Adolescence is a critical period in brain development that coincides with the initiation of alcohol use. Nicotinic acetylcholine receptors (nAChR) have been shown to modulate ethanol behaviors in adult humans and in animal models; however, the role of these receptors in adolescent ethanol behaviors has not been explored. Throughout adolescence, nAChR expression undergoes large-scale developmental changes which may alter behavioral responses to ethanol. Here we examined the effect of varenicline, a nAChR partial agonist, on ethanol consumption, ataxia, sedation, and metabolism in adolescent male and female C57BL/6J mice. The effect of varenicline on ethanol consumption was tested through the Drinking-in-the-Dark (DID) paradigm that models binge-like ethanol consumption. To ensure that results were specific for ethanol, we also tested the effect of varenicline on saccharin consumption. Additionally, varenicline was administered 30min prior to an acute injection of ethanol before being tested for ataxia on the balance beam, sedation using the loss of righting reflex, or ethanol metabolism. Varenicline dose dependently decreased ethanol consumption, but also influenced saccharin intake. Varenicline showed no significant effect on ethanol metabolism, ataxia, or sedation. Unlike its effects in adult animals, varenicline is able to reduce ethanol consumption without increasing the ataxic and sedative effects of ethanol. This work suggests that the neurobiological mechanisms of ethanol behaviors may change across the lifespan and highlights the need for more research on the role of nAChRs in ethanol behaviors throughout development.

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BackgroundNicotinic acetylcholine receptors have gained attention in the last several years as mediators of alcohol-related behaviors. The genes that code for the α5, α3, and β4 subunits (Chrna5, Chrna3, and Chrnb4, respectively) map adjacent to each other on human chromosome 15/mouse chromosome 9. Genetic variants in this region have been associated with alcohol phenotypes and mice that overexpress these three subunits have reduced ethanol intake. In the present experiments, we examined the role of the Chrnb4 gene in three ethanol behaviors: consumption, ataxia, and sedation. Wildtype, heterozygous, and knockout mice were tested for ethanol consumption with a 2-bottle choice procedure and the drinking-in-the-dark paradigm. Ethanol-induced ataxia was measured with the balance beam and dowel test. Finally, the sedative effects of ethanol were measured with the loss of righting reflex paradigm.ResultsWe observed no significant genotypic effects on any of the ethanol behaviors examined, suggesting that the β4 subunit is not involved in mediating these responses.ConclusionsWhile we found no evidence for the involvement of the β4 subunit in ethanol responses, it is possible that this subunit modulates other behaviors not tested and further work should address this before completely ruling out its involvement.Electronic supplementary materialThe online version of this article (doi:10.1186/s13104-017-2470-7) contains supplementary material, which is available to authorized users.

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Deaths related to opioid use have skyrocketed in the United States, leading to a public health epidemic. Research has shown that both biological (genes) and environmental (stress) precursors are linked to opioid use. In particular, stress during adolescence – a critical period of frontal lobe development–influences the likelihood of abusing drugs. However, little is known about the biological mechanisms through which adolescent stress leads to long-term risk of opioid use, or whether genetic background moderates this response. Male and female C57BL/6J and BALB/cJ mice were exposed to chronic variable social stress (CVSS) or control conditions throughout adolescence (postnatal days, PND, 25-59) and then tested for morphine locomotor sensitization or morphine consumption in adulthood. To examine possible mechanisms that underlie stress-induced changes in morphine behaviors, we assessed physiological changes in response to acute stress exposure and miRNA gene expression in the prefrontal cortex. Male C57BL/6J mice exposed to adolescent CVSS had blunted morphine sensitization compared to control animals. No differences were observed in the acute locomotor response to morphine administration or morphine consumption in adult C57BL/6J mice. Stress did not influence morphine behaviors in BALB/cJ animals. C57BL/6J mice exposed to CVSS had a blunted corticosterone recovery following an acute stressor. Twelve miRNA were downregulated in the prefrontal cortex of C57BL/6J mice exposed to CVSS in adolescence, which suggests a biological mechanism through which stress may alter later morphine responses. The specificity of the effects for C57BL/6J versus BALB/cJ mice provides evidence of a gene by environmental interaction influencing opioid behaviors.