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Mouse strain differences in punished ethanol self-administration.

ABSTRACT: Determining the neural factors contributing to compulsive behaviors such as alcohol-use disorders (AUDs) has become a significant focus of current preclinical research. Comparison of phenotypic differences across genetically distinct mouse strains provides one approach to identify molecular and genetic factors contributing to compulsive-like behaviors. Here we examine a rodent assay for punished ethanol self-administration in four widely used inbred strains known to differ on ethanol-related behaviors: C57BL/6J (B6), DBA/2J (D2), 129S1/SvImJ (S1), and BALB/cJ (BALB). Mice were trained in an operant task (FR1) to reliably lever-press for 10% ethanol using a sucrose-fading procedure. Once trained, mice received a punishment session in which lever pressing resulted in alternating ethanol reward and footshock, followed by tests to probe the effects of punishment on ethanol self-administration. Results indicated significant strain differences in training performance and punished attenuation of ethanol self-administration. S1 and BALB showed robust attenuation of ethanol self-administration after punishment, whereas behavior in B6 was attenuated only when the punishment and probe tests were conducted in the same contexts. By contrast, D2 were insensitive to punishment regardless of context, despite receiving more shocks during punishment and exhibiting normal footshock reactivity. Additionally, B6, but not D2, reduced operant self-administration when ethanol was devalued with a bitter tastant. B6 and D2 showed devaluation of sucrose self-administration, and punished suppression of sucrose seeking was context dependent in both the strains. While previous studies have demonstrated avoidance of ethanol in D2, particularly when ethanol is orally available from a bottle, current findings suggest this strain may exhibit heightened compulsive-like self-administration of ethanol, although there are credible alternative explanations for the phenotype of this strain. In sum, these findings offer a foundation for future studies examining the neural and genetic factors underlying AUDs.

SUBMITTER: Halladay LR

PROVIDER: S-EPMC6060418 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Mouse strain differences in punished ethanol self-administration.

Halladay Lindsay R LR Kocharian Adrina A Holmes Andrew A

Alcohol (Fayetteville, N.Y.) 20161018

Determining the neural factors contributing to compulsive behaviors such as alcohol-use disorders (AUDs) has become a significant focus of current preclinical research. Comparison of phenotypic differences across genetically distinct mouse strains provides one approach to identify molecular and genetic factors contributing to compulsive-like behaviors. Here we examine a rodent assay for punished ethanol self-administration in four widely used inbred strains known to differ on ethanol-related beh ...[more]

PMID: 27814928

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Project description:BackgroundA clinical hallmark of alcohol use disorder is persistent drinking despite potential adverse consequences. The ventromedial prefrontal cortex (vmPFC) and dorsomedial prefrontal cortex (dmPFC) are positioned to exert top-down control over subcortical regions, such as the nucleus accumbens shell (NAcS) and basolateral amygdala, which encode positive and negative valence of ethanol (EtOH)-related stimuli. Prior rodent studies have implicated these regions in regulation of punished EtOH self-administration (EtOH-SA).MethodsWe conducted in vivo electrophysiological recordings in mouse vmPFC and dmPFC to obtain neuronal correlates of footshock-punished EtOH-SA. Ex vivo recordings were performed in NAcS D1 receptor-expressing medium spiny neurons receiving vmPFC input to examine punishment-related plasticity in this pathway. Optogenetic photosilencing was employed to assess the functional contribution of the vmPFC, dmPFC, vmPFC projections to NAcS, or vmPFC projections to basolateral amygdala, to punished EtOH-SA.ResultsPunishment reduced EtOH lever pressing and elicited aborted presses (lever approach followed by rapid retraction). Neurons in the vmPFC and dmPFC exhibited phasic firing to EtOH lever presses and aborts, but only in the vmPFC was there a population-level shift in coding from lever presses to aborts with punishment. Closed-loop vmPFC, but not dmPFC, photosilencing on a postpunishment probe test negated the reduction in EtOH lever presses but not in aborts. Punishment was associated with altered plasticity at vmPFC inputs to D1 receptor-expressing medium spiny neurons in the NAcS. Photosilencing vmPFC projections to the NAcS, but not to the basolateral amygdala, partially reversed suppression of EtOH lever presses on probe testing.ConclusionsThese findings demonstrate a key role for the vmPFC in regulating EtOH-SA after punishment, with implications for understanding the neural basis of compulsive drinking in alcohol use disorder.

Dataset Information

Mouse strain differences in punished ethanol self-administration.

Publications

Mouse strain differences in punished ethanol self-administration.

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