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Per occasion, alcohol consumption is higher in adolescents than in adults in both humans and laboratory animals, with changes in the adolescent brain probably contributing to this elevated drinking. This Review examines the contributors to and consequences of the use of alcohol in adolescents. Human adolescents with a history of alcohol use differ neurally and cognitively from other adolescents; some of these differences predate the commencement of alcohol consumption and serve as potential risk factors for later alcohol use, whereas others emerge from its use. The consequences of alcohol use in human adolescents include alterations in attention, verbal learning, visuospatial processing and memory, along with altered development of grey and white matter volumes and disrupted white matter integrity. The functional consequences of adolescent alcohol use emerging from studies of rodent models of adolescence include decreased cognitive flexibility, behavioural inefficiencies and elevations in anxiety, disinhibition, impulsivity and risk-taking. Rodent studies have also showed that adolescent alcohol use can impair neurogenesis, induce neuroinflammation and epigenetic alterations, and lead to the persistence of adolescent-like neurobehavioural phenotypes into adulthood. Although only a limited number of studies have examined comparable measures in humans and laboratory animals, the available data provide evidence for notable across-species similarities in the neural consequences of adolescent alcohol exposure, providing support for further translational efforts in this context.

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.

In the initially published version of this article, the following sentence was incorrect: “Studies that have compared equivalent exposures to alcohol in adolescent and adult animals have found that the effects of alcohol exposure during adolescence are generally not evident or are less pronounced than after comparable alcohol exposure in adulthood”. The sentence should have read: “Studies that have compared equivalent exposures to alcohol in adolescent and adult animals have found that the effects of alcohol exposure during adulthood are generally not evident or are less pronounced than after comparable alcohol exposure in adolescence”. The sentence has been corrected in the HTML and PDF versions of the article.

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.

This study assessed long-lasting consequences of repeated ethanol exposure during two different periods of adolescence on 1) baseline levels of social investigation, play fighting, and social preference and 2) sensitivity to the social consequences of acute ethanol challenge. Adult male and female Sprague-Dawley rats were tested 25 days after repeated exposure to ethanol (3.5 g/kg intragastrically [i.g.], every other day for a total of 11 exposures) in a modified social interaction test. Early-mid adolescent intermittent exposure (e-AIE) occurred between postnatal days (P) 25 and 45, whereas late adolescent intermittent exposure (l-AIE) was conducted between P45 and P65. Significant decreases in social investigation and social preference were evident in adult male rats, but not their female counterparts following e-AIE, whereas neither males nor females demonstrated these alterations following l-AIE. In contrast, both e-AIE and l-AIE produced alterations in sensitivity to acute ethanol challenge in males tested 25 days after adolescent exposure. Ethanol-induced facilitation of social investigation and play fighting, reminiscent of that normally seen during adolescence, was evident in adult males after e-AIE, whereas control males showed an age-typical inhibition of social behavior. Males after l-AIE were found to be insensitive to the socially suppressing effects of acute ethanol challenge, suggesting the development of chronic tolerance in these animals. In contrast, females showed little evidence for alterations in sensitivity to acute ethanol challenge following either early or late AIE. The results of the present study demonstrate a particular vulnerability of young adolescent males to long-lasting detrimental effects of repeated ethanol. Retention of adolescent-typical sensitivity to the socially facilitating effects of ethanol could potentially make ethanol especially appealing to these males, therefore promoting relatively high levels of ethanol intake later in life.

Rationale NMDA antagonists consistently produce social inhibition in adult animals, although effects of these manipulations on social behavior of adolescents are relatively unknown. Objectives The aim of this study was to assess potential age differences in the socially inhibitory effects of the non-competitive NMDA antagonist, MK-801, as well as NR2 subunit selective effects, given the regional and developmental differences that exist for the NR2 subunit during ontogeny. Methods In separate experiments, adolescent and adult male Sprague–Dawley rats were treated acutely with MK-801 (0, 0.05, 0.1, 0.2 mg/kg, i.p.), the NR2A antagonist, PEAQX (2.5, 5, 10, 20 mg/kg, s.c.), or the NR2B antagonist, ifenprodil (1.5, 3, 6, 12 mg/kg, i.p.), 10 min prior to a social interaction test. Results Adolescents required higher doses of MK-801 (0.1 and 0.2 mg/kg) to induce social suppression, whereas adults demonstrated reductions in social activity after all doses. Likewise, adolescents required higher doses of ifenprodil (6 and 12 mg/kg) to produce social inhibitory effects relative to adults (all doses). In contrast, adults were less sensitive to PEAQX than adolescents, with adults showing social inhibition after 20 mg/kg whereas adolescents showed this effect following 10 and 20 mg/kg. Although locomotor activity was generally reduced at both ages by all drugs tested, ANCOVAs using locomotor activity as a covariate revealed similar patterns of social inhibitory effects. Conclusions Adolescents are less sensitive than adults to the disruption of social behavior by NMDA and NR2B-selective receptor antagonism, but not by an NR2A antagonist—age differences that may be related to different subunit expression patterns during development.

Although adolescence is a common age to initiate alcohol consumption, the long-term consequences of exposure to alcohol at this time of considerable brain maturation are largely unknown. In studies utilizing rodents, behavioral evidence is beginning to emerge suggesting that the hippocampus may be persistently affected by repeated ethanol exposure during adolescence, but not by comparable alcohol exposure in adulthood. The purpose of this series of experiments was to explore a potential mechanism of hippocampal dysfunction in adults exposed to ethanol during adolescence. Given that disruption in adult neurogenesis has been reported to impair performance on tasks thought to be hippocampally related, we used immunohistochemistry to assess levels of doublecortin (DCX), an endogenous marker of immature neurons, in the dentate gyrus (DG) of the hippocampus 3-4 weeks after adolescent (postnatal day, PD28-48) or adult (PD70-90) intermittent ethanol exposure to 4 g/kg ethanol administered intragastrically. We also investigated another neurogenic niche, the subventricular zone (SVZ), to determine if the effects of ethanol exposure were region specific. Levels of cell proliferation and cell death were also examined in the DG via assessing Ki67 and cleaved caspase-3 immunoreactivity, respectively. Significantly less DCX was observed in the DG of adolescent (but not adult) ethanol-exposed animals about 4 weeks after exposure when these animals were compared to control age-mates. The effects of adolescent ethanol on DCX immunoreactivity were specific to the hippocampus, with no significant exposure effects emerging in the SVZ. In both the DG and the SVZ there was a significant age-related decline in neurogenesis as indexed by DCX. The persistent effect of adolescent ethanol exposure on reduced DCX in the DG appears to be related to significant increases in cell death, with significantly more cleaved caspase-3-positive immunoreactivity observed in the adolescent ethanol group compared to controls, but no alterations in cell proliferation when indexed by Ki67. These results suggest that a history of adolescent ethanol exposure results in lowered levels of differentiating neurons, probably due at least in part to increased cell death of immature neurons. These effects were evident in adulthood, weeks following termination of the chronic exposure, and may contribute to previously reported behavioral deficits on hippocampal-related tasks after chronic ethanol exposure in adolescence.

Rationale Adolescent intermittent ethanol exposure (AIE) produces lasting, sex-specific social anxiety-like alterations in male, but not female rats. Oxytocin (OXT) and vasopressin (AVP) brain systems play opposite roles in regulating social preference/avoidance, with OXT increasing approach to, and AVP increasing avoidance of social stimuli. Objectives To test the hypothesis that social anxiety-like alterations seen in adult males after AIE are associated with a shift in the balance between OXT and AVP toward AVP, effectiveness of pharmacological activation of the OXT system and blockade of endogenous activity at AVP receptors for reversing AIE-induced social anxiety-like alterations was assessed, along with examination of the effects of AIE on OXT, vasopressin V1a, and V1b receptor (OXT-R, V1a-R, and V1b-R) surface expression in the hypothalamus. Methods Sprague-Dawley male and female rats were given 4 g/kg ethanol (AIE) or water intragastrically every 48 h for a total of 11 exposures during postnatal days (P) 25–45. On P70–72, animals were given a social interaction test following administration of a selective OXT-R agonist WAY-267464, selective V1a-R antagonist SR-49059, or V1b-R antagonist SSR-149415, and hypothalamic tissue was collected. Results Social anxiety-like behavior was induced by AIE in males but not females, and was selectively reversed by the selective OXT-R agonist and V1b-R antagonist, but not V1a-R antagonist. AIE was also found to decrease OXT-R, but increase V1b-R neuronal surface expression relative to water-exposed controls in the hypothalamus of males, but not females. Conclusions These findings demonstrate that AIE induces changes in OXT-R and AVP-R surface expression in the hypothalamus along with social anxiety-like alterations in male rats. These social anxiety-like alterations can be reversed either by activation of the OXT system or by suppression of the AVP system, data that support the hypothesis that social anxiety-like alterations induced by adolescent alcohol exposure in male rats are associated at least in part with an OXT/AVP imbalance.

Rationale Early onset of alcohol drinking has been associated with alcohol abuse in adulthood. The neurobiology of this phenomenon is unclear, but mesolimbic dopamine pathways, which are dynamic during adolescence, may play a role. Objectives We investigated the impact of adolescent binge-like alcohol on phasic dopaminergic neurotransmission during adulthood. Methods Rats received intermittent intragastric ethanol, water, or nothing during adolescence. In adulthood, electrically evoked dopamine release and subsequent uptake were measured in the nucleus accumbens core at baseline and after acute challenge of ethanol or saline. Results Adolescent ethanol exposure did not alter basal measures of evoked dopamine release or uptake. Ethanol challenge dose-dependently decreased the amplitude of evoked dopamine release in rats by 30–50 % in control groups, as previously reported, but did not alter evoked release in ethanol-exposed animals. To address the mechanism by which ethanol altered dopamine signaling, the evoked signals were modeled to estimate dopamine efflux per impulse and the velocity of the dopamine transporter. Dopamine uptake was slower in all exposure groups after ethanol challenge compared to saline, while dopamine efflux per pulse of electrical stimulation was reduced by ethanol only in ethanol-naive rats. Conclusions The results demonstrate that exposure to binge levels of ethanol during adolescence blunts the effect of ethanol challenge to reduce the amplitude of phasic dopamine release in adulthood. Large dopamine transients may result in more extracellular dopamine after alcohol challenge in adolescent-exposed rats and may be one mechanism by which alcohol is more reinforcing in people who initiated drinking at an early age.