Sex Differences in Local Nucleus Accumbens Circuitry and Motivated Behavior

Abstract

Drug addiction is a chronic, relapsing brain disease characterized by compulsive drug seeking, high levels of drug intake, and repeated cycles of abstinence and relapse. Historically, preclinical addiction research has focused almost entirely on male subjects; however, in humans, women take and use drugs in larger quantities, transition to addiction faster, and are more likely to relapse, thus representing a particularly vulnerable population. There are a variety of factors that could contribute to these sex differences – including estrous cycle dependent ovarian hormone fluctuations ‐ however the precise neural circuits and neurobiological mechanisms that underlie these differences in reward, motivation, and addiction vulnerability is largely unknown. The mesolimbic dopamine pathway, which connects the ventral tegmental area (VTA) to the nucleus accumbens (NAc), is an essential component of this process as it controls motivation and reward‐seeking behavior. To understand how these phenotypic differences in addiction vulnerability could be driven by estrous cycle‐dependent neurochemical mechanisms we took a multipronged approach to outlining sex‐differences in local circuit regulation of VTA dopamine terminals in the NAc. Using fast‐scan cyclic voltammetry (FSCV) paired with site‐specific pharmacology we measured subsecond dopamine kinetics in male and female mice in either diestrus (low circulating hormones) or estrus (high circulating hormones) and defined sex‐differences in local circuit regulation of dopamine release in the NAc. We found an enhanced dynamic range of calcium and presynaptic D2 autoreceptor control of dopamine release in females compared to males. During estrus, D2 autoreceptors were less effective at inhibiting dopamine release. Further, the relationship between calcium and dopamine release was enhanced in estrus. Finally, cholinergic regulation of dopamine signaling in the NAc was altered in a way that promotes and enhances dopamine release in estrus females. Together, these factors converge to increase the responsivity of dopamine terminals in the NAc to incoming stimuli and likely act to drive enhanced motivation and drug effects on this system. Moving forward it will be critical to directly link these sex‐differences to addiction vulnerability.Support or Funding InformationFunding was provided by startup funds from Vanderbilt University School of Medicine Department of Pharmacology (E.S.C, L.J.B.), as well as funding from the National Institutes of Health (NIH). Funds from the National Institute of Drug Abuse (NIDA) DA042111(E.S.C), National Institute of Mental Health (NIMH) MH065215 (A.R.J), the Brain and Behavior Research Foundation (to E.S.C), Whitehall Foundation (to E.S.C), Edward J Mallinckrodt Jr. Foundation (to E.S.C) also supported this work.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.