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Adolescent but not adult ethanol binge drinking modulates ethanol behavioral effects in mice later in life.

ABSTRACT: BACKGROUND:Alcohol use disorder is a serious illness marked by uncontrollable drinking and a negative withdrawal state when not using. Alcohol is one of the most commonly used drugs among adolescent populations. Given that adolescence is a unique developmental stage during which alcohol has long-term effects on future drug-taking behavior; it is essential to understand how early exposure to ethanol during adolescence may affect the abuse liability of the drug later in life. Our studies focused on characterizing how exposure to alcohol in adolescence alters later adult alcohol dependence behaviors, by using well-established mouse models of ethanol drinking. We hypothesized that early exposure to ethanol leads to increased ethanol intake in adults and other behavioral phenotypes that may lead to dependence. METHODS:We investigated the impact of ethanol drinking in early adolescent C57BL/6J mice using a modified Drinking in the Dark (DID) model. RESULTS:Our results showed that exposure to ethanol during adolescence enhanced ethanol intake in adulthood in the DID, and the 2-bottle choice drinking paradigms. In contrast, adult exposure of alcohol did not enhance later alcohol intake. We also conducted tests for ethanol behavioral sensitivity such as loss of righting reflex and anxiety-related behaviors to further elucidate the relationship between adolescent ethanol exposure and enhanced ethanol intake in adult mice. CONCLUSIONS:Overall, our results suggest that adolescence is a critical period of sensitivity and binge drinking that can lead to lasting changes in ethanol intake in adulthood. Further research will be required in order to more fully examine the neurochemical mechanisms underlying the lasting changes in adulthood.

SUBMITTER: Younis RM

PROVIDER: S-EPMC6697373 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Adolescent but not adult ethanol binge drinking modulates ethanol behavioral effects in mice later in life.

Younis Rabha M RM Wolstenholme Jennifer T JT Bagdas Deniz D Bettinger Jill C JC Miles Michael F MF Damaj M Imad MI

Pharmacology, biochemistry, and behavior 20190718

<h4>Background</h4>Alcohol use disorder is a serious illness marked by uncontrollable drinking and a negative withdrawal state when not using. Alcohol is one of the most commonly used drugs among adolescent populations. Given that adolescence is a unique developmental stage during which alcohol has long-term effects on future drug-taking behavior; it is essential to understand how early exposure to ethanol during adolescence may affect the abuse liability of the drug later in life. Our studies f ...[more]

PMID: 31326461

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Project description:Binge drinking is common in human adolescents. The adolescent brain is undergoing structural maturation and has a unique sensitivity to alcohol neurotoxicity. Therefore, adolescent binge ethanol may have long-term effects on the adult brain that alter brain structure and behaviors that are relevant to alcohol-use disorders.To determine whether adolescent ethanol (AE) binge drinking alters the adult brain, male C57BL/6 mice were treated with either water or ethanol during adolescence (5 g/kg/d, i.g., postnatal days P28 to P37) and assessed during adulthood (P60 to P88). An array of neurotransmitter-specific genes, behavioral tests (i.e., reversal learning, prepulse inhibition, and open field), and postmortem brain structure using magnetic resonance imaging (MRI) and immunohistochemistry, were employed to assess persistent alterations in adult brain.At P38, 24 hours after AE binge, many neurotransmitter genes, particularly cholinergic and dopaminergic, were reduced by ethanol treatment. Interestingly, dopamine receptor type 4 mRNA was reduced and confirmed using immunohistochemistry. Normal control maturation (P38 to P88) resulted in decreased neurotransmitter mRNA, e.g., an average decrease of 56%. Following AE treatment, adults showed greater gene expression reductions than controls, averaging 73%. Adult spatial learning assessed in the Morris water maze was not changed by AE treatment, but reversal learning experiments revealed deficits. Assessment of adult brain region volumes using MRI indicated that the olfactory bulb and basal forebrain were smaller in adults following AE. Immunohistochemical analyses found reduced basal forebrain area and fewer basal forebrain cholinergic neurons.Adolescent binge ethanol treatment reduces adult neurotransmitter gene expression, particularly cholinergic genes, reduces basal forebrain and olfactory bulb volumes, and causes a reduction in the density of basal forebrain acetylcholine neurons. Loss of cholinergic neurons and forebrain structure could underlie adult reversal learning deficits following adolescent binge drinking.

Project description:We previously determined that repeated binge ethanol drinking produced sex differences in the regulation of signaling downstream of Group 1 metabotropic glutamate receptors in the nucleus accumbens (NAc) of adult C57BL/6J mice. The purpose of the present study was to characterize RNA expression differences in the NAc of adult male and female C57BL/6J mice following 7 binge ethanol drinking sessions, when compared with controls consuming water. This binge drinking procedure produced high intakes (average >2.2 g/kg/30 min) and blood ethanol concentrations (average >1.3 mg/ml). Mice were euthanized at 24 h after the 7th binge session, and focused qPCR array analysis was employed on NAc tissue to quantify expression levels of 384 genes in a customized Mouse Mood Disorder array, with a focus on glutamatergic signaling (3 arrays/group). We identified significant regulation of 50 genes in male mice and 70 genes in female mice after 7 ethanol binges. Notably, 14 genes were regulated in both males and females, representing common targets to binge ethanol drinking. However, expression of 10 of these 14 genes was strongly dimorphic (e.g., opposite regulation for genes such as Crhr2, Fos, Nos1, and Star), and only 4 of the 14 genes were regulated in the same direction (Drd5, Grm4, Ranbp9, and Reln). Interestingly, the top 30 regulated genes by binge ethanol drinking for each sex differed markedly in the male and female mice, and this divergent neuroadaptive response in the NAc could result in dysregulation of distinct biological pathways between the sexes. Characterization of the expression differences with Ingenuity Pathway Analysis was used to identify Canonical Pathways, Upstream Regulators, and significant Biological Functions. Expression differences suggested that hormone signaling and immune function were altered by binge drinking in female mice, whereas neurotransmitter metabolism was a central target of binge ethanol drinking in male mice. Thus, these results indicate that the transcriptional response to repeated binge ethanol drinking was strongly influenced by sex, and they emphasize the importance of considering sex in the development of potential pharmacotherapeutic targets for the treatment of alcohol use disorder.

Project description:BackgroundBeyond yielding high blood ethanol (EtOH) concentrations (BECs), binge-drinking models allow examination of drinking patterns which may be associated with EtOH's rewarding effects, including front-loading and consummatory successive negative contrast (cSNC), a decrease in intake when only water is available to subjects expecting EtOH. The goals of the current study were to broaden our understanding of these reward-related behaviors during binge EtOH access in high alcohol-preferring (HAP) replicate lines (HAP2 and HAP3) of mice selectively bred to prefer alcohol. We hypothesized that both lines would show evidence of front-loading during binge EtOH access and that we would find a cSNC effect in groups where EtOH was replaced with water, as these results have been shown previously in HAP1 mice.MethodsHAP replicate 2 and replicate 3 female and male mice were given 2 hours of EtOH or water access in the home cage for 15 consecutive days using "drinking in the dark" (DID) procedures. Mice received the same fluid (either 20% unsweetened EtOH or water) for the first 14 days. However, on the 15th day, half of the mice from these 2 groups were provided with the opposite assigned fluid (EtOH groups received water and vice versa). Intake was measured in 1-minute bins using specialized sipper tubes, which allowed within-session analyses of binge-drinking patterns.ResultsEtOH front-loading was observed in both replicates. HAP3 mice displayed front-loading on the first day of EtOH access, whereas front-loading developed following alcohol experience in HAP2 mice, which may suggest differences in initial sensitivity to EtOH reward. Consummatory SNC, which manifests as lower water intake in mice expecting EtOH as compared to mice expecting water, was observed in both replicates.ConclusionsThese findings increase confidence that defined changes in home cage consummatory behavior are driven by the incentive value of EtOH. The presence of cSNC across HAP replicates indicates that this reaction to loss of reward is genetically mediated, which suggests that there is a biological mechanism that might be targeted.

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Adolescent but not adult ethanol binge drinking modulates ethanol behavioral effects in mice later in life.

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Adolescent but not adult ethanol binge drinking modulates ethanol behavioral effects in mice later in life.

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