Alterations in nucleus accumbens kappa opioid receptor‐mediated dopamine inhibition in response to stress and chronic alcohol exposure

Abstract

Alcohol use disorders (AUDs) are a widely prevalent condition in the United States, made more pernicious by their high comorbidity with disorders of negative affect, such as major depression, anxiety disorders, and post‐traumatic stress disorder. Though underlying disorders of negative affect often predispose individuals to the development of AUDs, emerging evidence has demonstrated the inverse ‐ exposure to chronic alcohol itself may engender vulnerabilities to the development of mood disorders. For example, chronic access to ethanol in a two bottle choice paradigm resulted in the expression of anxiety‐ and depression‐like behavior that lasted long into abstinence in animals that were behaviorally indistinguishable from their control counterparts prior to ethanol exposure. In the present study, we further explored alterations in stress‐related neurobiological systems that may contribute to negative affect‐like behaviors observed during abstinence from chronic ethanol. To this end, we turned to the kappa opioid receptor (KOR) system. Specifically, we focused on the ability of the KOR agonist U50,488 to decrease dopamine release in the nucleus accumbens, a characteristic that is enhanced during early withdrawal following chronic exposure to ethanol, and is believed to contribute to protracted anhedonia during abstinence. We exposed mice to four weeks of chronic intermittent ethanol (CIE) vapor, and subsequently examined negative affect‐like behavior and alterations in KOR‐mediated dopamine release inhibition using fast scan cyclic voltammetry in ex vivo brain slices, both basally and in response to ethanol or stress exposure, following two weeks of abstinence. We found that CIE exposed mice display an increase latency to feed in the novelty‐suppressed feeding paradigm, indicating an increase in negative affect‐like behavior. However, in a separate group of animals, we did not observe increased KOR agonist‐mediated dopamine release inhibition following CIE. We hypothesized that the inherent stress of the novelty‐suppressed feeding paradigm ‐ that is, a fasting period prior to testing ‐ may have uncovered an underlying vulnerability to stressors in animals with a history of CIE. We therefore tested acute exposure to two stressors, a heterotypic fasting stress and a homotypic 2g/kg ethanol (i.p.) stress, in animals with and without a history of chronic ethanol exposure. We found that both stressors were able to acutely augment KOR agonist‐mediated dopamine inhibition in the nucleus accumbens of ethanol‐naïve animals. Interestingly, we found that animals with a history of CIE did not display augmented KOR functioning in response to acute ethanol injection after two weeks of ethanol abstinence. Together, these data indicate that chronic exposure to ethanol may alter stress responsivity, resulting in tolerance to the homotypic stressor ethanol, and increased vulnerability to heterotypic stressors, such as food deprivation, which may confer further susceptibility to stress‐induced ethanol seeking during abstinence.Support or Funding InformationU01 AA014091; T32 AA007565This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.