Sex Differences in GABA Regulation of Dopamine Release in the Nucleus Accumbens and its Role in Cocaine Use Disorder

Abstract

Abstract ID 20953 Poster Board 543 Background: While sex differences in the pervasiveness and prognosis of neuropsychiatric disorders have long been known to exist, there are few instances where approaches to pharmacological treatment of these disorders differ between the sexes, which likely contributes to ineffective treatments in women. In substance use disorder (SUD), women exhibit increased propensity to use drugs, a faster transition to addiction from first use, greater problems maintaining abstinence, and relapse at a higher rate than men. At the center of sex-differences in addiction vulnerability is the mesolimbic dopamine system. While work has focused on sex differences in the anatomy of dopamine neurons and relative dopamine levels, an important characteristic of dopamine release from axon terminals in the nucleus accumbens (NAc) is that it is rapidly modulated by local regulatory mechanisms independent of somatic activity. GABA released from local microcircuitry in the NAc has been shown to play a critical role in regulating dopamine release at the terminals through ionotropic GABA-A and Gi-coupled GABA-B receptors and has also been implicated in cocaine-induced processes. Here we define basal sex differences in dopamine release regulation via GABA in the NAc and show how this is dysregulated by chronic cocaine exposure. Methods: To dissociate dopamine terminal regulation from somatic regulation, we utilize ex vivo fast scan cyclic voltammetry and optogenetics in striatal brain slices. Dopamine release was evoked from terminals, and GABA receptor modulation of this signal was determined via bath application of picrotoxin (GABA-A antagonist), muscimol (GABA-A agonist), saclofen (GABA-B antagonist), and baclofen (GABA-B agonist) to slices. This was done at baseline in both males and females as well as after chronic cocaine exposure. Results: First, we found that both GABA-A and GABA-B receptors modulate dopamine release on a rapid time scale directly at the terminals in the NAc. There were sex differences in this regulation, with enhanced GABA-A-mediated inhibition observed in females and greater GABA-B-mediated inhibition observed in males. Additionally, GABAergic modulation of dopamine release was blunted in males following chronic cocaine exposure. Conclusion: The results of these studies will contribute to the understanding of how sex fits into the comprehensive framework for dopamine release regulation and how dysregulation of these processes influences the trajectory of CUD in both males and females. Funding was provided by startup funds from V.U. School of Medicine, Department of Pharmacology and the National Institutes of Health (NIH) (to E.S.C.). Funds from the National Institute of Drug Abuse (NIDA) DA042111, DA048931, DA056221, the Brain and Behavior Research Foundation, Whitehall Foundation, and the Edward J Mallinckrodt Jr. Foundation (E.S.C) also supported this work.