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During the adolescent transition from childhood to adulthood, notable maturational changes occur in brain neurotransmitter systems. The cholinergic system is composed of several distinct nuclei that exert neuromodulatory control over cognition, arousal, and reward. Binge drinking and alcohol abuse are common during this stage, which might alter the developmental trajectory of this system leading to long-term changes in adult neurobiology. In Experiment 1, adolescent intermittent ethanol (AIE; 5.0 g/kg, i.g., 2-day on/2-day off from postnatal day [P] 25 to P55) treatment led to persistent, global reductions of choline acetyltransferase (ChAT) expression. Administration of the Toll-like receptor 4 agonist lipopolysaccharide to young adult rats (P70) produced a reduction in ChAT+IR that mimicked AIE. To determine if the binge ethanol-induced ChAT decline was unique to the adolescent, Experiment 2 examined ChAT+IR in the basal forebrain following adolescent (P28-P48) and adult (P70-P90) binge ethanol exposure. Twenty-five days later, ChAT expression was reduced in adolescent, but not adult, binge ethanol-exposed animals. In Experiment 3, expression of ChAT and vesicular acetylcholine transporter expression was found to be significantly reduced in the alcoholic basal forebrain relative to moderate drinking controls. Together, these data suggest that adolescent binge ethanol decreases adult ChAT expression, possibly through neuroimmune mechanisms, which might impact adult cognition, arousal, or reward sensitivity.

Underage alcohol drinking increases the risk of developing alcohol use disorder (AUD). In rodents, adolescent ethanol exposure augments ethanol consumption and anxiety-like behavior while reducing social interaction. However, the underlying mechanisms driving these adaptations are unclear. The dopamine and kappa opioid receptor (KOR) systems in the nucleus accumbens (NAc) are implicated in affective disorders, including AUD, with studies showing augmented KOR function and reduced dopamine transmission in ethanol-dependent adult animals. Thus, here we examine the impact of adolescent intermittent ethanol (AIE) exposure on dopamine transmission and KOR function in the NAc. Rats were exposed to water or ethanol (4 g/kg, intragastrically) every other day during early (postnatal day (PD) 25–45) or late (PD 45–65) adolescence. While AIE exposure during early adolescence (early-AIE) did not alter dopamine release in male and female rats, AIE exposure during late adolescence (late-AIE) resulted in greater dopamine release in males and lower dopamine release in females. To determine the impact of AIE on KOR function, we measured the effect of KOR activation using U50,488 (0.01–1.00 µM) on dopamine release. Early-AIE exposure potentiated KOR-mediated inhibition of dopamine release in females, while late-AIE exposure attenuated this effect in males. Interestingly, no differences in KOR function were observed in early-AIE exposed males and late-AIE exposed females. Together, these data suggest that AIE exposure impact on neural processes is dependent on sex and exposure timing. These differences likely arise from differential developmental timing in males and females. This is the first study to show changes in KOR function following AIE exposure.

SUMMARY: BACKGROUND The extensive use of alcohol during adolescence may be facilitated by an age-specific attenuation in sensitivity to adverse effects of ethanol. Adolescent rats are less sensitive than adults to some delayed effects of acute ethanol, including hangover-related anxiety on an elevated plus maze. The purpose of this study was to determine whether adolescent rats are also less sensitive than adults to hangover-related anxiogenesis when indexed in terms of social inhibition.METHODS Anxiety during ethanol hangover was indexed in adolescent and adult Sprague-Dawley rats of both genders by assessing the suppression in social behavior during a social interaction test. Animals were tested 18 hr after intraperitoneal administration of 0 g/kg (saline) or 4 g/kg ethanol (experiment 1) or at test intervals chosen on the basis of assessments of ethanol clearance time (experiment 2) to equate clearance-to-test intervals across age and gender (experiments 3-5).RESULTS Adults showed more hangover-related social suppression and slower postclearance recovery than adolescents. Sex differences were more pronounced in adults than adolescents, with males being more affected than females. Ethanol clearance time was considerably longer in adult males than in adolescent animals and adult females. In contrast to the modest decreases in social activity observed in adolescent animals shortly after ethanol clearance, adolescents showed a surprising increase in play fighting later in the recovery period- a hangover-related social facilitation that was not evident in adults.CONCLUSIONS The attenuated anxiety and increase in social interactions seen in adolescents during hangover are less likely to serve as deterrents for further drinking than the aversive increase in anxiety seen in adults. A facilitation of social interactions not only during a drinking episode, but also during the postalcohol recovery period, could help to establish a persisting cycle of drinking in at-risk adolescents, leading to dependency and a lifelong history of alcohol-related problems. [ABSTRACT FROM AUTHOR]