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Sex and Individual Differences in Alcohol Intake Are Associated with Differences in Ketamine Self-Administration Behaviors and Nucleus Accumbens Dendritic Spine Density.

ABSTRACT: Clinical and preclinical studies have shown that ketamine, an NMDA receptor antagonist, has promising therapeutic value for the treatment of alcohol use disorder (AUD). However, the maintenance of remission will ultimately require repeated infusions of ketamine, which may lead to abuse potential and may hinder its therapeutic benefits. It is therefore crucial to assess the effects of repeated treatments with ketamine on alcohol intake. Accordingly, this study aimed to examine in both sexes how individual differences in alcohol intake alter ketamine self-administration and how ketamine self-administration will alter subsequent alcohol-drinking behaviors. Male and female rats intermittently drank alcohol or water for 10 weeks and were divided into high- or low-alcohol intake groups prior to ketamine self-administration. Rats self-administered ketamine under fixed and progressive ratio schedules of reinforcement from week 4 to 7, and the incubation of ketamine craving was examined from week 8 to 10. To investigate structural plasticity in a brain region involved in reward, nucleus accumbens dendritic spine morphology was examined. Our results show that high alcohol intake in male rats attenuated ketamine self-administration, whereas in female rats high alcohol intake enhanced motivation to self-administer ketamine. Ketamine reduced alcohol intake in high-alcohol male rats but increased it in low-alcohol female rats. Incubation of ketamine craving developed in all groups except low-alcohol females. Three weeks of abstinence from ketamine was associated with increased mushroom spines in all groups except the high-alcohol male group. Overall, these data suggest that ketamine as a treatment for AUD may benefit male subjects, but not female subjects, and warrants further investigation before use as a therapeutic agent.

SUBMITTER: Strong CE

PROVIDER: S-EPMC6893233 | biostudies-literature | 2019 Nov/Dec

REPOSITORIES: biostudies-literature

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Sex and Individual Differences in Alcohol Intake Are Associated with Differences in Ketamine Self-Administration Behaviors and Nucleus Accumbens Dendritic Spine Density.

Strong Caroline E CE Wright Katherine N KN Kabbaj Mohamed M

eNeuro 20191101 6

Clinical and preclinical studies have shown that ketamine, an NMDA receptor antagonist, has promising therapeutic value for the treatment of alcohol use disorder (AUD). However, the maintenance of remission will ultimately require repeated infusions of ketamine, which may lead to abuse potential and may hinder its therapeutic benefits. It is therefore crucial to assess the effects of repeated treatments with ketamine on alcohol intake. Accordingly, this study aimed to examine in both sexes how i ...[more]

PMID: 31740575

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Project description:UnlabelledDepression is a recurring and life-threatening illness that affects up to 120 million people worldwide. In the present study, we show that chronic social defeat stress, an ethologically validated model of depression in mice, increases SIRT1 levels in the nucleus accumbens (NAc), a key brain reward region. Increases in SIRT1, a well characterized class III histone deacetylase, after chronic social defeat suggest a role for this enzyme in mediating depression-like behaviors. When resveratrol, a pharmacological activator of SIRT1, was directly infused bilaterally into the NAc, we observed an increase in depression- and anxiety-like behaviors. Conversely, intra-NAc infusions of EX-527, a SIRT1 antagonist, reduced these behaviors; EX-527 also reduced acute stress responses in stress-naive mice. Next, we increased SIRT1 levels directly in NAc by use of viral-mediated gene transfer and observed an increase in depressive- and anxiety-like behaviors when mice were assessed in the open-field, elevated-plus-maze, and forced swim tests. Using a Cre-inducible viral vector system to overexpress SIRT1 selectively in dopamine D1 or D2 subpopulations of medium spiny neurons (MSNs) in the NAc, we found that SIRT1 promotes depressive-like behaviors only when overexpressed in D1 MSNs, with no effect seen in D2 MSNs. Conversely, selective ablation of SIRT1 in the NAc using viral-Cre in floxed Sirt1 mice resulted in decreased depression- and anxiety-like behaviors. Together, these results demonstrate that SIRT1 plays an essential role in the NAc in regulating mood-related behavioral abnormalities and identifies a novel signaling pathway for the development of innovative antidepressants to treat major depressive disorders.Significance statementIn this study, we demonstrate a pivotal role for SIRT1 in anxiety- and depression-like behaviors in the nucleus accumbens (NAc), a key brain reward region. We show that stress stably induces SIRT1 expression in this brain region and that altering SIRT1 activity using a pharmacological or genetic approach regulates anxiety- and depression-like behaviors. These results suggest that SIRT1 plays an essential role in regulating mood-related behaviors and introduces a novel signaling pathway for the development of innovative antidepressants to treat depression and other stress-related disorders. A recent groundbreaking publication by the CONVERGE Consortium (2015) identified a reproducible association of the SIRT1 locus with major depression in humans. Therefore, our results are timely and have significant translational relevance.

Dataset Information

Sex and Individual Differences in Alcohol Intake Are Associated with Differences in Ketamine Self-Administration Behaviors and Nucleus Accumbens Dendritic Spine Density.

Publications

Sex and Individual Differences in Alcohol Intake Are Associated with Differences in Ketamine Self-Administration Behaviors and Nucleus Accumbens Dendritic Spine Density.

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