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Lorek M, Kamiński P, Baszyński J, Tadrowski T, Gorzelańczyk EJ, Feit J, Kurhaluk N, Woźniak A, Tkaczenko H. Molecular and Environmental Determinants of Addictive Substances. Biomolecules 2024; 14:1406. [PMID: 39595582 PMCID: PMC11592269 DOI: 10.3390/biom14111406] [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: 09/11/2024] [Revised: 10/25/2024] [Accepted: 11/02/2024] [Indexed: 11/28/2024] Open
Abstract
Knowledge about determinants of addiction in people taking addictive substances is poor and needs to be supplemented. The novelty of this paper consists in the analysis of innovative aspects of current research about relationships between determinants of addiction in Polish patients taking addictive substances and rare available data regarding the relationships between these factors from studies from recent years from other environments, mainly in Europe, and on the development of genetic determinants of physiological responses. We try to explain the role of the microelements Mn, Fe, Cu, Co, Zn, Cr, Ni, Tl, Se, Al, B, Mo, V, Sn, Sb, Ag, Sr, and Ba, the toxic metals Cd, Hg, As, and Pb, and the rare earth elements Sc, La, Ce, Pr, Eu, Gd, and Nd as factors that may shape the development of addiction to addictive substances or drugs. The interactions between factors (gene polymorphism, especially ANKK1 (TaqI A), ANKK1 (Taq1 A-CT), DRD2 (TaqI B, DRD2 Taq1 B-GA, DRD2 Taq1 B-AA, DRD2-141C Ins/Del), and OPRM1 (A118G)) in patients addicted to addictive substances and consumption of vegetables, consumption of dairy products, exposure to harmful factors, and their relationships with physiological responses, which confirm the importance of internal factors as determinants of addiction, are analyzed, taking into account gender and region. The innovation of this review is to show that the homozygous TT mutant of the ANKK1 TaqI A polymorphism rs 1800497 may be a factor in increased risk of opioid dependence. We identify a variation in the functioning of the immune system in addicted patients from different environments as a result of the interaction of polymorphisms.
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Affiliation(s)
- Małgorzata Lorek
- Division of Ecology and Environmental Protection, Department of Medical Biology and Biochemistry, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, M. Skłodowska-Curie St. 9, PL 85-094 Bydgoszcz, Poland; (M.L.); (J.B.)
| | - Piotr Kamiński
- Division of Ecology and Environmental Protection, Department of Medical Biology and Biochemistry, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, M. Skłodowska-Curie St. 9, PL 85-094 Bydgoszcz, Poland; (M.L.); (J.B.)
- Department of Biotechnology, Institute of Biological Sciences, Faculty of Biological Sciences, University of Zielona Góra, Prof. Z. Szafran St. 1, PL 65-516 Zielona Góra, Poland
| | - Jędrzej Baszyński
- Division of Ecology and Environmental Protection, Department of Medical Biology and Biochemistry, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, M. Skłodowska-Curie St. 9, PL 85-094 Bydgoszcz, Poland; (M.L.); (J.B.)
| | - Tadeusz Tadrowski
- Department of Dermatology and Venereology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, M. Skłodowska-Curie St. 9, PL 85-094 Bydgoszcz, Poland;
| | - Edward Jacek Gorzelańczyk
- Institute of Philosophy, Kazimierz Wielki University in Bydgoszcz, M.K. Ogiński St. 16, PL 85-092 Bydgoszcz, Poland;
- Faculty of Mathematics and Computer Science, Adam Mickiewicz University in Poznań, Uniwersytet Poznański St., 4, PL 61-614 Poznań, Poland
- Primate Cardinal Stefan Wyszyński Provincial Hospital in Sieradz, Psychiatric Centre in Warta, Sieradzka St. 3, PL 98-290 Warta, Poland
- Department of Theoretical Foundations of Biomedical Sciences and Medical Computer Science, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Jagiellońska St. 15, PL 85-067 Bydgoszcz, Poland
| | - Julia Feit
- Pallmed sp. z o.o., W. Roentgen St. 3, PL 85-796 Bydgoszcz, Poland;
| | - Natalia Kurhaluk
- Department of Animal Physiology, Institute of Biology, Pomeranian University in Słupsk, Arciszewski St. 22 B, PL 76-200 Słupsk, Poland; (N.K.); (H.T.)
| | - Alina Woźniak
- Department of Medical Biology and Biochemistry, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, M. Karłowicz St. 24, PL 85-092 Bydgoszcz, Poland;
| | - Halina Tkaczenko
- Department of Animal Physiology, Institute of Biology, Pomeranian University in Słupsk, Arciszewski St. 22 B, PL 76-200 Słupsk, Poland; (N.K.); (H.T.)
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Kalinowski D, Bogus-Nowakowska K, Kozłowska A, Równiak M. Dopaminergic and cholinergic modulation of the amygdala is altered in female mice with oestrogen receptor β deprivation. Sci Rep 2023; 13:897. [PMID: 36650256 PMCID: PMC9845293 DOI: 10.1038/s41598-023-28069-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 01/12/2023] [Indexed: 01/18/2023] Open
Abstract
The amygdala is modulated by dopaminergic and cholinergic neurotransmission, and this modulation is altered in mood disorders. Therefore, this study was designed to evaluate the presence/absence of quantitative alterations in the expression of main dopaminergic and cholinergic markers in the amygdala of mice with oestrogen receptor β (ERβ) knock-out which exhibit increased anxiety, using immunohistochemistry and quantitative methods. Such alterations could either contribute to increased anxiety or be a compensatory mechanism for reducing anxiety. The results show that among dopaminergic markers, the expression of tyrosine hydroxylase (TH), dopamine transporter (DAT) and dopamine D2-like receptor (DA2) is significantly elevated in the amygdala of mice with ERβ deprivation when compared to matched controls, whereas the content of dopamine D1-like receptor (DA1) is not altered by ERβ knock-out. In the case of cholinergic markers, muscarinic acetylcholine type 1 receptor (AChRM1) and alpha-7 nicotinic acetylcholine receptor (AChRα7) display overexpression while the content of acetylcholinesterase (AChE) and vesicular acetylcholine transporter (VAChT) remains unchanged. In conclusion, in the amygdala of ERβ knock-out female the dopaminergic and cholinergic signalling is altered, however, to determine the exact role of ERβ in the anxiety-related behaviour further studies are required.
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Affiliation(s)
- Daniel Kalinowski
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, pl. Łódzki 3, 10-727, Olsztyn, Poland.
| | - Krystyna Bogus-Nowakowska
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, pl. Łódzki 3, 10-727, Olsztyn, Poland
| | - Anna Kozłowska
- Department of Human Physiology and Pathophysiology, School of Medicine, University of Warmia and Mazury in Olsztyn, Warszawska 30, 10-082, Olsztyn, Poland
| | - Maciej Równiak
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, pl. Łódzki 3, 10-727, Olsztyn, Poland
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Short-Term Consequences of Single Social Defeat on Accumbal Dopamine and Behaviors in Rats. Biomolecules 2022; 13:biom13010035. [PMID: 36671420 PMCID: PMC9855991 DOI: 10.3390/biom13010035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 12/19/2022] [Accepted: 12/22/2022] [Indexed: 12/28/2022] Open
Abstract
The present study aimed to explore the consequences of a single exposure to a social defeat on dopamine release in the rat nucleus accumbens measured with a fast-scan cyclic voltammetry. We found that 24 h after a social defeat, accumbal dopamine responses, evoked by a high frequency electrical stimulation of the ventral tegmental area, were more profound in socially defeated rats in comparison with non-defeated control animals. The enhanced dopamine release was associated with the prolonged immobility time in the forced swim test. The use of the dopamine depletion protocol revealed no alteration in the reduction and recovery of the amplitude of dopamine release following social defeat stress. However, administration of dopamine D2 receptor antagonist, raclopride (2 mg/kg, i.p.), resulted in significant increase of the electrically evoked dopamine release in both groups of animals, nevertheless exhibiting less manifested effect in the defeated rats comparing to control animals. Taken together, our data demonstrated profound alterations in the dopamine transmission in the association with depressive-like behavior following a single exposure to stressful environment. These voltammetric findings pointed to a promising path for the identification of neurobiological mechanisms underlying stress-promoted behavioral abnormalities.
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Rami FZ, Nguyen TB, Oh YE, Karamikheirabad M, Le TH, Chung YC. Risperidone Induced DNA Methylation Changes in Dopamine Receptor and Stathmin Genes in Mice Exposed to Social Defeat Stress. CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE 2022; 20:373-388. [PMID: 35466108 PMCID: PMC9048015 DOI: 10.9758/cpn.2022.20.2.373] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 07/11/2021] [Accepted: 07/12/2021] [Indexed: 11/18/2022]
Abstract
Objective Methods Results Conclusion
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Affiliation(s)
- Fatima Zahra Rami
- Department of Psychiatry, Jeonbuk National University Medical School, Jeonju, Korea
- Research Institute of Clinical Medicine of Jeonbuk National University and Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju, Korea
| | - Thong Ba Nguyen
- Department of Psychiatry, Jeonbuk National University Medical School, Jeonju, Korea
- Research Institute of Clinical Medicine of Jeonbuk National University and Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju, Korea
| | - Young-Eun Oh
- Department of Psychiatry, Jeonbuk National University Medical School, Jeonju, Korea
- Research Institute of Clinical Medicine of Jeonbuk National University and Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju, Korea
| | - Maryam Karamikheirabad
- Department of Psychiatry, Jeonbuk National University Medical School, Jeonju, Korea
- Research Institute of Clinical Medicine of Jeonbuk National University and Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju, Korea
| | - Thi-Hung Le
- Department of Psychiatry, Jeonbuk National University Medical School, Jeonju, Korea
- Research Institute of Clinical Medicine of Jeonbuk National University and Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju, Korea
| | - Young-Chul Chung
- Department of Psychiatry, Jeonbuk National University Medical School, Jeonju, Korea
- Research Institute of Clinical Medicine of Jeonbuk National University and Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju, Korea
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Ugwu PI, Ben-Azu B, Ugwu SU, Uruaka CI, Nworgu CC, Okorie PO, Okafor KO, Anachuna KK, Elendu MU, Ugwu AO, Anyaehie UB, Nwankwo AA, Osim EE. Putative mechanisms involved in the psychopathologies of mice passively coping with psychosocial defeat stress by quercetin. Brain Res Bull 2022; 183:127-141. [DOI: 10.1016/j.brainresbull.2022.03.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Revised: 02/15/2022] [Accepted: 03/07/2022] [Indexed: 12/14/2022]
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Calpe-López C, Martínez-Caballero MA, García-Pardo MP, Aguilar MA. Resilience to the effects of social stress on vulnerability to developing drug addiction. World J Psychiatry 2022; 12:24-58. [PMID: 35111578 PMCID: PMC8783163 DOI: 10.5498/wjp.v12.i1.24] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 08/01/2021] [Accepted: 12/23/2021] [Indexed: 02/06/2023] Open
Abstract
We review the still scarce but growing literature on resilience to the effects of social stress on the rewarding properties of drugs of abuse. We define the concept of resilience and how it is applied to the field of drug addiction research. We also describe the internal and external protective factors associated with resilience, such as individual behavioral traits and social support. We then explain the physiological response to stress and how it is modulated by resilience factors. In the subsequent section, we describe the animal models commonly used in the study of resilience to social stress, and we focus on the effects of chronic social defeat (SD), a kind of stress induced by repeated experience of defeat in an agonistic encounter, on different animal behaviors (depression- and anxiety-like behavior, cognitive impairment and addiction-like symptoms). We then summarize the current knowledge on the neurobiological substrates of resilience derived from studies of resilience to the effects of chronic SD stress on depression- and anxiety-related behaviors in rodents. Finally, we focus on the limited studies carried out to explore resilience to the effects of SD stress on the rewarding properties of drugs of abuse, describing the current state of knowledge and suggesting future research directions.
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Affiliation(s)
| | | | - Maria P García-Pardo
- Faculty of Social and Human Sciences, University of Zaragoza, Teruel 44003, Spain
| | - Maria A Aguilar
- Department of Psychobiology, University of Valencia, Valencia 46010, Spain
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Zhao T, Gao X, Huang GB. Effects of Chronic Social Defeat Stress on Behavior and Dopamine Receptors in Adolescent Mice With 6-Hydroxydopamine Lesions of the Medial Prefrontal Cortex. Front Behav Neurosci 2021; 15:731373. [PMID: 34912197 PMCID: PMC8667729 DOI: 10.3389/fnbeh.2021.731373] [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: 07/27/2021] [Accepted: 10/20/2021] [Indexed: 11/26/2022] Open
Abstract
Background: Social stress factors in schizophrenia have long-term effects, but will only induce symptoms in a portion of individuals, even if exposed to identical stress. Methods: In the current experiment, we examined mice with 6-hydroxydopamine (6-OHDA)-induced medial prefrontal cortical (mPFC) injury to select for members of a “stress-susceptible group,” and observed the changes in their behavior and the expression of D1 and D2 dopamine receptors in the amygdala and hippocampus. Results: We observed that after chronic social defeat stress, 72.6% of the 6-OHDA lesioned mice exhibited stress response to aggressors, compared to 52.3% of the blank control group. Both the 6-OHDA lesion + social defeat and social defeat groups exhibited anxiety and depression-like behavior. However, social cognitive impairment in the mice from the 6-OHDA lesion + social defeat group was more significant and the D1 expression levels in the amygdala were significantly decreased. Conclusion: These results suggest that the reason that adolescent mice with cortical injury were highly sensitive to defeat stress and had more prominent social cognitive impairment may be the decreased selectivity of D1 in the amygdala.
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Affiliation(s)
- Tong Zhao
- Department of Psychiatry, The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
| | - XiaoLei Gao
- School of Nursing, Xinxiang Medical University, Xinxiang, China
| | - Guang-Biao Huang
- Department of Psychiatry, Huzhou Third Municipal Hospital, The Affiliated Hospital of Huzhou University, Huzhou, China
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Candesartan protects against d-galactose induced - Neurotoxicity and memory deficit via modulation of autophagy and oxidative stress. Toxicol Appl Pharmacol 2021; 435:115827. [PMID: 34906534 DOI: 10.1016/j.taap.2021.115827] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 11/22/2021] [Accepted: 12/08/2021] [Indexed: 01/25/2023]
Abstract
PURPOSE d-galactose induces neuroinflammation and memory deficit via oxidative stress. Candesartan is an angiotensin II-receptor blocker and has proved neuroprotective properties. This study aimed to investigate the neuroprotective effect of candesartan against d-galactose induced neuroinflammation and memory deficit via autophagy. METHODS Twenty-eight male Wistar rats aged 3 months were divided into four equal groups: control (vehicle), d-gal (100 mg/kg d-galactose), cand (1 mg/kg candesartan), and cand+d-gal (100 mg/kg d-galactose & 1 mg/kg candesartan). All treatments were given orally and daily for 4 weeks. Assessment of memory was done using Morris water maze (MWM) test. Brain tissue was assessed for malondialdehyde (MDA), total thiol, catalase activity, glial fibrillary acidic protein (GFAP) and gene expression of TNF-α, GDNF-1 as well as autophagy genes (Beclin 1 and ATG 5). RESULTS Prophylactic treatment of candesartan in d-galactose-treated rats significantly (p < 0.001) reduced oxidative stress via reduction of MDA as well as elevation of catalase activity and total thiol levels. Additionally, candesartan prophylactic treatment significantly increased gene expression of GDNF-1 and decreased gene expression of TNF-α. Furthermore, candesartan significantly increased the expression of autophagy related gene (Beclin 1 and ATG 5) in cand+d-gal treated rats. These results were supported by the histopathological findings which showed that candesartan prevented the neuronal injury in the cerebral cortex and hippocampus and decreased GFAP positive cells of the d-galactose-treated rats. Moreover, MWM test showed that candesartan significantly improved memory deficit in cand+d-gal treated rats. CONCLUSION Candesartan prevents d-galactose-induced neurotoxicity and memory deficit via activating autophagy and decreasing oxidative stress. Therefore, candesartan was a good candidate for age-related neurodegenerative disorders and memory deficit.
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Felippe RM, Oliveira GM, Barbosa RS, Esteves BD, Gonzaga BMS, Horita SIM, Garzoni LR, Beghini DG, Araújo-Jorge TC, Fragoso VMS. Experimental Social Stress: Dopaminergic Receptors, Oxidative Stress, and c-Fos Protein Are Involved in Highly Aggressive Behavior. Front Cell Neurosci 2021; 15:696834. [PMID: 34489642 PMCID: PMC8418094 DOI: 10.3389/fncel.2021.696834] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Accepted: 07/27/2021] [Indexed: 11/18/2022] Open
Abstract
Aggression is defined as hostile behavior that results in psychological damage, injury and even death among individuals. When aggression presents itself in an exacerbated and constant way, it can be considered escalating or pathological. The association between social stress and the emergence of exacerbated aggressiveness is common and is suggested to be interconnected through very complex neurobiological factors. For example, alterations in the expression of the dopaminergic receptors D1 and D2, reactive oxygen species (ROS) and the c-Fos protein in the cortex have been observed. Our objective was to analyze which factors are involved at the neurobiological level in the highly aggressive response of Swiss Webster adult male mice in a vivarium. In this work, we investigated the relationship among dopaminergic receptors, the production of ROS and the expression of c-Fos. Mice with exacerbated aggression were identified by the model of spontaneous aggression (MSA) based on the grouping of young mice and the regrouping of the same animals in adulthood. During the regrouping, we observed different categories of behavior resulting from social stress, such as (i) highly aggressive animals, (ii) defeated animals, and (iii) harmonic groups. To evaluate the dopaminergic system and the c-Fos protein, we quantified the expression of D1 and D2 dopaminergic receptors by Western blotting and fluorescence immunohistochemistry and that of the c-Fos protein by fluorescence immunohistochemistry. The possible production of ROS was also evaluated through the dihydroethidium (DHE) assay. The results showed that aggressive and subordinate mice showed a reduction in the expression of the D1 receptor, and no significant difference in the expression of the D2 receptor was observed between the groups. In addition, aggressive mice exhibited increased production of ROS and c-Fos protein. Based on our results, we suggest that exacerbated aggression is associated with social stress, dysregulation of the dopaminergic system and exacerbated ROS production, which leads to a state of cellular oxidative stress. The overexpression of c-Fos due to social stress suggests an attempt by the cell to produce antioxidant agents to reduce the toxic cellular concentration of ROS.
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Affiliation(s)
- Renata M Felippe
- Laboratory of Innovations in Therapies, Education and Bioproducts, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
| | - Gabriel M Oliveira
- Laboratory of Cell Biology, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
| | - Rafaela S Barbosa
- Laboratory of Innovations in Therapies, Education and Bioproducts, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
| | - Betina D Esteves
- Laboratory of Innovations in Therapies, Education and Bioproducts, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
| | - Beatriz M S Gonzaga
- Laboratory of Innovations in Therapies, Education and Bioproducts, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
| | - Samuel I M Horita
- Laboratory of Innovations in Therapies, Education and Bioproducts, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil.,Laboratory on Thymus Research, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
| | - Luciana R Garzoni
- Laboratory of Innovations in Therapies, Education and Bioproducts, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
| | - Daniela G Beghini
- Laboratory of Innovations in Therapies, Education and Bioproducts, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
| | - Tânia C Araújo-Jorge
- Laboratory of Innovations in Therapies, Education and Bioproducts, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
| | - Viviane M S Fragoso
- Laboratory of Innovations in Therapies, Education and Bioproducts, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
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Quessy F, Bittar T, Blanchette LJ, Lévesque M, Labonté B. Stress-induced alterations of mesocortical and mesolimbic dopaminergic pathways. Sci Rep 2021; 11:11000. [PMID: 34040100 PMCID: PMC8154906 DOI: 10.1038/s41598-021-90521-y] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Accepted: 05/04/2021] [Indexed: 02/07/2023] Open
Abstract
Our ability to develop the cognitive strategies required to deal with daily-life stress is regulated by region-specific neuronal networks. Experimental evidence suggests that prolonged stress in mice induces depressive-like behaviors via morphological, functional and molecular changes affecting the mesolimbic and mesocortical dopaminergic pathways. Yet, the molecular interactions underlying these changes are still poorly understood, and whether they affect males and females similarly is unknown. Here, we used chronic social defeat stress (CSDS) to induce depressive-like behaviors in male and female mice. Density of the mesolimbic and mesocortical projections was assessed via immuno-histochemistry combined with Sholl analysis along with the staining of activity-dependent markers pERK and c-fos in the ventral tegmental area (VTA), nucleus accumbens (NAc) and medial prefrontal cortex (mPFC). Our results show that social stress decreases the density of TH+ dopaminergic axonal projections in the deep layers of the mPFC in susceptible but not resilient male and female mice. Consistently, our analyses suggest that pERK expression is decreased in the mPFC but increased in the NAc following CSDS in males and females, with no change in c-fos expression in both sexes. Overall, our findings indicate that social defeat stress impacts the mesolimbic and mesocortical pathways by altering the molecular interactions regulating somatic and axonal plasticity in males and females.
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Affiliation(s)
- F Quessy
- CERVO Brain Research Centre, Quebec, QC, Canada
- Department of Psychiatry and Neuroscience, Faculty of Medicine, Université Laval, Quebec, QC, Canada
| | - T Bittar
- CERVO Brain Research Centre, Quebec, QC, Canada
- Department of Psychiatry and Neuroscience, Faculty of Medicine, Université Laval, Quebec, QC, Canada
| | - L J Blanchette
- CERVO Brain Research Centre, Quebec, QC, Canada
- Department of Psychiatry and Neuroscience, Faculty of Medicine, Université Laval, Quebec, QC, Canada
| | - M Lévesque
- CERVO Brain Research Centre, Quebec, QC, Canada.
- Department of Psychiatry and Neuroscience, Faculty of Medicine, Université Laval, Quebec, QC, Canada.
| | - B Labonté
- CERVO Brain Research Centre, Quebec, QC, Canada.
- Department of Psychiatry and Neuroscience, Faculty of Medicine, Université Laval, Quebec, QC, Canada.
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Lee MY, Lin BF, Chan MH, Chen HH. Increased behavioral and neuronal responses to a hallucinogenic drug after adolescent toluene exposure in mice: Effects of antipsychotic treatment. Toxicology 2020; 445:152602. [PMID: 32980479 DOI: 10.1016/j.tox.2020.152602] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 09/19/2020] [Accepted: 09/22/2020] [Indexed: 01/23/2023]
Abstract
Toluene has been characterized as a non-classical hallucinogen drug through activation of 5-HT2A receptors and antagonism of NMDA receptors. It remains unclear whether psychotic symptoms after long-term and intense toluene exposure are associated with abnormalities in 5-HT2A receptor function. The present study examined whether the responses to a hallucinogenic 5-HT2A receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) were altered in a mouse model of toluene psychosis. Male NMRI mice were subchronically treated with toluene during adolescence. Reciprocal social interaction test and novel object recognition test were conducted to confirm the persistent behavioral deficits in adulthood. Subsequently, DOI-induced head twitch, c-Fos and Egr-2 expression, field potentials in the medial prefrontal cortex (mPFC), and the levels of 5-HT2A, 5-HT1A and mGlu2 receptors in the mPFC were monitored. Toluene exposure during adolescence produced social and memory impairments and enhanced DOI-induced behavioral, molecular and electrophysiological responses, but did not change the levels of 5-HT2A, 5-HT1A or mGlu2 receptors in the mPFC. Moreover, the effects of haloperidol and risperidone on the behavioral deficits and hyper-responsiveness to DOI after adolescent toluene exposure were compared. When administered after adolescent toluene exposure, risperidone could reverse social withdrawal, cognitive impairment and hypersensitivity to DOI, whereas haloperidol was only beneficial for social withdrawal. These findings suggest that increased functionality of 5-HT2A receptors may play a critical role in solvent-induced psychosis and recommend the antipsychotics with more selective 5-HT2A receptor antagonism as the first-line treatment for solvent-induced psychosis.
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Affiliation(s)
- Mei-Yi Lee
- Center for Neuropsychiatric Research, National Health Research Institutes, 35 Keyan Rd. Zhunan, Miaoli, 35053, Taiwan
| | - Bih-Fen Lin
- Department of Laboratory Medicine and Biotechnology School of Medicine, Tzu Chi University, No. 701, Sec. 3, Zhongyang Rd., Hualien, 97004, Taiwan
| | - Ming-Huan Chan
- Institute of Neuroscience, National Chengchi University, NO. 64, Sec. 2, Zhinan Rd., Taipei, 11605, Taiwan; Research Center for Mind, Brain, and Learning, National Chengchi University, NO. 64, Sec. 2, Zhinan Rd., Taipei, 11605, Taiwan; Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, 40402, Taiwan.
| | - Hwei-Hsien Chen
- Center for Neuropsychiatric Research, National Health Research Institutes, 35 Keyan Rd. Zhunan, Miaoli, 35053, Taiwan; Institute of Neuroscience, National Chengchi University, NO. 64, Sec. 2, Zhinan Rd., Taipei, 11605, Taiwan; Ph.D. Program in Tissue Engineering and Regenerative Medicine, National Chung Hsing University, No. 145, Xingda Rd., Taichung, 40227, Taiwan.
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Calpe-López C, García-Pardo MP, Martínez-Caballero MA, Santos-Ortíz A, Aguilar MA. Behavioral Traits Associated With Resilience to the Effects of Repeated Social Defeat on Cocaine-Induced Conditioned Place Preference in Mice. Front Behav Neurosci 2020; 13:278. [PMID: 31998090 PMCID: PMC6962131 DOI: 10.3389/fnbeh.2019.00278] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Accepted: 12/06/2019] [Indexed: 12/25/2022] Open
Abstract
The relationship between stress and drug use is well demonstrated. Stress-induced by repeated social defeat (RSD) enhances the conditioned place preference (CPP) induced by cocaine in mice. The phenomenon of resilience understood as the ability of subjects to overcome the negative effects of stress is the focus of increasing interest. Our aim is to characterize the behavior of resilient animals with respect to the effects of RSD on the CPP induced by cocaine. To this end, 25 male C57BL/6 mice were exposed to stress by RSD during late adolescence, while other 15 male mice did not undergo stress (controls). On the 2 days following the last defeat, all the animals carried out the elevated plus maze (EPM) and Hole Board, Social Interaction, Tail Suspension and Splash tests. Three weeks later, all the animals performed the CPP paradigm with a low dose of cocaine (1 mg/kg). Exposure to RSD decreased all measurements related to the open arms of the EPM. It also reduced social interaction, immobility in the tail suspension test (TST) and grooming in the splash test. RSD exposure also increased the sensitivity of the mice to the rewarding effects of cocaine, since only defeated animals acquired CPP. Several behavioral traits were related to resilience to the potentiating effect of RSD on cocaine CPP. Mice that showed less submission during defeat episodes, a lower percentage of time in the open arms of the EPM, low novelty-seeking, high social interaction, greater immobility in the TST and a higher frequency of grooming were those that were resilient to the long-term effects of social defeat on cocaine reward since they behaved like controls and did not develop CPP. These results suggest that the behavioral profile of resilient defeated mice is characterized by an active coping response during episodes of defeat, a greater concern for potential dangers, less reactivity in a situation of inevitable moderate stress and fewer depressive-like symptoms after stress. Determining the neurobehavioral substrates of resilience is the first step towards developing behavioral or pharmacological interventions that increase resilience in individuals at a high risk of suffering from stress.
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Affiliation(s)
- Claudia Calpe-López
- Neurobehavioural Mechanisms and Endophenotypes of Addictive Behavior Research Unit, Department of Psychobiology, University of Valencia, Valencia, Spain
| | - Maria Pilar García-Pardo
- Department of Psychology and Sociology, Faculty of Social Sciences, University of Zaragoza, Teruel, Spain
| | - Maria Angeles Martínez-Caballero
- Neurobehavioural Mechanisms and Endophenotypes of Addictive Behavior Research Unit, Department of Psychobiology, University of Valencia, Valencia, Spain
| | - Alejandra Santos-Ortíz
- Neurobehavioural Mechanisms and Endophenotypes of Addictive Behavior Research Unit, Department of Psychobiology, University of Valencia, Valencia, Spain
| | - Maria Asunción Aguilar
- Neurobehavioural Mechanisms and Endophenotypes of Addictive Behavior Research Unit, Department of Psychobiology, University of Valencia, Valencia, Spain
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Balog J, Hintz F, Isstas M, Teichert M, Winter C, Lehmann K. Social hierarchy regulates ocular dominance plasticity in adult male mice. Brain Struct Funct 2019; 224:3183-3199. [DOI: 10.1007/s00429-019-01959-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Accepted: 09/14/2019] [Indexed: 11/25/2022]
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Obese mice exposed to psychosocial stress display cardiac and hippocampal dysfunction associated with local brain-derived neurotrophic factor depletion. EBioMedicine 2019; 47:384-401. [PMID: 31492565 PMCID: PMC6796537 DOI: 10.1016/j.ebiom.2019.08.042] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2019] [Revised: 08/13/2019] [Accepted: 08/20/2019] [Indexed: 01/14/2023] Open
Abstract
INTRODUCTION Obesity and psychosocial stress (PS) co-exist in individuals of Western society. Nevertheless, how PS impacts cardiac and hippocampal phenotype in obese subjects is still unknown. Nor is it clear whether changes in local brain-derived neurotrophic factor (BDNF) account, at least in part, for myocardial and behavioral abnormalities in obese experiencing PS. METHODS In adult male WT mice, obesity was induced via a high-fat diet (HFD). The resident-intruder paradigm was superimposed to trigger PS. In vivo left ventricular (LV) performance was evaluated by echocardiography and pressure-volume loops. Behaviour was indagated by elevated plus maze (EPM) and Y-maze. LV myocardium was assayed for apoptosis, fibrosis, vessel density and oxidative stress. Hippocampus was analyzed for volume, neurogenesis, GABAergic markers and astrogliosis. Cardiac and hippocampal BDNF and TrkB levels were measured by ELISA and WB. We investigated the pathogenetic role played by BDNF signaling in additional cardiac-selective TrkB (cTrkB) KO mice. FINDINGS When combined, obesity and PS jeopardized LV performance, causing prominent apoptosis, fibrosis, oxidative stress and remodeling of the larger coronary branches, along with lower BDNF and TrkB levels. HFD/PS weakened LV function similarly in WT and cTrkB KO mice. The latter exhibited elevated LV ROS emission already at baseline. Obesity/PS augmented anxiety-like behaviour and impaired spatial memory. These changes were coupled to reduced hippocampal volume, neurogenesis, local BDNF and TrkB content and augmented astrogliosis. INTERPRETATION PS and obesity synergistically deteriorate myocardial structure and function by depleting cardiac BDNF/TrkB content, leading to augmented oxidative stress. This comorbidity triggers behavioral deficits and induces hippocampal remodeling, potentially via lower BDNF and TrkB levels. FUND: J.A. was in part supported by Rotary Foundation Global Study Scholarship. G.K. was supported by T32 National Institute of Health (NIH) training grant under award number 1T32AG058527. S.C. was funded by American Heart Association Career Development Award (19CDA34760185). G.A.R.C. was funded by NIH (K01HL133368-01). APB was funded by a Grant from the Friuli Venezia Giulia Region entitled: "Heart failure as the Alzheimer disease of the heart; therapeutic and diagnostic opportunities". M.C. was supported by PRONAT project (CNR). N.P. was funded by NIH (R01 HL136918) and by the Magic-That-Matters fund (JHU). V.L. was in part supported by institutional funds from Scuola Superiore Sant'Anna (Pisa, Italy), by the TIM-Telecom Italia (WHITE Lab, Pisa, Italy), by a research grant from Pastificio Attilio Mastromauro Granoro s.r.l. (Corato, Italy) and in part by ETHERNA project (Prog. n. 161/16, Fondazione Pisa, Italy). Funding source had no such involvement in study design, in the collection, analysis, interpretation of data, in the writing of the report; and in the decision to submit the paper for publication.
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Effects of Stathmin 1 Gene Knockout on Behaviors and Dopaminergic Markers in Mice Exposed to Social Defeat Stress. Brain Sci 2019; 9:brainsci9090215. [PMID: 31454951 PMCID: PMC6769668 DOI: 10.3390/brainsci9090215] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2019] [Revised: 08/19/2019] [Accepted: 08/23/2019] [Indexed: 01/08/2023] Open
Abstract
Stathmin (STMN), a microtubule-destabilizing factor, can regulate fear, anxiety, and learning. Social defeat stress (SDS) has detrimental effects on mental health and increases the risk of various psychiatric diseases. This study investigated the effects of STMN1 gene knockout (KO) on behavioral parameters and dopaminergic markers using an SDS mouse model. The STMN1 KO mice showed anxious hyperactivity, impaired object recognition, and decreased levels of neutral and social investigating behaviors at baseline compared to wild-type (WT) mice. The impact of SDS on neutral, social investigating and dominant behaviors differed markedly between the STMN1 WT and KO mice. In addition, different levels of total DARPP-32 and pDARPP-32 Thr75 expression were observed among the control, unsusceptible, and susceptible groups of STMN1 KO mice. Our results show that STMN1 has specific roles in locomotion, object recognition, and social interactions. Moreover, SDS had differential impacts on social interactions and dopaminergic markers between STMN1 WT and KO mice.
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Birla H, Keswani C, Rai SN, Singh SS, Zahra W, Dilnashin H, Rathore AS, Singh SP. Neuroprotective effects of Withania somnifera in BPA induced-cognitive dysfunction and oxidative stress in mice. BEHAVIORAL AND BRAIN FUNCTIONS : BBF 2019; 15:9. [PMID: 31064381 PMCID: PMC6503545 DOI: 10.1186/s12993-019-0160-4] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Accepted: 04/26/2019] [Indexed: 01/16/2023]
Abstract
BACKGROUND Bisphenol A (BPA), a major endocrine disruptor and a xenobiotic compound is used abundantly in the production of polycarbonate plastics and epoxy resins. Human exposure to this compound is primarily via its leaching from the protective internal epoxy resin coatings of containers into the food and beverages. In addition, the plastics used in dental prostheses and sealants also contain considerable amount of BPA and have a high risk of human exposure. Since it is a well-known endocrine disruptor and closely mimics the molecular structure of human estrogen thereby impairing learning and memory. Withania somnifera (Ws), commonly known as Ashwagandha is known for its varied therapeutic uses in Ayurvedic system of medicine. The present study was undertaken to demonstrate the impairment induced by BPA on the spatial learning, working memory and its alleviation by Ws in Swiss albino mice. The study was conducted on thirty Swiss albino mice, randomly distributed among three groups: control, BPA and BPA + Ws. The behavioral recovery after treatment with Ws was investigated using the Y-maize and Morris water maize test. Whereas, for the estimation of recovery of NMDA receptor which is related to learning and memory in hippocampus region by western blot and immunohistochemistry. Furthermore, the oxidative stress and antioxidant level was assessed by biochemical tests like MDA, SOD and catalase. RESULTS The study revealed that administration of Ws alleviated the behavioral deficits induced by BPA. Alongside, Ws treatment reinstated the number of NMDA receptors in hippocampus region and showed anti-oxidative property while ameliorating the endogenous anti-oxidant level in the brain. CONCLUSION These findings suggest that Ws significantly ameliorates the level of BPA intoxicated oxidative stress thereby potentially treating cognitive dysfunction which acts as the primary symptom in a number of neurodegenerative diseases.
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Affiliation(s)
- Hareram Birla
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, 221005 India
| | - Chetan Keswani
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, 221005 India
| | - Sachchida Nand Rai
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, 221005 India
| | - Saumitra Sen Singh
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, 221005 India
| | - Walia Zahra
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, 221005 India
| | - Hagera Dilnashin
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, 221005 India
| | - Aaina Singh Rathore
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, 221005 India
| | - Surya Pratap Singh
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, 221005 India
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