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.

Sheketha R Hauser,R Aaron Waeiss,Eric A Engleman,Zachary A Rodd,William A Truitt,Richard L Bell,Patrick J Mulholland

doi:10.3390/ijms222111733

Abstract

A consistent preclinical finding is that exposure to alcohol during adolescence produces a persistent hyperdopaminergic state during adulthood. The current experiments determine that effects of Adolescent Intermittent Ethanol (AIE) on the adult neurochemical response to EtOH administered directly into the mesolimbic dopamine system, alterations in dendritic spine and gene expression within the nucleus accumbens shell (AcbSh), and if treatment with the HDACII inhibitor TSA could normalize the consequences of AIE. Rats were exposed to the AIE (4 g/kg ig; 3 days a week) or water (CON) during adolescence, and all testing occurred during adulthood. CON and AIE rats were microinjected with EtOH directly into the posterior VTA and dopamine and glutamate levels were recorded in the AcbSh. Separate groups of AIE and CON rats were sacrificed during adulthood and Taqman arrays and dendritic spine morphology assessments were performed. The data indicated that exposure to AIE resulted in a significant leftward and upward shift in the dose-response curve for an increase in dopamine in the AcbSh following EtOH microinjection into the posterior VTA. Taqman array indicated that AIE exposure affected the expression of target genes (Chrna7, Impact, Chrna5). The data indicated no alterations in dendritic spine morphology in the AcbSh or any alteration in AIE effects by TSA administration. Binge-like EtOH exposure during adolescence enhances the response to acute ethanol challenge in adulthood, demonstrating that AIE produces a hyperdopaminergic mesolimbic system in both male and female Wistar rats. The neuroadaptations induced by AIE in the AcbSh could be part of the biological basis of the observed negative consequences of adolescent binge-like alcohol exposure on adult drug self-administration behaviors.

Highlights

The current study examines the ability of the HDACII inhibitor Trichostatin A (TSA) to prevent adolescent alcohol induced enhancement in the reinforcing properties of EtOH within the posterior VTA and enhanced dopamine release in the accumbens shell (AcbSh) following EtOH microinjection into the posterior VTA
The hyperdopaminergic state during adulthood in Adolescent Intermittent Ethanol (AIE) rats is indicated by the greater sensitivity and enhanced responsivity in the ability of EtOH microinjected into the posterior VTA to stimulate DA release in the AcbSh (Figure 1)
The enhancement in activity within the mesolimbic DA system produced by AIE exposure was combined with specific alterations in the genetic expression of dopaminergic and cholinergic factors within the AcbSh (Figures 2 and 3)

Summary

Introduction

The overall drinking rate of adolescence in the US has remained relatively constant for decades [1,2]. Adolescent/young adult binge drinking has become more prevalent in younger adolescents and there has been an increase in the overall rate of binge drinking during the transition from late adolescent/young adulthood into adulthood [3]. The increase in the occurrence of binge drinking in adolescents/young adults has required the further classification of high-intensity, and extreme-intensity adolescents that have recently emerged [4,5]. Almost a third of young adults (21–26) in the US report recent bouts of binge-drinking (30%), 11% report high-intensity drinking, and

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Results

Conclusion