Sex Differences in Nicotine-induced Changes of the Mouse Brain Proteome

Tobacco smoking continues to be the leading cause of premature death in the United States, and a significant public health burden worldwide. Addiction to tobacco is driven by nicotine, the primary psychoactive and addictive component in tobacco smoke. Studies demonstrate that nicotine addiction has a disproportionate impact on women, who are more likely to progress from initial use to dependence, and less likely to attain and maintain abstinence. The neurobiological mechanisms underlying sex differences in nicotine addiction have been studied through various experimental approaches, ranging from genetic and molecular to behavioral and neuroimaging techniques, in both humans and animal models. These studies have found sex differences in key brain regions of the mesocorticolimbic system, including the ventral tegmental area (VTA), striatum, and cortex, which have an established role in addiction to many drugs of abuse, including nicotine. However, no proteomic studies have investigated sex differences in nicotine addiction. One possibility is that underlying sex differences in the proteome of these structures result in baseline sex differences in neuronal activity and function that lead to differences in behavior. Additionally, nicotine exposure itself may differentially impact the proteome in males and females. With the cutting-edge technologies and expertise available through the Yale/NIDA Neuroproteomics Center, we propose to study sex differences in nicotine addiction by 1) evaluating sex differences in the proteome at baseline and after chronic nicotine administration in the mouse VTA, striatum and cortex and 2) evaluating sex differences in the proteome after a minimalistic, behaviorally relevant paradigm of nicotine exposure. Previous research into sex differences has overwhelmingly focused on neurobiological substrates that were selected as interesting targets based on initial studies conducted only in male subjects. Our approach will allow an unbiased investigation of sex differences in the proteome at baseline and after nicotine exposure, as well as a comparison between different nicotine regimens. Importantly, our results may identify new targets for future hypothesis-driven research into sex-specific mechanisms of nicotine addiction, specifically, or drug addictions more generally.