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Adolescence is a developmental period associated with rapid age-specific physiological, neural, and hormonal changes. Behaviorally, human adolescents are characterized by age-typical increases in novelty-seeking and risk-taking, including the frequent initiation of alcohol and drug use. Alcohol use typically begins during early adolescence, and older adolescents often report high levels of alcohol consumption, commonly referred to as high-intensity drinking. Early-onset and heavy drinking during adolescence are associated with an increased risk of developing alcohol use disorders later in life. Yet, long-term behavioral consequences of adolescent alcohol use that might contribute to excessive drinking in adulthood are still not well understood. Recent animal research, however, using different exposure regimens and routes of ethanol administration, has made substantial progress in identifying the consequences of adolescent ethanol exposure that last into adulthood. Alterations associated with adolescent ethanol exposure include increases in anxiety-like behavior, impulsivity, risk-taking, and ethanol intake, although the observed alterations differ as a function of exposure regimens and routes of ethanol administration. Rodent studies have also shown that adolescent ethanol exposure produces alterations in sensitivity to ethanol, with these alterations reminiscent of adolescent-typical ethanol responsiveness. The goal of this mini-review article is to summarize the current state of animal research, focusing on the long-term consequences related to adolescent ethanol exposure, with a special emphasis on the behavioral alterations and changes to ethanol sensitivity that can foster high levels of drinking in adulthood.

Adolescence is a sensitive developmental period during which alcohol use is often initiated and consumed in high quantities, often at binge or even high-intensity drinking levels. Our lab has repeatedly found that adolescent intermittent ethanol (AIE) exposure in rats results in long-lasting social impairments, specifically in males, however our knowledge of the neuronal underpinnings to this sex-specific effect of AIE is limited. The present study was designed to test whether social anxiety-like alterations in AIE-exposed males would be accompanied by alterations of neuronal activation across brain regions associated with social behavior, with AIE females demonstrating no social impairments and alterations in neuronal activation. Adolescent male and female cFos-LacZ transgenic rats on a Sprague-Dawley background were exposed to ethanol (4 g/kg, 25% v/v) or water via intragastric gavage every other day during postnatal days (P) 25–45 for a total of 11 exposures (n = 13 per group). Social behavior of adult rats was assessed on P70 using a modified social interaction test, and neuronal activation in brain regions implicated in social responding was assessed via β-galactosidase (β-gal) expression. We found that AIE exposure in males resulted in a significantly lower social preference coefficient relative to water-exposed controls, with no effect evident in females. Exposure-specific relationships between social behavior and neuronal activation were identified, with AIE eliminating correlations found in water controls related to social interaction, and eliciting negative correlations mainly in limbic regions in a sex-specific manner. AIE exposure in the absence of social testing was also found to differentially affect neural activity in the orbitofrontal cortex and central amygdala in males and females. These data suggest that AIE produces sex-specific social impairments that are potentially driven by differential neuronal activation states in regions important for social behavior, including the medial prefrontal and orbitofrontal cortices, nucleus accumbens, lateral septum, and central amygdala. Future studies should be focused on identification of specific neuronal phenotypes activated by interaction with a social partner in AIE-exposed subjects and their control counterparts.

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Binge drinking during adolescence can have behavioral and neurobiological consequences. We have previously found that adolescent intermittent ethanol (AIE) exposure produces a sex-specific social impairment in rats. The prelimbic cortex (PrL) regulates social behavior, and alterations within the PrL resulting from AIE may contribute to social impairments. The current study sought to determine whether AIE-induced PrL dysfunction underlies social deficits in adulthood. We first examined social stimulus-induced neuronal activation of the PrL and several other regions of interest implicated in social behavior. Male and female cFos-LacZ rats were exposed to water (control) or ethanol (4 g/kg, 25% v/v) via intragastric gavage every other day between postnatal day (P) 25 and 45 (total 11 exposures). Since cFos-LacZ rats express β-galactosidase (β-gal) as a proxy for cFos, activated cells that express of β-gal can be inactivated by Daun02. β-gal expression in most ROIs was elevated in socially tested adult rats relative to home cage controls, regardless of sex. However, differences in social stimulus-induced β-gal expression between controls and AIE-exposed rats was evident only in the PrL of males. A separate cohort underwent PrL cannulation surgery in adulthood and were subjected to Daun02-induced inactivation. Inactivation of PrL ensembles previously activated by a social stimulus led to a reduction of social behavior in control males, with no changes evident in AIE-exposed males or females. These findings highlight the role of the PrL in male social behavior and suggest an AIE-associated dysfunction of the PrL may contribute to social deficits following adolescent ethanol exposure.