Adolescent Intermittent Ethanol Increases the Sensitivity to the Reinforcing Properties of Ethanol and the Expression of Select Cholinergic and Dopaminergic Genes within the Posterior Ventral Tegmental Area

Abstract

Background: Although not legally allowed to consume alcohol, adolescents account for 11% of all alcohol use in the United States and approximately 90% of adolescent intake is in the form of an alcohol binge. The adolescent intermittent ethanol (AIE) model developed by the NADIA consortium produces binge-like EtOH exposure episodes. The current experiment examined the effects of AIE on the reinforcing properties of EtOH and genetic expression of cholinergic and dopaminergic factors within the posterior ventral tegmental area (pVTA) in Wistar male and female rats and in male alcohol-preferring (P) rats.Methods: Rats were exposed to the AIE or water during adolescence, and all testing occurred during adulthood. Wistar control and AIE rats were randomly assigned to groups that self-administered 0 to 200 mg% EtOH. Male P rats self-administered 0 to 100 mg%.Results: The data indicated that exposure to AIE in both Wistar male and female rats (and male P rats) resulted in a significant leftward shift in dose-response curve for EtOH self-administration into the pVTA. TaqMan array indicated that AIE exposure had divergent effects on the expression of nicotinic receptors (increased a7, reduction in a4 and a5). There were also sex-specific effects of AIE on gene expression; male only reduction in D3 receptors.Conclusion: Binge-like EtOH exposure during adolescence enhances the sensitivity to the reinforcing properties of EtOH during adulthood which could be part of biological sequelae that are the basis for the deleterious effects of adolescent alcohol consumption on the rate of alcoholism during adulthood.

Adolescent Ethanol Exposure: Anxiety-Like Behavioral Alterations, Ethanol Intake, and Sensitivity

“…Adolescent ethanol exposure (P25-45, IG, 4 g/kg) of Sprague-Dawley male rats resulted in precipitation of adolescent-typical responding to acute ethanol challenge with social facilitation (i.e., ethanol-induced increases in peer-directed social behavior) when these males were tested in adulthood (Varlinskaya et al, 2014). Enhanced sensitivity to ethanol reinforcement indexed via a significant leftward shift in the dose-response curve for ethanol self-administration into the posterior ventral tegmental area following adolescent ethanol exposure (4 g/kg IG, P28-48) was also evident in adult male and female Wistar rats, as well as in alcohol-preferring (P) male rats (Hauser et al, 2019). Carrara-Nascimento et al (2014) showed that adult male Swiss mice exposed to ethanol during adolescence displayed a robust CPP to 2.0 g/kg ethanol, whereas adult exposure decreased sensitivity to the reinforcing properties of ethanol.…”

Sex Differences in the Neurobiology of Alcohol Use Disorder

“…Rats will press a lever to self-administer alcohol directly into the VTA, but a higher dose of alcohol is needed for reinforcement of this behavior in males compared to females. 48 , 49 Moreover, a prior history of adolescent intermittent alcohol exposure leads to heightened sensitivity to the rewarding properties of alcohol in both sexes, indexed by a leftward shift in alcohol dose-response curves in rats. 48 In humans, a familial history of AUD is associated with an exaggerated ventral striatum dopamine response to the expectation of alcohol.…”

“… 48 , 49 Moreover, a prior history of adolescent intermittent alcohol exposure leads to heightened sensitivity to the rewarding properties of alcohol in both sexes, indexed by a leftward shift in alcohol dose-response curves in rats. 48 In humans, a familial history of AUD is associated with an exaggerated ventral striatum dopamine response to the expectation of alcohol. 50 Although this study did not find a sex difference in this dopamine response, perhaps a larger number of subjects would be needed to detect a subtle, but statistically significant, difference in this measure in men and women.…”

Adolescent Intermittent Ethanol (AIE) Enhances the Dopaminergic Response to Ethanol within the Mesolimbic Pathway during Adulthood: Alterations in Cholinergic/Dopaminergic Genes Expression in the Nucleus Accumbens Shell

“…Alcohol (and other drugs of abuse) alters the normal neuronal developmental processes. Replicated findings indicate that alcohol exposure/consumption during adolescence results in a hyperdopaminergic response to stimuli, reduction in choline acetyltransferase (ChAT), alterations in the neuroimmune system, and non-specific modulation of epigenetic factors [12][13][14][15]. The mesolimbic dopamine system mediates several motivated behaviors (sex, consummatory behaviors, maternal behaviors, and other response-contingent behaviors; [16,17]).…”

“…The enhanced drug self-administration observed in adults following adolescent EtOH exposure is thought to be mediated, in part, by a series of biological events: (1) alcohol acts on receptors or ion channels (perhaps more targets) to alter activity within the adolescent brain, (2) activation of these EtOH targets induce production of epigenetic factors that persistently alter the genetic expression of specific proteins, alterations in protein structures and other processes, (3) the compromised adult brain (containing the neuroadaptations produced by adolescent alcohol exposure) reacts differently to alcohol and other drugs of abuse which increases the propensity or these individuals to consume drugs [31]. Alterations in the mesolimbic dopamine system (pVTA projections into the AcbSh) could be the biological basis for the increase in the propensity to consume alcohol and other drugs of abuse during adulthood [12,22,32,33]. Therefore, it is critical to examine the effect of adolescent EtOH exposure on adult response to EtOH within the mesolimbic dopamine system during adulthood.…”