Characterizing the Role of Nicotine on Sex-Specific Neural Circuit Mechanisms Underlying Sensory Reinforcement

Abstract

<b>Abstract ID 23911</b> <b>Poster Board 574</b> Substance use disorder is characterized by motivational circuit dysfunction that leads to maladaptive behaviors associated with reward processing and drug consumption. Men and women are differentially vulnerable to the harmful effects of substances of abuse, and women are most at risk. The goal of this study was to understand how sex contributed to the behavioral effects of nicotine in mice. In both animals and humans, nicotine is shown to be a weak primary reinforcer in the absence of cues, but in the presence of cues produces high rates of responding in reinforcement tasks. Thus, defining the mechanism underlying the interaction between sensory stimuli in the environment and nicotine’s pharmacological effects are important for understanding nicotine addiction. We took a multifaceted approach to determine sex-dependent neurochemical mechanisms that underlie the role of repeated nicotine exposure on sensory reinforcement in male and female mice. First mice were trained for sensory reinforcement, where they emitted a nose poke for the presentation of visual and auditory stimuli. Mice showed rates of responding that were significantly higher than the unreinforced condition. Interestingly, sensory stimuli were more reinforcing in females compared to males. Next, mice were treated with saline or nicotine via subcutaneous injection for five days. We found a significant increase in sensory reinforcement in response to nicotine in males, but not females. Sensory reinforcement is dependent on dopamine release in reward-related brain regions such as the nucleus accumbens, thus, to understand potential mechanisms by which this occurred we assessed dopamine release dynamics and the effects of nicotine on these dynamics using fast scan cyclic voltammetry. We then correlated the effects of nicotine on dopamine release with behavior in the same animals during sensory reinforcement. There was a significant positive correlation between the rate of responding in the sensory reinforcement task and the effects of low dose nicotine on dopamine release in females, but not males. Further, we found that reinforced responses to sensory cues after repeated nicotine injections positively predicted dopamine release in response to tonic and phasic stimulation parameters following bath application of a higher desensitizing nicotine dose. Interestingly, this effect was not sex-specific, suggesting that nicotine’s ability to activate vs desensitize receptors may play differential roles in sex-specific behavioral effects. Overall, these data suggest that sex differences in nicotine regulation of dopamine neurotransmission underlies sex-specific behavior in sensory reinforcement. Determining the effect of nicotine on sex differences in the interaction between cues and nicotine effects on behavior, as well as understanding the neural circuitry controlling the differences in reward processing and behavior between males and females will aid in the development of sex-specific treatment interventions for nicotine dependence and broad substance use disorders. Funding for this project was provided by funds from Vanderbilt University School of Medicine (E.S.C.), and funding from the National Institute of Health (NIH). Funds from the National Institute on Drug Abuse (NIDA) DA042111 (E.S.C.), the Brain &amp; Behavior Research Foundation (E.S.C.), the Vanderbilt University Academic Pathways Postdoctoral Research Fellowship (L.J.B.) and the NIH / NIDA (1K99DA052641) MOSAIC K99/R00 (L.J.B.) also supported this work.