Sex differences in cholinergic regulation of behavioral responses to rewarding and aversive stimuli

Abstract

Substance use disorder (SUD) is a major public health concern, characterized by dysregulation in drug taking, drug seeking, and compulsive behavior, as well as deficits in the valuation of drugs and alternative reinforcers. Determining neurobiological factors that contribute to individual variability of SUD is critical for identification of at‐risk populations as well as the use of preventative measures and personalized medicine in treatment. Women represent a particularly vulnerable population when it comes to the development and trajectory of SUD, therefore understanding the sex‐specific mechanisms underlying the differential control of reward and motivation will be critical for improving treatment outcomes in women. At the core of this SUD vulnerability is an enhancement in reward processing and motivation for both natural and drug rewards. Nicotinic acetylcholine receptors (nAChR) have been directly linked to the control of reward‐related behavior for both natural and drug reinforcers, thus, here we aimed to understand how these receptor populations differentially control motivated behavior for positive and negative stimuli in a sex‐specific fashion. Mice were trained to acquire positive (response = reward delivery) and negative (response = shock removal) reinforcement in the presence of discrete antecedent auditory cues. We found sex differences in performance at baseline, with females showing reduced rates of acquisition for negative reinforcement and increase motivation for positive reinforcers. Next, the non‐selective nAChR antagonist, mecamylamine, was administered systemically to assess the effect of nAChRs on task performance. Blocking nAChRs reduced discrimination for auditory cues in both sexes regardless of what task type they were predicting, demonstrating that its effects on reinforcement are not stimulus specific. Further, while we saw sex‐differences in reinforcement at baseline, we observed no sex differences following mecamylamine treatment. Together this data shows that nAChR modulation of reward‐related behavior eliminates basal sex differences in reinforcement behavior and suggests that the cholinergic system may be a crucial factor in sex differences in motivation.Support or Funding Information Funding was provided by startup funds from Vanderbilt University School of Medicine Department of Pharmacology and the National Institutes of Health (NIH) (to E.S.C.) and the Vanderbilt University Academic Pathways Postdoctoral Research Fellowship (to L.J.B.). Funds from the National Institute of Drug Abuse (NIDA) DA042111 and DA048931(E.S.C), the Brain and Behavior Research Foundation (to E.S.C), Whitehall Foundation (to E.S.C), and the Edward J Mallinckrodt Jr. Foundation (to E.S.C) also supported this work.