Department of Otorhinolaryngology-Head and Neck Surgery, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Yugo Fukazawa
- Division of Brain Structure and Function, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
- Life Science Innovation Center, University of Fukui, Fukui, Japan
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17
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Alsina-Llanes M, Olazábal DE. NMDA- and 6-OHDA-induced Lesions in the Nucleus Accumbens Differently Affect Maternal and Infanticidal Behavior in Pup-naïve Female and Male Mice. Neuroscience 2024; 539:35-50. [PMID: 38176609 DOI: 10.1016/j.neuroscience.2023.12.009] [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: 11/08/2023] [Revised: 12/18/2023] [Accepted: 12/20/2023] [Indexed: 01/06/2024]
Abstract
Virgin and pups-naïve female and male adult mice display two opposite responses when they are exposed to pups for the first time. While females generally take care of the pups, males attack them. Since the nucleus accumbens (NA), and its dopaminergic modulation, is critical in integrating information and processing reward and aversion, we investigated if NMDA- and 6-OHDA-induced lesions, damaging mostly NA output and dopaminergic inputs respectively, affected female maternal behavior (MB) or male infanticidal behavior (IB) in mice. Our results revealed minor or no effects of both smaller and larger NMDA-induced lesions in MB and IB. On the other hand, while 6-OHDA-induced lesions in females reduced the incidence of full MB (12.5% 6-OHDA vs. 85.7% SHAM) increasing the latency to retrieve the pups, those lesions did not affect IB in males. There were no differences in locomotor and exploratory activity between the lesioned- and SHAM- females. Despite those lesions did not induce any major effect on IB, NMDA-lesioned males spent less time in the central area of an open field, while dopaminergic-lesioned males showed reduced number of rearing and peripheral crosses. The current study shows that an intact NA is not necessary for the expression of MB and IB. However, dopaminergic inputs to NA play different role in MB and IB. While damaging dopaminergic terminals into the NA did not affect IB, it clearly delayed the more flexible and rewarding expression of parental behavior.
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Affiliation(s)
- M Alsina-Llanes
- Departamento de Fisiología, Facultad de Medicina, UdelaR. Av. Gral. Flores 2125, Montevideo 11800, Uruguay.
| | - D E Olazábal
- Departamento de Fisiología, Facultad de Medicina, UdelaR. Av. Gral. Flores 2125, Montevideo 11800, Uruguay.
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18
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Lu X, Xue J, Lai Y, Tang X. Heterogeneity of mesencephalic dopaminergic neurons: From molecular classifications, electrophysiological properties to functional connectivity. FASEB J 2024; 38:e23465. [PMID: 38315491 DOI: 10.1096/fj.202302031r] [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: 10/07/2023] [Revised: 01/06/2024] [Accepted: 01/22/2024] [Indexed: 02/07/2024]
Abstract
The mesencephalic dopamine (DA) system is composed of neuronal subtypes that are molecularly and functionally distinct, are responsible for specific behaviors, and are closely associated with numerous brain disorders. Existing research has made significant advances in identifying the heterogeneity of mesencephalic DA neurons, which is necessary for understanding their diverse physiological functions and disease susceptibility. Moreover, there is a conflict regarding the electrophysiological properties of the distinct subsets of midbrain DA neurons. This review aimed to elucidate recent developments in the heterogeneity of midbrain DA neurons, including subpopulation categorization, electrophysiological characteristics, and functional connectivity to provide new strategies for accurately identifying distinct subtypes of midbrain DA neurons and investigating the underlying mechanisms of these neurons in various diseases.
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Affiliation(s)
- Xiaying Lu
- Department of Pathophysiology, School of Basic Medical Sciences, Gannan Medical University, Ganzhou, China
| | - Jinhua Xue
- Department of Pathophysiology, School of Basic Medical Sciences, Gannan Medical University, Ganzhou, China
| | - Yudong Lai
- Department of Human Anatomy, School of Basic Medical Sciences, Gannan Medical University, Ganzhou, China
| | - Xiaolu Tang
- The First Clinical Medical College, Gannan Medical University, Ganzhou, China
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19
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Bagalkot T, Sorkin A. Amphetamine Induces Sex-Dependent Loss of the Striatal Dopamine Transporter in Sensitized Mice. eNeuro 2024; 11:ENEURO.0491-23.2023. [PMID: 38164591 PMCID: PMC10849026 DOI: 10.1523/eneuro.0491-23.2023] [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: 11/23/2023] [Revised: 12/10/2023] [Accepted: 12/12/2023] [Indexed: 01/03/2024] Open
Abstract
Dopamine transporter (DAT) controls dopamine signaling in the brain through the reuptake of synaptically released dopamine. DAT is a target of abused psychostimulants such as amphetamine (Amph). Acute Amph administration induces transient DAT endocytosis, which, among other Amph effects on dopaminergic neurons, elevates extracellular dopamine. However, the effects of repeated Amph abuse, leading to behavioral sensitization and drug addiction, on DAT are unknown. Hence, we developed a 14 d Amph-sensitization protocol in knock-in mice expressing HA-epitope-tagged DAT (HA-DAT) and investigated the effects of Amph challenge on sensitized HA-DAT animals. The Amph challenge resulted in the highest locomotor activity on Day 14 in both sexes, which was sustained for 1 h in male but not female mice. Strikingly, significant (by 30-60%) loss of the HA-DAT protein in the striatum was caused by the Amph challenge of sensitized males but not females. Amph also reduced V max of dopamine transport in the striatal synaptosomes of males without changing K m values. Consistently, immunofluorescence microscopy revealed a significant increase of HA-DAT colocalization with the endosomal protein VPS35 only in Amph-challenged males. Amph-induced loss of striatal HA-DAT in sensitized mice was blocked by chloroquine, vacuolin-1, and inhibitor of Rho-associated kinases ROCK1/2, indicative of the involvement of endocytic trafficking in the DAT protein loss. Interestingly, an apparent degradation of HA-DAT protein was observed in the nucleus accumbens and not in the dorsal striatum. We propose that Amph challenge in sensitized mice triggers Rho-mediated endocytosis and post-endocytic trafficking of DAT in a brain-region-specific and sex-dependent manner.
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Affiliation(s)
- Tarique Bagalkot
- Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh 15261, Pennsylvania
| | - Alexander Sorkin
- Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh 15261, Pennsylvania
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20
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Belge JB, Mulders P, Van Diermen L, Sienaert P, Sabbe B, Abbott CC, Tendolkar I, Schrijvers D, van Eijndhoven P. Reviewing the neurobiology of electroconvulsive therapy on a micro- meso- and macro-level. Prog Neuropsychopharmacol Biol Psychiatry 2023; 127:110809. [PMID: 37331685 DOI: 10.1016/j.pnpbp.2023.110809] [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: 01/22/2023] [Revised: 05/27/2023] [Accepted: 06/07/2023] [Indexed: 06/20/2023]
Abstract
BACKGROUND Electroconvulsive therapy (ECT) remains the one of the most effective of biological antidepressant interventions. However, the exact neurobiological mechanisms underlying the efficacy of ECT remain unclear. A gap in the literature is the lack of multimodal research that attempts to integrate findings at different biological levels of analysis METHODS: We searched the PubMed database for relevant studies. We review biological studies of ECT in depression on a micro- (molecular), meso- (structural) and macro- (network) level. RESULTS ECT impacts both peripheral and central inflammatory processes, triggers neuroplastic mechanisms and modulates large scale neural network connectivity. CONCLUSIONS Integrating this vast body of existing evidence, we are tempted to speculate that ECT may have neuroplastic effects resulting in the modulation of connectivity between and among specific large-scale networks that are altered in depression. These effects could be mediated by the immunomodulatory properties of the treatment. A better understanding of the complex interactions between the micro-, meso- and macro- level might further specify the mechanisms of action of ECT.
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Affiliation(s)
- Jean-Baptiste Belge
- Department of Psychiatry, Collaborative Antwerp Psychiatric Research Institute (CAPRI), Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium; Department of Psychiatry, Radboud University Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.
| | - Peter Mulders
- Department of Psychiatry, Radboud University Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands; Donders Institute for Brain, Cognition and Behavior, Centre for Neuroscience, P.O. Box 9010, 6500 GL Nijmegen, The Netherlands
| | - Linda Van Diermen
- Department of Psychiatry, Collaborative Antwerp Psychiatric Research Institute (CAPRI), Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium; Psychiatric Center Bethanië, Andreas Vesaliuslaan 39, Zoersel 2980, Belgium
| | - Pascal Sienaert
- KU Leuven - University of Leuven, University Psychiatric Center KU Leuven, Academic Center for ECT and Neuromodulation (AcCENT), Leuvensesteenweg 517, Kortenberg 3010, Belgium
| | - Bernard Sabbe
- Department of Psychiatry, Collaborative Antwerp Psychiatric Research Institute (CAPRI), Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
| | | | - Indira Tendolkar
- Department of Psychiatry, Radboud University Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands; Donders Institute for Brain, Cognition and Behavior, Centre for Neuroscience, P.O. Box 9010, 6500 GL Nijmegen, The Netherlands
| | - Didier Schrijvers
- Department of Psychiatry, Collaborative Antwerp Psychiatric Research Institute (CAPRI), Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium; Department of Psychiatry, University Psychiatric Center Duffel, Stationstraat 22, Duffel 2570, Belgium
| | - Philip van Eijndhoven
- Department of Psychiatry, Radboud University Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands; Donders Institute for Brain, Cognition and Behavior, Centre for Neuroscience, P.O. Box 9010, 6500 GL Nijmegen, The Netherlands
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21
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Li C, Chen Z, He S, Chen Y, Liu J. Unveiling the influence of daily dietary patterns on brain cortical structure: insights from bidirectional Mendelian randomization. Food Funct 2023; 14:10418-10429. [PMID: 37960880 DOI: 10.1039/d3fo02879h] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2023]
Abstract
Cognitive impairment is a significant concern in aging populations. This study utilized Mendelian randomization analysis to explore the impact of dietary habits and macro-nutrients on cortical structure. A bidirectional Mendelian randomization approach was employed, incorporating large-scale genetic data on dietary habits and brain cortical structure. The results did not reveal significant causal relationships between dietary factors and overall cortical structure and thickness. However, specific dietary factors showed associations with cortical structure in certain regions. For instance, fat intake affected six cortical regions, while milk, protein, fruits, and water were associated with changes in specific regions. Reverse analysis suggested that cortical thickness influenced the consumption of alcohol, carbohydrates, coffee, and fish. These findings contribute to understanding the potential mechanisms underlying the role of dietary factors in cognitive function changes and provide evidence supporting the existence of the gut-brain axis.
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Affiliation(s)
- Cong Li
- Department of Radiology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
| | - Zhe Chen
- Department of Thoracic Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Shaqi He
- Department of Radiology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
| | - Yanjing Chen
- Department of Radiology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
| | - Jun Liu
- Department of Radiology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
- Clinical Research Center for Medical Imaging in Hunan Province, Changsha, Hunan Province, 410011, People's Republic of China
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22
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Hámor PU, Hartmann MC, Garcia A, Liu D, Pleil KE. Morphine-context associative memory and locomotor sensitization in mice are modulated by sex and context in a dose-dependent manner. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.11.03.565492. [PMID: 37961152 PMCID: PMC10635120 DOI: 10.1101/2023.11.03.565492] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/15/2023]
Abstract
Sex differences in opioid use, development of opioid used disorder, and relapse behaviors indicate potential variations in opioid effects between men and women. The locomotor and interoceptive effects of opioids play essential roles in opioid addiction, and uncovering the neural mechanisms underlying these effects remain crucial for developing effective treatments. In this study, we examined the dose-dependent effects of morphine on locomotor sensitization and the strength and stability of morphine-context associations in the conditioned place preference (CPP) paradigm in male and female mice, as well as the relationships between these measures. We observed that while CPP is similar between sexes, the locomotor effects of repeated morphine administration and withdrawal differentially contributed to the strength and stability of morphine-context associations. Specifically, females exhibited higher morphine-induced hyperlocomotion than males regardless of the context in which morphine was experienced. Greater locomotor sensitization to morphine in females than males emerged in a dose-dependent manner only when there was sufficient context information for CPP to be established. Additionally, the relationships between the locomotor effects of morphine and the strength and stability of CPP were different in males and females. In females, positive acute and sensitizing locomotor effects of morphine were correlated with a higher CPP score, while the opposite direction of this relationship was found in males. These results suggest that different aspects of the subjective experience of morphine intoxication and withdrawal are important for morphine abuse-related behaviors and highlight the importance of sex-specific responses in the context of opioid addiction.
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Affiliation(s)
- Peter U. Hámor
- Department of Pharmacology, Weill Cornell Medicine, Cornell University, New York, NY 10065
| | - Matthew C. Hartmann
- Department of Pharmacology, Weill Cornell Medicine, Cornell University, New York, NY 10065
| | - Aaron Garcia
- Department of Pharmacology, Weill Cornell Medicine, Cornell University, New York, NY 10065
| | - Dezhi Liu
- Department of Pharmacology, Weill Cornell Medicine, Cornell University, New York, NY 10065
| | - Kristen E. Pleil
- Department of Pharmacology, Weill Cornell Medicine, Cornell University, New York, NY 10065
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23
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Wang Y, Qin Y, Li H, Yao D, Sun B, Gong J, Dai Y, Wen C, Zhang L, Zhang C, Luo C, Zhu T. Acupuncture modulates the functional connectivity among the subcortical nucleus and fronto-parietal network in adolescents with internet addiction. Brain Behav 2023; 13:e3241. [PMID: 37721727 PMCID: PMC10636388 DOI: 10.1002/brb3.3241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Revised: 08/18/2023] [Accepted: 08/22/2023] [Indexed: 09/19/2023] Open
Abstract
BACKGROUND Internet addiction (IA), recognized as a behavioral addiction, is emerging as a global public health problem. Acupuncture has been demonstrated to be effective in alleviating IA; however, the mechanism is not yet clear. To fill this knowledge gap, our study aimed to investigate the modulatory effects of acupuncture on the functional interactions among the addiction-related networks in adolescents with IA. METHODS Thirty individuals with IA and thirty age- and sex-matched healthy control subjects (HCs) were recruited. Subjects with IA were given a 40-day acupuncture treatment, and resting-state functional magnetic resonance imaging (fMRI) data were collected before and after acupuncture sessions. HCs received no treatment and underwent one fMRI scan after enrollment. The intergroup differences in functional connectivity (FC) among the subcortical nucleus (SN) and fronto-parietal network (FPN) were compared between HCs and subjects with IA at baseline. Then, the intragroup FC differences between the pre- and post-treatment were analyzed in the IA group. A multiple linear regression model was further employed to fit the FC changes to symptom relief in the IA group. RESULTS In comparison to HCs, subjects with IA exhibited significantly heightened FC within and between the SN and FPN at baseline. After 40 days of acupuncture treatment, the FC within the FPN and between the SN and FPN were significantly decreased in individuals with IA. Symptom improvement in subjects with IA was well fitted by the decrease in FC between the left midbrain and ventral prefrontal cortex and between the left thalamus and ventral anterior prefrontal cortex. CONCLUSION These findings confirmed the modulatory effects of acupuncture on the aberrant functional interactions among the SN and FPN, which may partly reflect the neurophysiological mechanism of acupuncture for IA.
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Affiliation(s)
- Yang Wang
- School of Sports Medicine and HealthChengdu Sport UniversityChengduChina
- Postdoctoral Workstation, Affiliated Sport Hospital of Chengdu Sport UniversityChengduChina
- School of Rehabilitation and Health PreservationChengdu University of TCMChengduChina
- College of Traditional Chinese MedicineChongqing Medical UniversityShapingbaChina
| | - Yun Qin
- Key Laboratory for NeuroInformation of Ministry of EducationUniversity of Electronic Science and Technology of ChinaChengduChina
| | - Hui Li
- School of MedicineChengdu UniversityChengduChina
| | - Dezhong Yao
- Key Laboratory for NeuroInformation of Ministry of EducationUniversity of Electronic Science and Technology of ChinaChengduChina
| | - Bo Sun
- Key Laboratory for NeuroInformation of Ministry of EducationUniversity of Electronic Science and Technology of ChinaChengduChina
| | - Jinnan Gong
- Key Laboratory for NeuroInformation of Ministry of EducationUniversity of Electronic Science and Technology of ChinaChengduChina
- School of Computer ScienceChengdu University of Information TechnologyChengduChina
| | - Yu Dai
- Department of Chinese MedicineChengdu Eighth People's HospitalChengduChina
| | - Chao Wen
- Department of RehabilitationZigong Fifth People's HospitalZigongChina
| | - Lingrui Zhang
- Department of MedicineLeshan Vocational and Technical CollegeLeshanChina
| | - Chenchen Zhang
- Department of RehabilitationTCM Hospital of Longquanyi DistrictChengduChina
| | - Cheng Luo
- Key Laboratory for NeuroInformation of Ministry of EducationUniversity of Electronic Science and Technology of ChinaChengduChina
- Research Unit of NeuroInformationChinese Academy of Medical SciencesBeijingChina
| | - Tianmin Zhu
- School of Rehabilitation and Health PreservationChengdu University of TCMChengduChina
- Library, Chengdu University of TCMChengduChina
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24
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Nguyen VT, Harris AC, Eltit JM. Structural and functional perspectives on interactions between synthetic cathinones and monoamine transporters. ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 2023; 99:83-124. [PMID: 38467490 DOI: 10.1016/bs.apha.2023.09.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/13/2024]
Abstract
Synthetic cathinone derivatives comprise a family of psychoactive compounds structurally related to amphetamine. Over the last decade, clandestine chemists have synthesized a consistent stream of innovative cathinone derivatives to outpace governmental regulatory restrictions. Many of these unregulated substances are produced and distributed as designer drugs. Two of the principal chemical scaffolds exploited to expand the synthetic cathinone family are methcathinone and α-pyrrolidinopentiophenone (or α-pyrrolidinovalerophenone, α-PVP). These compounds' main physiological targets are monoamine transporters, where they promote addiction by potentiating dopaminergic neurotransmission. This chapter describes techniques used to study the pharmacodynamic properties of cathinones at monoamine transporters in vitro. Biochemical techniques described include uptake inhibition and release assays in rat brain synaptosomes and in mammalian expression systems. Electrophysiological techniques include current measurements using the voltage clamp technique. We describe a Ca2+ mobilization assay wherein voltage-gated Ca2+ channels function as reporters to study the action of synthetic cathinones at monoamine transporters. We discuss results from systematic structure-activity relationship studies on simple and complex cathinones at monoamine transporters with an emphasis on identifying structural moieties that modulate potency and selectivity at these transporters. Moreover, different profiles of selectivity at monoamine transporters directly predict compounds associated with behavioral and subjective effects within animals and humans. In conclusion, clarification of the structural aspects of compounds which modulate potency and selectivity at monoamine transporters is critical to identify and predict potential addictive drugs. This knowledge may allow prompt allocation of resources toward drugs that represent the greatest threats after drugs are identified by forensic laboratories.
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Affiliation(s)
- Vy T Nguyen
- Department of Physiology and Biophysics, School of Medicine, Virginia Commonwealth University, Richmond, VA, United States
| | - Alan C Harris
- Department of Physiology and Biophysics, School of Medicine, Virginia Commonwealth University, Richmond, VA, United States
| | - Jose M Eltit
- Department of Physiology and Biophysics, School of Medicine, Virginia Commonwealth University, Richmond, VA, United States.
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25
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Ronström JW, Williams SB, Payne A, Obray DJ, Hafen C, Burris M, Scott Weber K, Steffensen SC, Yorgason JT. Interleukin-10 enhances activity of ventral tegmental area dopamine neurons resulting in increased dopamine release. Brain Behav Immun 2023; 113:145-155. [PMID: 37453452 PMCID: PMC10530119 DOI: 10.1016/j.bbi.2023.07.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 07/06/2023] [Accepted: 07/09/2023] [Indexed: 07/18/2023] Open
Abstract
Dopamine transmission from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) regulates important aspects of motivation and is influenced by the neuroimmune system. The neuroimmune system is a complex network of leukocytes, microglia and astrocytes that detect and remove foreign threats like bacteria or viruses and communicate with each other to regulate non-immune (e.g neuronal) cell activity through cytokine signaling. Inflammation is a key regulator of motivational states, though the effects of specific cytokines on VTA circuitry and motivation are largely unknown. Therefore, electrophysiology, neurochemical, immunohistochemical and behavioral studies were performed to determine the effects of the anti-inflammatory cytokine interleukin-10 (IL-10) on mesolimbic activity, dopamine transmission and conditioned behavior. IL-10 enhanced VTA dopamine firing and NAc dopamine levels via decreased VTA GABA currents in dopamine neurons. The IL-10 receptor was localized on VTA dopamine and non-dopamine cells. The IL-10 effects on dopamine neurons required post-synaptic phosphoinositide 3-kinase activity, and IL-10 appeared to have little-to-no efficacy on presynaptic GABA terminals. Intracranial IL-10 enhanced NAc dopamine levels in vivo and produced conditioned place aversion. Together, these studies identify the IL-10R on VTA dopamine neurons as a potential regulator of motivational states.
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Affiliation(s)
- Joakim W Ronström
- Brigham Young University, Department of Psychology/Neuroscience, Provo, UT 84602, United States
| | - Stephanie B Williams
- Brigham Young University, Department of Psychology/Neuroscience, Provo, UT 84602, United States
| | - Andrew Payne
- Brigham Young University, Department of Psychology/Neuroscience, Provo, UT 84602, United States
| | - Daniel J Obray
- Brigham Young University, Department of Psychology/Neuroscience, Provo, UT 84602, United States
| | - Caylor Hafen
- Brigham Young University, Department of Psychology/Neuroscience, Provo, UT 84602, United States
| | - Matthew Burris
- Brigham Young University, Department of Cellular Biology and Physiology, Provo, UT 84602, United States
| | - K Scott Weber
- Brigham Young University, Department of Microbiology and Molecular Biology, Provo, UT 84602, United States
| | - Scott C Steffensen
- Brigham Young University, Department of Psychology/Neuroscience, Provo, UT 84602, United States
| | - Jordan T Yorgason
- Brigham Young University, Department of Psychology/Neuroscience, Provo, UT 84602, United States; Brigham Young University, Department of Cellular Biology and Physiology, Provo, UT 84602, United States.
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26
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Jones GC, Small CA, Otteson DZ, Hafen CW, Breinholt JT, Flora PD, Burris MD, Sant DW, Ruchti TR, Yorgason JT, Steffensen SC, Bills KB. Whole-Body Vibration Prevents Neuronal, Neurochemical, and Behavioral Effects of Morphine Withdrawal in a Rat Model. Int J Mol Sci 2023; 24:14147. [PMID: 37762450 PMCID: PMC10532581 DOI: 10.3390/ijms241814147] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 09/01/2023] [Accepted: 09/05/2023] [Indexed: 09/29/2023] Open
Abstract
Peripheral mechanoreceptor-based treatments such as acupuncture and chiropractic manipulation have shown success in modulating the mesolimbic dopamine (DA) system originating in the ventral tegmental area (VTA) of the midbrain and projecting to the nucleus accumbens (NAc) of the striatum. We have previously shown that mechanoreceptor activation via whole-body vibration (WBV) ameliorates neuronal and behavioral effects of chronic ethanol exposure. In this study, we employ a similar paradigm to assess the efficacy of WBV as a preventative measure of neuronal and behavioral effects of morphine withdrawal in a Wistar rat model. We demonstrate that concurrent administration of WBV at 80 Hz with morphine over a 5-day period significantly reduced adaptations in VTA GABA neuronal activity and NAc DA release and modulated expression of δ-opioid receptors (DORs) on NAc cholinergic interneurons (CINs) during withdrawal. We also observed a reduction in behavior typically associated with opioid withdrawal. WBV represents a promising adjunct to current intervention for opioid use disorder (OUD) and should be examined translationally in humans.
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Affiliation(s)
- Gavin C. Jones
- Neuroscience Center, Brigham Young University, Provo, UT 84602, USA
| | | | | | - Caylor W. Hafen
- Neuroscience Center, Brigham Young University, Provo, UT 84602, USA
| | | | - Paul D. Flora
- Neuroscience Center, Brigham Young University, Provo, UT 84602, USA
| | | | - David W. Sant
- Department of Biomedical Sciences, Noorda College of Osteopathic Medicine, Provo, UT 84606, USA
| | - Tysum R. Ruchti
- Neuroscience Center, Brigham Young University, Provo, UT 84602, USA
| | | | - Scott C. Steffensen
- Neuroscience Center, Brigham Young University, Provo, UT 84602, USA
- Department of Biomedical Sciences, Noorda College of Osteopathic Medicine, Provo, UT 84606, USA
| | - Kyle B. Bills
- Department of Biomedical Sciences, Noorda College of Osteopathic Medicine, Provo, UT 84606, USA
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Dresp-Langley B. From Reward to Anhedonia-Dopamine Function in the Global Mental Health Context. Biomedicines 2023; 11:2469. [PMID: 37760910 PMCID: PMC10525914 DOI: 10.3390/biomedicines11092469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2023] [Revised: 08/29/2023] [Accepted: 09/04/2023] [Indexed: 09/29/2023] Open
Abstract
When "hijacked" by compulsive behaviors that affect the reward and stress centers of the brain, functional changes in the dopamine circuitry occur as the consequence of pathological brain adaptation. As a brain correlate of mental health, dopamine has a central functional role in behavioral regulation from healthy reward-seeking to pathological adaptation to stress in response to adversity. This narrative review offers a spotlight view of the transition from healthy reward function, under the control of dopamine, to the progressive deregulation of this function in interactions with other brain centers and circuits, producing what may be called an anti-reward brain state. How such deregulation is linked to specific health-relevant behaviors is then explained and linked to pandemic-related adversities and the stresses they engendered. The long lockdown periods where people in social isolation had to rely on drink, food, and digital rewards via the internet may be seen as the major triggers of changes in motivation and reward-seeking behavior worldwide. The pathological adaptation of dopamine-mediated reward circuitry in the brain is discussed. It is argued that, when pushed by fate and circumstance into a physiological brain state of anti-reward, human behavior changes and mental health is affected, depending on individual vulnerabilities. A unified conceptual account that places dopamine function at the centre of the current global mental health context is proposed.
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Affiliation(s)
- Birgitta Dresp-Langley
- Centre National de la Recherche Scientifique, UMR 7357 ICube CNRS, Université de Strasbourg Hôpitaux Universitaires Faculté de Médecine, Pavillon Clovis Vincent, 4 Rue Kirschleger, CEDEX, 67085 Strasbourg, France
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28
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Zinani DB, Desai JN, Norman AB. SCH23390 and a humanized anti-cocaine mAb decrease the latency to cocaine-induced reinstatement of lever pressing behavior in rats that self-administer cocaine. Sci Rep 2023; 13:14566. [PMID: 37666873 PMCID: PMC10477340 DOI: 10.1038/s41598-023-41284-1] [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: 05/25/2023] [Accepted: 08/24/2023] [Indexed: 09/06/2023] Open
Abstract
In rats that self-administer cocaine, the latency to the reinstatement of lever pressing behavior induced by a single dose of cocaine is due to the time taken for cocaine levels to fall to the satiety threshold. The D1 dopamine receptor antagonist SCH23390, and the recombinant humanized anti-cocaine mAb h2E2 increase the cocaine satiety threshold and would be expected to alter the latency to reinstatement. Male rats acquired cocaine self-administration behavior on an FR1 schedule. These rats received a single injection of cocaine (12 µmol/kg i.v.) after an i.v. injection of SCH23390 or an infusion of h2E2 or vehicle. The latency to, and the duration of, lever pressing was measured but the presses had no consequence. SCH23390 decreased the latency to lever pressing consistent with dose-dependent increases in satiety threshold. The duration of lever pressing behavior was inversely proportional to the SCH23390 dose suggesting that SCH23390 also increased the cocaine compulsion zone. The mAb h2E2 also produced a similar decrease in latency to responding that gradually reversed over 2 weeks. SCH23390 and h2E2 had an additive effect on the decreased latency to cocaine-induced lever pressing. The single cocaine dose reinstatement paradigm within the context of the compulsion zone theory is a useful pharmacological bioassay system to explore potential pharmacotherapies for relapse prevention in cocaine use disorder.
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Affiliation(s)
- Dakota B Zinani
- Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Jhanvi N Desai
- Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Andrew B Norman
- Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
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29
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Kozlova AA, Rubets E, Vareltzoglou MR, Jarzebska N, Ragavan VN, Chen Y, Martens-Lobenhoffer J, Bode-Böger SM, Gainetdinov RR, Rodionov RN, Bernhardt N. Knock-out of the critical nitric oxide synthase regulator DDAH1 in mice impacts amphetamine sensitivity and dopamine metabolism. J Neural Transm (Vienna) 2023; 130:1097-1112. [PMID: 36792833 PMCID: PMC10460711 DOI: 10.1007/s00702-023-02597-7] [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: 11/09/2022] [Accepted: 01/28/2023] [Indexed: 02/17/2023]
Abstract
The enzyme dimethylarginine dimethylaminohydrolase 1 (DDAH1) plays a pivotal role in the regulation of nitric oxide levels by degrading the main endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA). Growing evidence highlight the potential implication of DDAH/ADMA axis in the etiopathogenesis of several neuropsychiatric and neurological disorders, yet the underlying molecular mechanisms remain elusive. In this study, we sought to investigate the role of DDAH1 in behavioral endophenotypes with neuropsychiatric relevance. To achieve this, a global DDAH1 knock-out (DDAH1-ko) mouse strain was employed. Behavioral testing and brain region-specific neurotransmitter profiling have been conducted to assess the effect of both genotype and sex. DDAH1-ko mice exhibited increased exploratory behavior toward novel objects, altered amphetamine response kinetics and decreased dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) level in the piriform cortex and striatum. Females of both genotypes showed the most robust amphetamine response. These results support the potential implication of the DDAH/ADMA pathway in central nervous system processes shaping the behavioral outcome. Yet, further experiments are required to complement the picture and define the specific brain-regions and mechanisms involved.
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Affiliation(s)
- Alena A Kozlova
- Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307, Dresden, Germany
| | - Elena Rubets
- Division of Angiology, Department of Internal Medicine III, University Center for Vascular Medicine, Technische Universität Dresden, 01307, Dresden, Germany
| | - Magdalini R Vareltzoglou
- Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307, Dresden, Germany
| | - Natalia Jarzebska
- Division of Angiology, Department of Internal Medicine III, University Center for Vascular Medicine, Technische Universität Dresden, 01307, Dresden, Germany
| | - Vinitha N Ragavan
- Division of Angiology, Department of Internal Medicine III, University Center for Vascular Medicine, Technische Universität Dresden, 01307, Dresden, Germany
| | - Yingjie Chen
- Department of Physiology & Biophysics, University of Mississippi Medical Center, Jackson, MS, 39216, USA
| | | | - Stefanie M Bode-Böger
- Institute of Clinical Pharmacology, Otto-Von-Guericke University, Magdeburg, Germany
| | - Raul R Gainetdinov
- Institute of Translational Biomedicine and Saint-Petersburg University Hospital, Saint-Petersburg State University, 199034, Saint-Petersburg, Russia
| | - Roman N Rodionov
- Division of Angiology, Department of Internal Medicine III, University Center for Vascular Medicine, Technische Universität Dresden, 01307, Dresden, Germany
| | - Nadine Bernhardt
- Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307, Dresden, Germany.
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30
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Zanella D, Smith NK, Hardaway JA, Buchanan AM, Mullins CH, Galli A, Carter AM. Bile acids modulate reinstatement of cocaine conditioned place preference and accumbal dopamine dynamics without compromising appetitive learning. Sci Rep 2023; 13:13359. [PMID: 37591972 PMCID: PMC10435481 DOI: 10.1038/s41598-023-40456-3] [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: 06/08/2023] [Accepted: 08/10/2023] [Indexed: 08/19/2023] Open
Abstract
Psychostimulants target the dopamine transporter (DAT) to elicit their psychomotor actions. Bile acids (BAs) can also bind to DAT and reduce behavioral responses to cocaine, suggesting a potential therapeutic application of BAs in psychostimulant use disorder. Here, we investigate the potential of BAs to decrease drug-primed reinstatement when administered during an abstinence phase. To do this, after successful development of cocaine-associated contextual place preference (cocaine CPP), cocaine administration was terminated, and animals treated with vehicle or obeticholic acid (OCA). When preference for the cocaine-associated context was extinguished, mice were challenged with a single priming dose of cocaine, and reinstatement of cocaine-associated contextual preference was measured. Animals treated with OCA demonstrate a significantly lower reinstatement for cocaine CPP. OCA also impairs the ability of cocaine to reduce the clearance rate of electrically stimulated dopamine release and diminishes the area under the curve (AUC) observed with amperometry. Furthermore, the AUC of the amperometric signal positively correlates with the reinstatement index. Using operant feeding devices, we demonstrate that OCA has no effect on contextual learning or motivation for natural rewards. These data highlight OCA as a potential therapeutic for cocaine use disorder.
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Affiliation(s)
- Daniele Zanella
- Department of Surgery, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, USA
| | - Nicholas K Smith
- Department of Biology, University of Pennsylvania, Philadelphia, USA
| | - J Andrew Hardaway
- Department of Psychiatry and Behavioral Neurobiology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, USA
| | - Anna Marie Buchanan
- Department of Surgery, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, USA
| | - Clarence H Mullins
- Department of Surgery, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, USA
| | - Aurelio Galli
- Department of Surgery, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, USA
- Center for Inter-Systemic Networks and Enteric Medical Advances (UAB CINEMA), Birmingham, USA
| | - Angela M Carter
- Department of Surgery, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, USA.
- Center for Inter-Systemic Networks and Enteric Medical Advances (UAB CINEMA), Birmingham, USA.
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Small C, Cheng MH, Belay SS, Bulloch SL, Zimmerman B, Sorkin A, Block ER. The Alkylamine Stimulant 1,3-Dimethylamylamine Exhibits Substrate-Like Regulation of Dopamine Transporter Function and Localization. J Pharmacol Exp Ther 2023; 386:266-273. [PMID: 37348963 PMCID: PMC10353075 DOI: 10.1124/jpet.122.001573] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 02/16/2023] [Accepted: 05/04/2023] [Indexed: 06/24/2023] Open
Abstract
The alkylamine stimulant 1,3-dimethylamylamine (DMAA) is used nonmedically as an appetite suppressant and exercise performance enhancer despite adverse cardiovascular effects that have limited its legal status. There is scant research describing the mechanism of action of DMAA, making it difficult to gauge risks or therapeutic potential. An important molecular target of structurally related phenethylamines, such as amphetamine, for regulating mood, cognition, movement, and the development of substance use disorder is the dopamine transporter, which limits the range and magnitude of dopamine signaling via reuptake from the extracellular space. The present studies were therefore initiated to characterize the effects of DMAA on dopamine transporter function. Specifically, we tested the hypothesis that DMAA exhibits substrate-like effects on dopamine transporter function and trafficking. In transport assays in human embryonic kidney cells, DMAA inhibited dopamine uptake by the human dopamine transporter in a competitive manner. Docking analysis and molecular dynamics simulations supported these findings, revealing that DMAA binds to the S1 substrate binding site and induces a conformational change from outward-facing open to outward-facing closed states, similar to the known substrates. Further supporting substrate-like effects of DMAA, the drug stimulated dopamine transporter endocytosis in a heterologous expression system via cocaine- and protein kinase A-sensitive mechanisms, mirroring findings with amphetamine. Together, these data indicate that DMAA elicits neurologic effects by binding to and regulating function of the dopamine transporter. Furthermore, pharmacologic distinctions from amphetamine reveal structural determinants for regulating transporter conformation and add mechanistic insight for the regulation of dopamine transporter endocytosis. SIGNIFICANCE STATEMENT: The alkylamine stimulant 1,3-dimethylamylamine (DMAA) is used as an appetite suppressant and athletic performance enhancer and is structurally similar to amphetamine, but there is scant research describing its mechanism of action. Characterizing the effects of DMAA on dopamine transporter function supports evaluation of potential risks and therapeutic potential while also revealing mechanistic details of dynamic transporter-substrate interactions.
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Affiliation(s)
- Cassandra Small
- Science Department, Chatham University, Pittsburgh, Pennsylvania (C.S., S.S.B., S.L.B., B.Z., E.R.B.) and Departments of Computational and Systems Biology (M.H.C.) and Cell Biology (A.S.), School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Mary Hongying Cheng
- Science Department, Chatham University, Pittsburgh, Pennsylvania (C.S., S.S.B., S.L.B., B.Z., E.R.B.) and Departments of Computational and Systems Biology (M.H.C.) and Cell Biology (A.S.), School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Saron S Belay
- Science Department, Chatham University, Pittsburgh, Pennsylvania (C.S., S.S.B., S.L.B., B.Z., E.R.B.) and Departments of Computational and Systems Biology (M.H.C.) and Cell Biology (A.S.), School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Sarah L Bulloch
- Science Department, Chatham University, Pittsburgh, Pennsylvania (C.S., S.S.B., S.L.B., B.Z., E.R.B.) and Departments of Computational and Systems Biology (M.H.C.) and Cell Biology (A.S.), School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Brooke Zimmerman
- Science Department, Chatham University, Pittsburgh, Pennsylvania (C.S., S.S.B., S.L.B., B.Z., E.R.B.) and Departments of Computational and Systems Biology (M.H.C.) and Cell Biology (A.S.), School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Alexander Sorkin
- Science Department, Chatham University, Pittsburgh, Pennsylvania (C.S., S.S.B., S.L.B., B.Z., E.R.B.) and Departments of Computational and Systems Biology (M.H.C.) and Cell Biology (A.S.), School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Ethan R Block
- Science Department, Chatham University, Pittsburgh, Pennsylvania (C.S., S.S.B., S.L.B., B.Z., E.R.B.) and Departments of Computational and Systems Biology (M.H.C.) and Cell Biology (A.S.), School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
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Scott R. Methamphetamine dependence in Australia-why is 'ice' (crystal meth) so addictive? PSYCHIATRY, PSYCHOLOGY, AND LAW : AN INTERDISCIPLINARY JOURNAL OF THE AUSTRALIAN AND NEW ZEALAND ASSOCIATION OF PSYCHIATRY, PSYCHOLOGY AND LAW 2023; 31:671-704. [PMID: 39118784 PMCID: PMC11305059 DOI: 10.1080/13218719.2023.2206870] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Accepted: 04/13/2023] [Indexed: 08/10/2024]
Abstract
Australia has one of the highest rates in the world of the use of the crystalline form of methamphetamine, a highly addictive stimulant that is often associated with a chronic, relapsing dependency. Methamphetamine use is associated with both acquisitive and violent offending, which cause substantial personal and societal costs. Whilst the short-term euphoria and stimulation provide a positive reinforcement to methamphetamine use, the aversive states of withdrawing from methamphetamine and the associated craving, which may last up to five weeks into abstinence, underlie the negative reinforcement to continued methamphetamine use. Although many methamphetamine-dependent users experience high levels of psychological distress, it is likely that less than half engage with treatment or support services, and current intervention and treatment programmes have high discontinuation rates. Stigma and discrimination, even from paramedics and health clinicians, are prominent barriers to methamphetamine-dependent users accessing treatment in Australia.
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Affiliation(s)
- Russ Scott
- West Moreton Prison Mental Health Service, Brisbane, QLD, Australia
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Handley ED, Russotti J, Ross AJ, Toth SL, Cicchetti D. A person-centered data analytic approach to dopaminergic polygenic moderation of child maltreatment exposure. Dev Psychobiol 2023; 65:e22403. [PMID: 37338249 PMCID: PMC10287038 DOI: 10.1002/dev.22403] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 04/27/2023] [Accepted: 05/03/2023] [Indexed: 06/21/2023]
Abstract
The present study illustrates the utility of latent class analysis, a person-centered data analytic approach, as an innovative method for identifying naturally occurring patterns of polygenic risk, specifically within the dopaminergic system. Moreover, this study tests whether latent classes of polygenic variation moderate the effect of child maltreatment exposure on internalizing symptoms among African ancestry youth. African ancestry youth were selected for this study because youth of color are overrepresented in the child welfare system and because African ancestry individuals are significantly underrepresented in genomics research. Results identified three latent classes of dopaminergic gene variation. Class 1 was marked predominately by homozygous minor alleles, Class 2 was characterized by homozygous major and heterozygous presentations, and Class 3 was marked by heterozygous alleles on the DAT-1 single-nucleotide polymorphisms (SNPs) and a combination of homozygous major and minor alleles on the other SNPs. Results indicated that a greater number of maltreatment subtypes experienced were associated with higher internalizing symptoms only for children with the latent polygenic Class 2 pattern. This latent class was distinctly characterized by more homozygous major or heterozygous allelic presentations along all three DAT-1 SNPs. This significant latent polygenic class by environment interaction was replicated in an independent replication sample. Together, findings suggest that African ancestry children with a pattern of dopaminergic variation characterized by this specific combination of polygenic variation are more vulnerable to developing internalizing symptoms following maltreatment exposure, relative to their peers with other dopamine-related polygenic patterns.
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Affiliation(s)
| | | | | | | | - Dante Cicchetti
- Mt. Hope Family Center, University of Rochester
- University of Minnesota
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Salin A, Dugast E, Lardeux V, Solinas M, Belujon P. The amygdala-ventral pallidum pathway contributes to a hypodopaminergic state in the ventral tegmental area during protracted abstinence from chronic cocaine. Br J Pharmacol 2023; 180:1819-1831. [PMID: 36645812 DOI: 10.1111/bph.16034] [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: 09/07/2022] [Revised: 12/01/2022] [Accepted: 01/06/2023] [Indexed: 01/17/2023] Open
Abstract
BACKGROUND AND PURPOSE Incubation of craving, the progressive increase in drug seeking over the first weeks of abstinence, is associated with temporal changes during abstinence in the activity of several structures involved in drug-seeking behaviour. Decreases of dopamine (DA) release and DA neuronal activity (hypodopaminergic state) have been reported in the ventral tegmental area (VTA) during cocaine abstinence, but the mechanisms underlying these neuroadaptations are not well understood. We investigated the potential involvement of a VTA inhibiting circuit (basolateral amygdala [BLA]-ventral pallidum [VP] pathway) in the hypodopaminergic state associated with abstinence from chronic cocaine. EXPERIMENTAL APPROACH In a model of cocaine self-administration, we performed in vivo electrophysiological recordings of DA VTA neurons and BLA neurons from anaesthetised rats during early and protracted abstinence and evaluated the involvement of the BLA-VP pathway using a pharmacological approach. KEY RESULTS We found significant decreases in VTA DA population activity and significant increases in BLA activity after protracted but not after short-term abstinence from chronic cocaine. The decrease in VTA DA activity was restored by pharmacological inhibition of the activity of either the BLA or the VP, suggesting that these regions exert a negative influence on DA activity. CONCLUSION AND IMPLICATIONS Our study sheds new lights on neuroadaptations occurring during incubation of craving leading to relapse. In particular, we describe the involvement of the BLA-VP pathway in cocaine-induced decreases of DA activity in the VTA. This study adds important information about the specific brain network dysfunctions underlying hypodopaminergic activity during abstinence.
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Affiliation(s)
- Adélie Salin
- Université de Poitiers, INSERM, U-1084, Laboratoire des Neurosciences Expérimentales et Cliniques, Poitiers, France
- Université de Rennes, Institut Numecan INRAE, INSERM, Rennes, France
| | - Emilie Dugast
- Université de Poitiers, INSERM, U-1084, Laboratoire des Neurosciences Expérimentales et Cliniques, Poitiers, France
- CHU de Poitiers, Poitiers, France
| | - Virginie Lardeux
- Université de Poitiers, INSERM, U-1084, Laboratoire des Neurosciences Expérimentales et Cliniques, Poitiers, France
| | - Marcello Solinas
- Université de Poitiers, INSERM, U-1084, Laboratoire des Neurosciences Expérimentales et Cliniques, Poitiers, France
| | - Pauline Belujon
- Université de Poitiers, INSERM, U-1084, Laboratoire des Neurosciences Expérimentales et Cliniques, Poitiers, France
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35
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Wadsworth HA, Anderson EQ, Williams BM, Ronström JW, Moen JK, Lee AM, McIntosh JM, Wu J, Yorgason JT, Steffensen SC. Role of α6-Nicotinic Receptors in Alcohol-Induced GABAergic Synaptic Transmission and Plasticity to Cholinergic Interneurons in the Nucleus Accumbens. Mol Neurobiol 2023; 60:3113-3129. [PMID: 36802012 PMCID: PMC10690621 DOI: 10.1007/s12035-023-03263-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Accepted: 02/03/2023] [Indexed: 02/21/2023]
Abstract
The prevailing view is that enhancement of dopamine (DA) transmission in the mesolimbic system, consisting of DA neurons in the ventral tegmental area (VTA) that project to the nucleus accumbens (NAc), underlies the reward properties of ethanol (EtOH) and nicotine (NIC). We have shown previously that EtOH and NIC modulation of DA release in the NAc is mediated by α6-containing nicotinic acetylcholine receptors (α6*-nAChRs), that α6*-nAChRs mediate low-dose EtOH effects on VTA GABA neurons and EtOH preference, and that α6*-nAChRs may be a molecular target for low-dose EtOH. However, the most sensitive target for reward-relevant EtOH modulation of mesolimbic DA transmission and the involvement of α6*-nAChRs in the mesolimbic DA reward system remains to be elucidated. The aim of this study was to evaluate EtOH effects on GABAergic modulation of VTA GABA neurons and VTA GABAergic input to cholinergic interneurons (CINs) in the NAc. Low-dose EtOH enhanced GABAergic input to VTA GABA neurons that was blocked by knockdown of α6*-nAChRs. Knockdown was achieved either by α6-miRNA injected into the VTA of VGAT-Cre/GAD67-GFP mice or by superfusion of the α-conotoxin MII[H9A;L15A] (MII). Superfusion of MII blocked EtOH inhibition of mIPSCs in NAc CINs. Concomitantly, EtOH enhanced CIN firing rate, which was blocked by knockdown of α6*-nAChRs with α6-miRNA injected into the VTA of VGAT-Cre/GAD67-GFP mice. The firing rate of CINs was not enhanced by EtOH in EtOH-dependent mice, and low-frequency stimulation (LFS; 1 Hz, 240 pulses) caused inhibitory long-term depression at this synapse (VTA-NAc CIN-iLTD) which was blocked by knockdown of α6*-nAChR and MII. Ethanol inhibition of CIN-mediated evoked DA release in the NAc was blocked by MII. Taken together, these findings suggest that α6*-nAChRs in the VTA-NAc pathway are sensitive to low-dose EtOH and play a role in plasticity associated with chronic EtOH.
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Affiliation(s)
- Hillary A Wadsworth
- Department of Psychology and Neuroscience, Brigham Young University, 1050 KMBL, Provo, UT, 84602, USA
| | - Elizabeth Q Anderson
- Department of Psychology and Neuroscience, Brigham Young University, 1050 KMBL, Provo, UT, 84602, USA
| | - Benjamin M Williams
- Department of Psychology and Neuroscience, Brigham Young University, 1050 KMBL, Provo, UT, 84602, USA
| | - Joakim W Ronström
- Department of Psychology and Neuroscience, Brigham Young University, 1050 KMBL, Provo, UT, 84602, USA
| | - Janna K Moen
- Department of Pharmacology, Graduate Program in Neuroscience, University of Minnesota, Minneapolis, MN, 55455, USA
| | - Anna M Lee
- Department of Pharmacology, Graduate Program in Neuroscience, University of Minnesota, Minneapolis, MN, 55455, USA
| | - J Michael McIntosh
- School of Biological Sciences and Department of Psychiatry, University of Utah, Salt Lake City, UT, 84108, USA
- George E. Whalen Veterans Affairs Medical Center, Salt Lake City, UT, 84148, USA
| | - Jie Wu
- Brain Function and Disease Laboratory, Shantou University Medical College, Shantou, 515041, Guangdong, China
| | - Jordan T Yorgason
- Department of Psychology and Neuroscience, Brigham Young University, 1050 KMBL, Provo, UT, 84602, USA
| | - Scott C Steffensen
- Department of Psychology and Neuroscience, Brigham Young University, 1050 KMBL, Provo, UT, 84602, USA.
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36
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Bagalkot T, Sorkin A. Endocytic down-regulation of the striatal dopamine transporter by amphetamine in sensitized mice in sex-dependent manner. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.05.17.541165. [PMID: 37293021 PMCID: PMC10245703 DOI: 10.1101/2023.05.17.541165] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Dopamine transporter (DAT) controls dopamine signaling in the brain through the reuptake of synaptically released dopamine. DAT is a target of abused psychostimulants such as amphetamine (Amph). Acute Amph is proposed to cause transient DAT endocytosis which among other Amph effects on dopaminergic neurons elevates extracellular dopamine. However, the effects of repeated Amph abuse, leading to behavioral sensitization and drug addiction, on DAT traffic are unknown. Hence, we developed a 14-day Amph-sensitization protocol in knock-in mice expressing HA-epitope tagged DAT (HA-DAT) and investigated effects of Amph challenge on HA-DAT in sensitized animals. Amph challenge resulted in the highest locomotor activity on day 14 in both sexes, which was however sustained for 1 hour in male but not female mice. Strikingly, significant (by 30-60%) reduction in the amount of the HA-DAT protein in striatum was observed in response to Amph challenge of sensitized males but not females. Amph reduced Vmax of dopamine transport in striatal synaptosomes of males without changing Km values. Consistently, immunofluorescence microscopy revealed a significant increase of HA-DAT co-localization with the endosomal protein VPS35 only in males. Amph-induced HA-DAT down-regulation in the striatum of sensitized mice was blocked by chloroquine, vacuolin-1 (inhibitor of PIKfive kinase), and inhibitor of Rho-associated kinases (ROCK1/2), indicative of the involvement of endocytic trafficking in DAT down-regulation. Interestingly, HA-DAT protein down-regulation was observed in nucleus accumbens and not in dorsal striatum. We propose that Amph challenge in sensitized mice leads to ROCK-dependent endocytosis and post-endocytic traffic of DAT in a brain-region-specific and sex-dependent manner.
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37
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Di Domenico D, Mapelli L. Dopaminergic Modulation of Prefrontal Cortex Inhibition. Biomedicines 2023; 11:biomedicines11051276. [PMID: 37238947 DOI: 10.3390/biomedicines11051276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 04/21/2023] [Accepted: 04/23/2023] [Indexed: 05/28/2023] Open
Abstract
The prefrontal cortex is the highest stage of integration in the mammalian brain. Its functions vary greatly, from working memory to decision-making, and are primarily related to higher cognitive functions. This explains the considerable effort devoted to investigating this area, revealing the complex molecular, cellular, and network organization, and the essential role of various regulatory controls. In particular, the dopaminergic modulation and the impact of local interneurons activity are critical for prefrontal cortex functioning, controlling the excitatory/inhibitory balance and the overall network processing. Though often studied separately, the dopaminergic and GABAergic systems are deeply intertwined in influencing prefrontal network processing. This mini review will focus on the dopaminergic modulation of GABAergic inhibition, which plays a significant role in shaping prefrontal cortex activity.
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Affiliation(s)
- Danila Di Domenico
- Department of Brain and Behavioral Sciences, University of Pavia, 27100 Pavia, Italy
| | - Lisa Mapelli
- Department of Brain and Behavioral Sciences, University of Pavia, 27100 Pavia, Italy
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38
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Carney AE, Clarke C, Pratt WE. Administration of neuropeptide Y into the rat nucleus accumbens shell, but not core, attenuates the motivational impairment from systemic dopamine receptor antagonism by α-flupenthixol. Neurosci Lett 2023; 797:137069. [PMID: 36641044 DOI: 10.1016/j.neulet.2023.137069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 01/09/2023] [Accepted: 01/10/2023] [Indexed: 01/13/2023]
Abstract
Previous research has demonstrated that dopamine and Neuropeptide Y (NPY) promote motivated behavior, and there is evidence to suggest that they interact within neural circuitry involved in motivation. NPY and dopamine both modulate appetitive motivation towards food through direct actions in the nucleus accumbens (NAc), although how they interact in this region to promote motivation is presently unclear. In this study, we sought to further elucidate the relationship between NAc NPY and dopamine and their effects on motivated behavior. Specifically, we examined whether NAc injections of NPY might reverse behavioral deficits caused by reduced dopamine signaling due to systemic dopamine receptor antagonism. Appetitive motivation was measured using a progressive ratio-2 paradigm. Male Sprague Dawley rats were treated with systemic injections of the dopamine antagonist, α-flupenthixol or a saline vehicle. Two hours following injections, they were administered infusions of NPY (at 0, 156, or 235 pmol) into either the NAc shell (n = 12) or the NAc core (n = 10) and were placed in operant chambers. In both groups, α-flupenthixol impaired performance on the PR-2 task. NPY receptor stimulation of the NAc shell significantly increased both breakpoint and active lever presses during the PR-2 task, and dose-dependently increased responding following systemic dopamine receptor blockade. NPY did not affect appetitive motivation when injected into the NAc core. These data demonstrate that NPY in the NAc shell can improve motivational impairments that result from dopamine antagonism, and that these effects are site specific. These results also suggest that upregulation of NPY in neurodegenerative diseases may possibly buffer early motivational deficits caused by dopamine depletion in Parkinson's and Huntington's disease patients, both of which show increased NPY expression after disease onset.
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39
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Zhu J, Quizon PM, Wang Y, Adeniran CA, Strauss MJ, Jiménez-Torres AC, Patel P, Cirino TJ, Eans SO, Hammond HR, Deliscar LS, O'Hara P, Saini SK, Ofori E, Vekariya RH, Zhang S, Moukha-Chafiq O, Nguyen TH, Ananthan S, Augelli-Szafran CE, Zhan CG, McLaughlin JP. SRI-32743, a novel allosteric modulator, attenuates HIV-1 Tat protein-induced inhibition of the dopamine transporter and alleviates the potentiation of cocaine reward in HIV-1 Tat transgenic mice. Neuropharmacology 2022; 220:109239. [PMID: 36126727 DOI: 10.1016/j.neuropharm.2022.109239] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Revised: 08/09/2022] [Accepted: 09/01/2022] [Indexed: 11/21/2022]
Abstract
Cocaine abuse increases the incidence of HIV-1-associated neurocognitive disorders. We have demonstrated that HIV-1 transactivator of transcription (Tat) allosterically modulates dopamine (DA) reuptake through the human DA transporter (hDAT), potentially contributing to Tat-induced cognitive impairment and potentiation of cocaine conditioned place preference (CPP). This study determined the effects of a novel allosteric modulator of DAT, SRI-32743, on the interactions of HIV-1 Tat, DA, cocaine, and [3H]WIN35,428 with hDAT in vitro. SRI-32743 (50 nM) attenuated Tat-induced inhibition of [3H]DA uptake and decreased the cocaine-mediated dissociation of [3H]WIN35,428 binding in CHO cells expressing hDAT, suggesting a SRI-32743-mediated allosteric modulation of the Tat-DAT interaction. In further in vivo studies utilizing doxycycline-inducible Tat transgenic (iTat-tg) mice, 14 days of Tat expression significantly reduced the recognition index by 31.7% in the final phase of novel object recognition (NOR) and potentiated cocaine-CPP 2.7-fold compared to responses of vehicle-treated control iTat-tg mice. The Tat-induced NOR deficits and potentiation of cocaine-CPP were not observed in saline-treated iTat-tg or doxycycline-treated G-tg (Tat-null) mice. Systemic administration (i.p.) of SRI-32743 prior to behavioral testing ameliorated Tat-induced impairment of NOR (at a dose of 10 mg/kg) and the Tat-induced potentiation of cocaine-CPP (at doses of 1 or 10 mg/kg). These findings demonstrate that Tat and cocaine interactions with DAT may be regulated by compounds interacting at the DAT allosteric modulatory sites, suggesting a potential therapeutic intervention for HIV-infected patients with concurrent cocaine abuse.
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Affiliation(s)
- Jun Zhu
- Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC 29208, USA.
| | - Pamela M Quizon
- Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC 29208, USA
| | - Yingying Wang
- Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC 29208, USA
| | - Charles A Adeniran
- Molecular Modeling and Biopharmaceutical Center, USA; Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA
| | - Matthew J Strauss
- Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC 29208, USA
| | - Ana C Jiménez-Torres
- Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC 29208, USA
| | - Palak Patel
- Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC 29208, USA
| | - Thomas J Cirino
- Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL 32611, USA
| | - Shainnel O Eans
- Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL 32611, USA
| | - Haylee R Hammond
- Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL 32611, USA
| | - Laure S Deliscar
- Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL 32611, USA
| | - Priscilla O'Hara
- Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL 32611, USA
| | - Surendra K Saini
- Department of Chemistry, Scientific Platforms, Southern Research, Birmingham, AL 35205, USA
| | - Edward Ofori
- Department of Chemistry, Scientific Platforms, Southern Research, Birmingham, AL 35205, USA
| | - Rakesh H Vekariya
- Department of Chemistry, Scientific Platforms, Southern Research, Birmingham, AL 35205, USA
| | - Sixue Zhang
- Department of Chemistry, Scientific Platforms, Southern Research, Birmingham, AL 35205, USA
| | - Omar Moukha-Chafiq
- Department of Chemistry, Scientific Platforms, Southern Research, Birmingham, AL 35205, USA
| | - Theresa H Nguyen
- Department of Chemistry, Scientific Platforms, Southern Research, Birmingham, AL 35205, USA
| | - Subramaniam Ananthan
- Department of Chemistry, Scientific Platforms, Southern Research, Birmingham, AL 35205, USA
| | | | - Chang-Guo Zhan
- Molecular Modeling and Biopharmaceutical Center, USA; Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA
| | - Jay P McLaughlin
- Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL 32611, USA
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40
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Blum K, Bowirrat A, Gomez LL, Downs BW, Bagchi D, Barh D, Modestino EJ, Baron D, McLaughlin T, Thanos P, Ceccanti M, Elman I, Badgaiyan RD, Dennen C, Gupta A, Braverman ER, Gold MS. Why haven't we solved the addiction crisis? J Neurol Sci 2022; 442:120404. [PMID: 36084363 DOI: 10.1016/j.jns.2022.120404] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2022] [Accepted: 08/25/2022] [Indexed: 11/22/2022]
Abstract
The current addiction crisis has destroyed a multitude of lives, leaving millions of fatalities worldwide in its wake. At the same time, various governmental agencies dedicated to solving this seemingly never-ending dilemma have not yet succeeded or delivered on their promises. We understand that addictive behavioral seeking is a multi-faceted neurobiological and spiritually complicated phenomenon. However, although the substitution replacement approach, especially to treat Opioid Use Disorder (OUD), has importance for harm reduction in the short term, it does not bring about a harm-free recovery or prevention. Instead, we propose a promising novel approach that uses genetic risk testing with induction of dopamine homeostasis and an objective Brain Health Check during youth. Our model involves a six-hit approach known as the "Reward Dysregulation Syndrome Solution System," which can identify addiction risk and target the root cause of addiction, dopamine dysregulation. While we applaud all past sophisticated neurogenetic and neuropharmacological research, our opinion is that in the long term, addiction scientists and clinicians might characterize preaddiction using tests; for example, administering the validated RDSQuestionarre29, genetic risk assessment, a modified brain health check, or diagnostic framing of mild to moderate Substance Use Disorder (SUD). The preaddiction concept could incentivize the development of interventions to prevent addiction from developing in the first place and target and treat neurotransmitter imbalances and other early indications of addiction. WC 222.
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Affiliation(s)
- Kenneth Blum
- Division of Addiction Research & Education, Center for Sports and Mental Health, Western University of Health Sciences, Pomona, CA, USA; Division of Nutrigenomics, The Kenneth Blum Neurogenetic & Behavioral Institute, LLC, Austin, TX., USA; Institute of Psychology, ELTE Eötvös Loránd University, Budapest, Hungary; Department of Psychiatry, University of Vermont, Burlington, VT., USA; Department of Psychiatry, Wright University Boonshoff School of Medicine, Dayton, OH, USA; Centre for Genomics and Applied Gene Technology, Institute of Integrative Omics and Applied Biotechnology (IIOAB), Nonakuri, Purba Medinipur, West Bengal 721172; India; Department of Nutrigenomic Research, Victory Nutrition International, Inc., Bonita Springs, FL, USA.
| | - Abdalla Bowirrat
- Department of Molecular Biology, Adelson School of Medicine, Ariel University, Ariel 40700, Israel
| | - Luis Llanos Gomez
- Division of Nutrigenomics, The Kenneth Blum Neurogenetic & Behavioral Institute, LLC, Austin, TX., USA
| | - B William Downs
- Department of Nutrigenomic Research, Victory Nutrition International, Inc., Bonita Springs, FL, USA
| | - Debasis Bagchi
- Department of Nutrigenomic Research, Victory Nutrition International, Inc., Bonita Springs, FL, USA; Department of Pharmaceutical Sciences, Texas Southern University College of Pharmacy and Health Sciences, Houston, TX, USA
| | - Debmalya Barh
- Centre for Genomics and Applied Gene Technology, Institute of Integrative Omics and Applied Biotechnology (IIOAB), Nonakuri, Purba Medinipur, West Bengal 721172; India
| | | | - David Baron
- Division of Addiction Research & Education, Center for Sports and Mental Health, Western University of Health Sciences, Pomona, CA, USA
| | - Thomas McLaughlin
- Division of Nutrigenomics, The Kenneth Blum Neurogenetic & Behavioral Institute, LLC, Austin, TX., USA
| | - Panayotis Thanos
- Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions, Clinical Research Institute on Addictions, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biosciences, State University of New York at Buffalo, Buffalo, NY, USA; Department of Psychology, State University of New York at Buffalo, Buffalo, NY., USA
| | - Mauro Ceccanti
- Alcohol Addiction Program, Latium Region Referral Center, Sapienza University of Rome, Roma, Italy
| | - Igor Elman
- Cambridge Health Alliance, Harvard Medical School, Cambridge, MA, USA
| | - Rajendra D Badgaiyan
- Department of Psychiatry, South Texas Veteran Health Care System, Audie L. Murphy Memorial VA Hospital, Long School of Medicine, University of Texas Health Science Center, San Antonio, TX., USA; Department of Psychiatry, Mt. Sinai School of Medicine, New York, NY., USA
| | - Catherine Dennen
- Department of Family Medicine, Jefferson Health Northeast, Philadelphia, PA, USA
| | - Ashim Gupta
- Future Biologics, Lawrenceville, GA 30043, USA; Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
| | - Eric R Braverman
- Division of Nutrigenomics, The Kenneth Blum Neurogenetic & Behavioral Institute, LLC, Austin, TX., USA
| | - Mark S Gold
- Future Biologics, Lawrenceville, GA 30043, USA
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Mechanical Stimulation Alters Chronic Ethanol-Induced Changes to VTA GABA Neurons, NAc DA Release and Measures of Withdrawal. Int J Mol Sci 2022; 23:ijms232012630. [PMID: 36293482 PMCID: PMC9604215 DOI: 10.3390/ijms232012630] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 10/11/2022] [Accepted: 10/14/2022] [Indexed: 11/25/2022] Open
Abstract
Therapeutic activation of mechanoreceptors (MStim) in osteopathy, chiropractic and acupuncture has been in use for hundreds of years with a myriad of positive outcomes. It has been previously shown to modulate the firing rate of neurons in the ventral tegmental area (VTA) and dopamine (DA) release in the nucleus accumbens (NAc), an area of interest in alcohol-use disorder (AUD). In this study, we examined the effects of MStim on VTA GABA neuron firing rate, DA release in the NAc, and behavior during withdrawal from chronic EtOH exposure in a rat model. We demonstrate that concurrent administration of MStim and EtOH significantly reduced adaptations in VTA GABA neurons and DA release in response to a reinstatement dose of EtOH (2.5 g/kg). Behavioral indices of EtOH withdrawal (rearing, open-field crosses, tail stiffness, gait, and anxiety) were substantively ameliorated with concurrent application of MStim. Additionally, MStim significantly increased the overall frequency of ultrasonic vocalizations, suggesting an increased positive affective state.
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42
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McWain MA, Pace RL, Nalan PA, Lester DB. Age-dependent effects of social isolation on mesolimbic dopamine release. Exp Brain Res 2022; 240:2803-2815. [PMID: 36057752 PMCID: PMC9440747 DOI: 10.1007/s00221-022-06449-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 08/21/2022] [Indexed: 12/02/2022]
Abstract
In humans, social isolation is a known risk factor for disorders such as substance use disorder and depression. In rodents, social isolation is a commonly used environmental manipulation that increases the occurrence of behaviors related to these disorders. Age is thought to influence the effects of social isolation, but this predictive relationship is not well-understood. The present study aimed to determine the effects of social isolation on mesolimbic dopamine release at different developmental age points in mice. The experimental ages and their corresponding comparison to human age stages are as follows: 1 month = adolescence, 4 months = mature adulthood, 12 months = middle adulthood, and 18 months = older adult. Mice were socially isolated for 6 weeks during these developmental stages, then in vivo fixed potential amperometry with recording electrodes in the nucleus accumbens was used to measure stimulation-evoked dopamine release, the synaptic half-life of dopamine, dopamine autoreceptor functioning, and the dopaminergic response to cocaine. Isolation altered dopamine functioning in an age-dependent manner. Specifically, isolation increased dopamine release in the adult ages, but not adolescence, potentially due to increased inhibitory effects of dopamine autoreceptors following adolescent social isolation. Regarding the cocaine challenge, isolation increased dopaminergic responses to cocaine in adolescent mice, but not the adult mice. These findings have implications for clinical and experimental settings. Elucidating the relationship between age, social isolation, and neurochemical changes associated with substance use disorder and depression may lead to improvements in preventing and treating these disorders.
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Affiliation(s)
- Megan A McWain
- Department of Psychology, The University of Memphis, Memphis, TN, 38152-6400, USA
| | - Rachel L Pace
- Department of Psychology, The University of Memphis, Memphis, TN, 38152-6400, USA
| | - Patricia A Nalan
- Department of Psychology, The University of Memphis, Memphis, TN, 38152-6400, USA
| | - Deranda B Lester
- Department of Psychology, The University of Memphis, Memphis, TN, 38152-6400, USA.
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Zhang M, Gao X, Yang Z, Han S, Zhou B, Niu X, Wang W, Wei Y, Cheng J, Zhang Y. Abnormal resting‐state effective connectivity in reward network among long‐term male smokers. Addict Biol 2022; 27:e13221. [DOI: 10.1111/adb.13221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 07/15/2022] [Accepted: 07/21/2022] [Indexed: 11/29/2022]
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Uliana DL, Gomes FV, Grace AA. Nucleus reuniens inactivation reverses stress-induced hypodopaminergic state and altered hippocampal-accumbens synaptic plasticity. Neuropsychopharmacology 2022; 47:1513-1522. [PMID: 35488085 PMCID: PMC9205859 DOI: 10.1038/s41386-022-01333-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 03/11/2022] [Accepted: 04/19/2022] [Indexed: 11/09/2022]
Abstract
The nucleus reuniens of the thalamus (RE) is a pivotal area responsible for the connectivity of the prefrontal-hippocampus pathway that regulates cognitive, executive, and fear learning processes. Recently, it was proposed that the RE participates in the pathophysiological states related to affective dysregulation. We investigated the role of RE in motivational behavioral and electrophysiological dysregulation induced by stress. Adult Sprague-Dawley rats were exposed to a combination of stressors (restraint stress+footshock) for 10 days and tested one to two weeks later in the forced swim test (FST), ventral tegmental area (VTA)dopamine (DA) neuron electrophysiological activity, and hippocampal-nucleus accumbens plasticity. The RE was inactivated by injecting TTX prior to the procedures. The stress exposure increased the immobility in the FST and decreased VTA DA neuron population activity. Whereas an early long-term potentiation (e-LTP) in the ventral hippocampus-nucleus accumbens pathway was found after fimbria high-frequency stimulation in naïve animals, stressed animals showed an early long-term depression (e-LTD). Inactivation of the RE reversed the stress-induced changes in the FST and restored dopaminergic activity. RE inactivation partially recovered the stress-induced abnormal hippocampal-accumbens plasticity observed in controls. Our findings support the role of the RE in regulating affective dysregulation and blunted VTA DA system function induced by stress. Also, it points to the hippocampal-accumbens pathway as a potential neural circuit through which RE could modulate activity. Therefore, RE may represent a key brain region involved in the neurobiology of amotivational states and may provide insights into circuit dysfunction and markers of the maladaptive stress response.
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Affiliation(s)
- Daniela L. Uliana
- grid.21925.3d0000 0004 1936 9000Departments of Neuroscience, Psychiatry and Psychology, University of Pittsburgh, Pittsburgh, PA USA
| | - Felipe V. Gomes
- grid.21925.3d0000 0004 1936 9000Departments of Neuroscience, Psychiatry and Psychology, University of Pittsburgh, Pittsburgh, PA USA ,grid.11899.380000 0004 1937 0722Present Address: Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP Brazil
| | - Anthony A. Grace
- grid.21925.3d0000 0004 1936 9000Departments of Neuroscience, Psychiatry and Psychology, University of Pittsburgh, Pittsburgh, PA USA
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Camchong J, Haynos AF, Hendrickson T, Fiecas MB, Gilmore CS, Mueller BA, Kushner MG, Lim KO. Resting Hypoconnectivity of Theoretically Defined Addiction Networks during Early Abstinence Predicts Subsequent Relapse in Alcohol Use Disorder. Cereb Cortex 2022; 32:2688-2702. [PMID: 34671808 PMCID: PMC9393062 DOI: 10.1093/cercor/bhab374] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 09/15/2021] [Accepted: 09/16/2021] [Indexed: 11/13/2022] Open
Abstract
Theoretical models of addiction suggest that alterations in addiction domains including incentive salience, negative emotionality, and executive control lead to relapse in alcohol use disorder (AUD). To determine whether the functional organization of neural networks underlying these domains predict subsequent relapse, we generated theoretically defined addiction networks. We collected resting functional magnetic resonance imaging data from 45 individuals with AUD during early abstinence (number of days abstinent M = 25.40, SD = 16.51) and calculated the degree of resting-state functional connectivity (RSFC) within these networks. Regression analyses determined whether the RSFC strength in domain-defined addiction networks measured during early abstinence predicted subsequent relapse (dichotomous or continuous relapse metrics). RSFC within each addiction network measured during early abstinence was significantly lower in those that relapsed (vs. abstained) and predicted subsequent time to relapse. Lower incentive salience RSFC during early abstinence increased the odds of relapsing. Neither RSFC in a control network nor clinical self-report measures predicted relapse. The association between low incentive salience RSFC and faster relapse highlights the need to design timely interventions that enhance RSFC in AUD individuals at risk of relapsing faster.
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Affiliation(s)
- J Camchong
- Department of Psychiatry and Behavioral Sciences, University of Minnesota, MN 55454, USA
| | - A F Haynos
- Department of Psychiatry and Behavioral Sciences, University of Minnesota, MN 55454, USA
| | - T Hendrickson
- University of Minnesota Informatics Institute, University of Minnesota, Minneapolis, MN 55455, USA
| | - M B Fiecas
- Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN 55455, USA
| | - C S Gilmore
- Geriatric Research, Education, and Clinical Center (GRECC), Minneapolis VA Health Care System, Minneapolis, MN 55417, USA
| | - B A Mueller
- Department of Psychiatry and Behavioral Sciences, University of Minnesota, MN 55454, USA
| | - M G Kushner
- Department of Psychiatry and Behavioral Sciences, University of Minnesota, MN 55454, USA
| | - K O Lim
- Department of Psychiatry and Behavioral Sciences, University of Minnesota, MN 55454, USA
- Geriatric Research, Education, and Clinical Center (GRECC), Minneapolis VA Health Care System, Minneapolis, MN 55417, USA
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Digital Addiction and Sleep. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:ijerph19116910. [PMID: 35682491 PMCID: PMC9179985 DOI: 10.3390/ijerph19116910] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 06/02/2022] [Accepted: 06/03/2022] [Indexed: 12/25/2022]
Abstract
In 2020, the World Health Organization formally recognized addiction to digital technology (connected devices) as a worldwide problem, where excessive online activity and internet use lead to inability to manage time, energy, and attention during daytime and produce disturbed sleep patterns or insomnia during nighttime. Recent studies have shown that the problem has increased in magnitude worldwide during the COVID-19 pandemic. The extent to which dysfunctional sleep is a consequence of altered motivation, memory function, mood, diet, and other lifestyle variables or results from excess of blue-light exposure when looking at digital device screens for long hours at day and night is one of many still unresolved questions. This article offers a narrative overview of some of the most recent literature on this topic. The analysis provided offers a conceptual basis for understanding digital addiction as one of the major reasons why people, and adolescents in particular, sleep less and less well in the digital age. It discusses definitions as well as mechanistic model accounts in context. Digital addiction is identified as functionally equivalent to all addictions, characterized by the compulsive, habitual, and uncontrolled use of digital devices and an excessively repeated engagement in a particular online behavior. Once the urge to be online has become uncontrollable, it is always accompanied by severe sleep loss, emotional distress, depression, and memory dysfunction. In extreme cases, it may lead to suicide. The syndrome has been linked to the known chronic effects of all drugs, producing disturbances in cellular and molecular mechanisms of the GABAergic and glutamatergic neurotransmitter systems. Dopamine and serotonin synaptic plasticity, essential for impulse control, memory, and sleep function, are measurably altered. The full spectrum of behavioral symptoms in digital addicts include eating disorders and withdrawal from outdoor and social life. Evidence pointing towards dysfunctional melatonin and vitamin D metabolism in digital addicts should be taken into account for carving out perspectives for treatment. The conclusions offer a holistic account for digital addiction, where sleep deficit is one of the key factors.
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Wetzel HN, Tsibulsky VL, Norman AB. Differential effects of acute and chronic antagonist and an irreversible antagonist treatment on cocaine self-administration behavior in rats. Sci Rep 2022; 12:8782. [PMID: 35610298 PMCID: PMC9130121 DOI: 10.1038/s41598-022-12798-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Accepted: 05/09/2022] [Indexed: 11/21/2022] Open
Abstract
According to pharmacological theory, the magnitude of an agonist-induced response is related to the number of receptors occupied. If there is a receptor reserve, when the number of receptors is altered the fractional occupancy required to maintain this set number of receptors will change. Therefore, any change in dopamine receptor number will result in a change in the concentration of cocaine required to induce the satiety response. Rats that self-administered cocaine were treated with the irreversible monoamine receptor antagonist, EEDQ, or were infused continuously for 14 days with the D1-like antagonist, SCH23390, treatments known to decrease or increase, respectively, the number of dopamine receptors with a concomitant decrease or increase in response to dopaminergic agonists. The rate of cocaine maintained self-administration increased or decreased in rats treated with EEDQ or withdrawn from chronic SCH23390 infusion, respectively. After EEDQ treatment, the effect ratio of a single dose of SCH23390 or eticlopride were unchanged, indicating that the same SCH23390- and eticlopride-sensitive receptor populations (presumably dopamine) mediated the accelerated cocaine self-administration. Changing the receptor reserve is a key determinant of the rate of cocaine self-administration because the resulting increased or decreased concentration of cocaine results in an accelerated or decelerated rate of cocaine elimination as dictated by first-order kinetics.
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Affiliation(s)
- Hanna N Wetzel
- Department of Pharmacology and Systems Physiology, University of Cincinnati, College of Medicine, 231 Albert Sabin Way, Cincinnati, OH, 45267-0575, USA.,Department of Biology, Xavier University, 3800 Victory Parkway, Cincinnati, OH, 45207, USA
| | - Vladimir L Tsibulsky
- Department of Pharmacology and Systems Physiology, University of Cincinnati, College of Medicine, 231 Albert Sabin Way, Cincinnati, OH, 45267-0575, USA
| | - Andrew B Norman
- Department of Pharmacology and Systems Physiology, University of Cincinnati, College of Medicine, 231 Albert Sabin Way, Cincinnati, OH, 45267-0575, USA.
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Becker-Krail DD, Walker WH, Nelson RJ. The Ventral Tegmental Area and Nucleus Accumbens as Circadian Oscillators: Implications for Drug Abuse and Substance Use Disorders. Front Physiol 2022; 13:886704. [PMID: 35574492 PMCID: PMC9094703 DOI: 10.3389/fphys.2022.886704] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 04/04/2022] [Indexed: 12/15/2022] Open
Abstract
Circadian rhythms convergently evolved to allow for optimal synchronization of individuals’ physiological and behavioral processes with the Earth’s 24-h periodic cycling of environmental light and temperature. Whereas the suprachiasmatic nucleus (SCN) is considered the primary pacemaker of the mammalian circadian system, many extra-SCN oscillatory brain regions have been identified to not only exhibit sustainable rhythms in circadian molecular clock function, but also rhythms in overall region activity/function and mediated behaviors. In this review, we present the most recent evidence for the ventral tegmental area (VTA) and nucleus accumbens (NAc) to serve as extra-SCN oscillators and highlight studies that illustrate the functional significance of the VTA’s and NAc’s inherent circadian properties as they relate to reward-processing, drug abuse, and vulnerability to develop substance use disorders (SUDs).
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Affiliation(s)
- Darius D Becker-Krail
- Department of Neuroscience, Rockefeller Neuroscience Institute, West Virginia University, Morgantown, WV, United States
| | - William H Walker
- Department of Neuroscience, Rockefeller Neuroscience Institute, West Virginia University, Morgantown, WV, United States
| | - Randy J Nelson
- Department of Neuroscience, Rockefeller Neuroscience Institute, West Virginia University, Morgantown, WV, United States
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Operant Responding: Beyond Rate and Interresponse Times. Brain Res Bull 2022; 186:79-87. [DOI: 10.1016/j.brainresbull.2022.05.009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 05/10/2022] [Accepted: 05/19/2022] [Indexed: 11/30/2022]
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Sheikh-Wu SF, Gerber KS, Pinto MD, Downs CA. Mechanisms and Methods to Understand Depressive Symptoms. Issues Ment Health Nurs 2022; 43:434-446. [PMID: 34752200 DOI: 10.1080/01612840.2021.1998261] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Depressive symptoms, feelings of sadness, anger, and loss that interfere with a person's daily life, are prevalent health concerns across populations that significantly result in adverse health outcomes with direct and indirect economic burdens at a national and global level. This article aims to synthesize known mechanisms of depressive symptoms and the established and emerging methodologies used to understand depressive symptoms; implications and directions for future nursing research are discussed. A comprehensive search was performed by Cumulative Index to Nursing and Allied Health Literature, MEDLINE, and PUBMED databases between 2000-2021 to examine contributing factors of depressive symptoms. Many environmental, psychological, and physiological factors are associated with the development or increased severity of depressive symptoms (anhedonia, fatigue, sleep and appetite disturbances to depressed mood). This paper discusses biological and psychological theories that guide our understanding of depressive symptoms, as well as known biomarkers (gut microbiome, specific genes, multi-cytokine, and hormones) and established and emerging methods. Disruptions within the nervous system, hormonal and neurotransmitters levels, brain structure, gut-brain axis, leaky-gut syndrome, immune and inflammatory process, and genetic variations are significant mediating mechanisms in depressive symptomology. Nursing research and practice are at the forefront of furthering depressive symptoms' mechanisms and methods. Utilizing advanced technology and measurement tools (big data, machine learning/artificial intelligence, and multi-omic approaches) can provide insight into the psychological and biological mechanisms leading to effective intervention development. Thus, understanding depressive symptomology provides a pathway to improve patients' health outcomes, leading to reduced morbidity and mortality and the overall nation-wide economic burden.Supplemental data for this article is available online at https://doi.org/10.1080/01612840.2021.1998261 .
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Affiliation(s)
- Sameena F Sheikh-Wu
- School of Nursing and Health Studies, University of Miami, Coral Gables, Florida, USA
| | - Kathryn S Gerber
- School of Nursing and Health Studies, University of Miami, Coral Gables, Florida, USA
| | - Melissa D Pinto
- Sue and Bill Gross School of Nursing, University of California, Irvine, California, USA
| | - Charles A Downs
- School of Nursing and Health Studies, University of Miami, Coral Gables, Florida, USA
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