mGlu5 Receptor Blockade Within the Nucleus Accumbens Shell Reduces Behavioral Indices of Alcohol Withdrawal-Induced Anxiety in Mice
Withdrawal from binge-drinking increases negative affect, coinciding with increased expression of the metabotropic glutamate receptor 5 (mGlu5) within the shell of the nucleus accumbens (AcbSh). Supporting a causal-effect relationship, systemic treatment with the mGlu5 receptor antagonist MTEP [3-((...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2018-11-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fphar.2018.01306/full |
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| author | Kaziya M. Lee Michal A. Coelho MacKayla A. Class Kimberly R. Sern Mark D. Bocz Karen K. Szumlinski Karen K. Szumlinski |
| author_facet | Kaziya M. Lee Michal A. Coelho MacKayla A. Class Kimberly R. Sern Mark D. Bocz Karen K. Szumlinski Karen K. Szumlinski |
| author_sort | Kaziya M. Lee |
| collection | DOAJ |
| description | Withdrawal from binge-drinking increases negative affect, coinciding with increased expression of the metabotropic glutamate receptor 5 (mGlu5) within the shell of the nucleus accumbens (AcbSh). Supporting a causal-effect relationship, systemic treatment with the mGlu5 receptor antagonist MTEP [3-((2-Methyl-4-thiazolyl)ethynyl)pyridine] is anxiolytic in binge-drinking adult and adolescent mice. Here, we employed neuropharmacological approaches to examine the functional relevance of AcbSh mGlu5 for behavioral indices of alcohol withdrawal-induced hyper-anxiety. Adult (PND 56) and adolescent (PND 28) male C57BL/6J mice consumed alcohol under modified Drinking-in-the-Dark procedures (10, 20, and 40% alcohol v/v) for 14 days. At an alcohol withdrawal time-point when mice manifest robust behavioral signs of hyper-anxiety (1 and 28 days withdrawal for adults and adolescents, respectively), mice were infused intra-AcbSh with 0, 1 or 10 μg MTEP and then affect was assayed in the light-dark shuttle box, marble-burying and forced swim tests. Brain tissue was collected to evaluate changes in Egr1 (early growth response protein 1) induction to index AcbSh neuronal activity. As expected, alcohol-experienced mice exhibited behavioral signs of hyper-emotionality. The anxiolytic effects of intra-AchSh MTEP were modest, but dose-dependent, and varied with age of drinking-onset. In adult-onset mice, only the 1 μg MTEP dose reduced withdrawal-induced hyper-anxiety, whereas only the higher dose was effective in adolescent-onset animals. MTEP reduced Egr1 expression within the AcbSh, irrespective of alcohol drinking history or age of drinking-onset. However, only the high MTEP dose reduced Egr1 expression in adolescent-onset binging mice. These results implicate AcbSh mGlu5 in modulating alcohol withdrawal-induced negative affect and suggest age differences in the neurobiological effects of alcohol withdrawal and behavioral responsiveness to mGlu5 blockade within the AcbSh. |
| first_indexed | 2024-04-14T05:50:53Z |
| format | Article |
| id | doaj.art-d1899161eee244e1bbf3e2b92a7098e6 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-14T05:50:53Z |
| publishDate | 2018-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-d1899161eee244e1bbf3e2b92a7098e62022-12-22T02:09:07ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122018-11-01910.3389/fphar.2018.01306392189mGlu5 Receptor Blockade Within the Nucleus Accumbens Shell Reduces Behavioral Indices of Alcohol Withdrawal-Induced Anxiety in MiceKaziya M. Lee0Michal A. Coelho1MacKayla A. Class2Kimberly R. Sern3Mark D. Bocz4Karen K. Szumlinski5Karen K. Szumlinski6Department of Psychological & Brain Sciences, University of California, Santa Barbara, Santa Barbara, CA, United StatesDepartment of Psychological & Brain Sciences, University of California, Santa Barbara, Santa Barbara, CA, United StatesDepartment of Psychological & Brain Sciences, University of California, Santa Barbara, Santa Barbara, CA, United StatesDepartment of Psychological & Brain Sciences, University of California, Santa Barbara, Santa Barbara, CA, United StatesDepartment of Psychological & Brain Sciences, University of California, Santa Barbara, Santa Barbara, CA, United StatesDepartment of Psychological & Brain Sciences, University of California, Santa Barbara, Santa Barbara, CA, United StatesDepartment of Molecular, Cellular, and Developmental Biology and the Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, CA, United StatesWithdrawal from binge-drinking increases negative affect, coinciding with increased expression of the metabotropic glutamate receptor 5 (mGlu5) within the shell of the nucleus accumbens (AcbSh). Supporting a causal-effect relationship, systemic treatment with the mGlu5 receptor antagonist MTEP [3-((2-Methyl-4-thiazolyl)ethynyl)pyridine] is anxiolytic in binge-drinking adult and adolescent mice. Here, we employed neuropharmacological approaches to examine the functional relevance of AcbSh mGlu5 for behavioral indices of alcohol withdrawal-induced hyper-anxiety. Adult (PND 56) and adolescent (PND 28) male C57BL/6J mice consumed alcohol under modified Drinking-in-the-Dark procedures (10, 20, and 40% alcohol v/v) for 14 days. At an alcohol withdrawal time-point when mice manifest robust behavioral signs of hyper-anxiety (1 and 28 days withdrawal for adults and adolescents, respectively), mice were infused intra-AcbSh with 0, 1 or 10 μg MTEP and then affect was assayed in the light-dark shuttle box, marble-burying and forced swim tests. Brain tissue was collected to evaluate changes in Egr1 (early growth response protein 1) induction to index AcbSh neuronal activity. As expected, alcohol-experienced mice exhibited behavioral signs of hyper-emotionality. The anxiolytic effects of intra-AchSh MTEP were modest, but dose-dependent, and varied with age of drinking-onset. In adult-onset mice, only the 1 μg MTEP dose reduced withdrawal-induced hyper-anxiety, whereas only the higher dose was effective in adolescent-onset animals. MTEP reduced Egr1 expression within the AcbSh, irrespective of alcohol drinking history or age of drinking-onset. However, only the high MTEP dose reduced Egr1 expression in adolescent-onset binging mice. These results implicate AcbSh mGlu5 in modulating alcohol withdrawal-induced negative affect and suggest age differences in the neurobiological effects of alcohol withdrawal and behavioral responsiveness to mGlu5 blockade within the AcbSh.https://www.frontiersin.org/article/10.3389/fphar.2018.01306/fullbinge drinkingadolescencegroup 1 metabotropic glutamate receptorsanxietydepressionalcoholism |
| spellingShingle | Kaziya M. Lee Michal A. Coelho MacKayla A. Class Kimberly R. Sern Mark D. Bocz Karen K. Szumlinski Karen K. Szumlinski mGlu5 Receptor Blockade Within the Nucleus Accumbens Shell Reduces Behavioral Indices of Alcohol Withdrawal-Induced Anxiety in Mice Frontiers in Pharmacology binge drinking adolescence group 1 metabotropic glutamate receptors anxiety depression alcoholism |
| title | mGlu5 Receptor Blockade Within the Nucleus Accumbens Shell Reduces Behavioral Indices of Alcohol Withdrawal-Induced Anxiety in Mice |
| title_full | mGlu5 Receptor Blockade Within the Nucleus Accumbens Shell Reduces Behavioral Indices of Alcohol Withdrawal-Induced Anxiety in Mice |
| title_fullStr | mGlu5 Receptor Blockade Within the Nucleus Accumbens Shell Reduces Behavioral Indices of Alcohol Withdrawal-Induced Anxiety in Mice |
| title_full_unstemmed | mGlu5 Receptor Blockade Within the Nucleus Accumbens Shell Reduces Behavioral Indices of Alcohol Withdrawal-Induced Anxiety in Mice |
| title_short | mGlu5 Receptor Blockade Within the Nucleus Accumbens Shell Reduces Behavioral Indices of Alcohol Withdrawal-Induced Anxiety in Mice |
| title_sort | mglu5 receptor blockade within the nucleus accumbens shell reduces behavioral indices of alcohol withdrawal induced anxiety in mice |
| topic | binge drinking adolescence group 1 metabotropic glutamate receptors anxiety depression alcoholism |
| url | https://www.frontiersin.org/article/10.3389/fphar.2018.01306/full |
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