Sex Differences in Nicotinic Receptor Regulation of Local Nucleus Accumbens Circuitry underlying Motivated Behavior

Abstract

Sex is a critical biological variable in neurological conditions characterized by abnormalities in motivation and reward processing – e.g. anxiety, schizophrenia, depression, and substance use disorder. In both human and animal studies, females exhibit faster reward learning and increased reward‐associated cue responses, highlighting the need for preclinical investigation of reward learning and motivation in female subjects. The neural control of reward and motivation is dependent upon the mesolimbic dopamine pathway connecting the ventral tegmental area (VTA) to the nucleus accumbens (NAc), where dopamine release in the NAc causally controls motivation and reward seeking. A particularly potent regulator of dopamine release is cholinergic (ChAT) interneurons signaling through pentameric nicotinic acetylcholine receptors (nAChRs) located on dopamine terminals. In fact, ChAT interneurons can elicit dopamine release directly via the α4β2 subunit containing nAChRs. Further, nAChRs have been shown to directly modulate tonic‐to‐phasic dopamine release, a process that is vital to encode reward information and drive behavior – highlighting the importance of nAChRs in dopaminergic control of behavior. Previous work has shown that Mecamylamine, a non‐selective nAChR antagonist, typically reduces tonic dopamine release, while enhancing or not changing phasic release in males; however, we show here, in females it reduces dopamine release across all frequencies. This suggests that females require more potent regulation of dopamine terminals by nicotinic systems to drive dopamine release, yet, it is unclear how subunit specific nAChRs differentially regulate this process in females. To understand how these differences in nAChR regulation of dopamine release could be driven by subunit specific neurochemical mechanisms we took a multipronged approach to outlining sex‐differences in nAChR regulation of VTA dopamine terminals in the NAc. Using fast‐scan cyclic voltammetry paired with pharmacology we measured subsecond dopamine kinetics in male and female mice using the selective α4β2 nAChR antagonist, DHβE, to determine the specific role of the α4β2 subunits on sex‐differences in nAChR modulation of tonic‐to‐phasic dopamine release. We found that, in males, DHβE had a trending effect toward reducing tonic dopamine release while not effecting phasic release. Contrary to this, DHβE decreased phasic dopamine release while not having a significant effect on tonic release in females. This data suggests an α4β2 nAChR‐dependent gating mechanism for the adaptation of activity‐dependent dopamine release in females, which likely acts to drive enhanced motivation. Moving forward it will be critical to directly link these sex‐differences to reward processing and reinforcement learning for the development of sex‐specific pharmacotherapies to treat a variety of debilitating neurological disorders.Support or Funding InformationFunding 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 and DA048931, the Brain and Behavior Research Foundation, Whitehall Foundation, and the Edward J Mallinckrodt Jr. Foundation (E.S.C) also supported this work.