Abstract
Sex differences in behaviors relevant to nicotine addiction have been observed in rodent models and human subjects. Behavioral, imaging, and epidemiological studies also suggest underlying sex differences in mesolimbic dopamine signaling pathways. In this study we evaluated the proteome in the ventral tegmental area (VTA) and nucleus accumbens (NAc) shell in male and female mice. Experimental groups included two mouse strains (C3H/HeJ and C57BL/6J) at baseline, a sub-chronic, rewarding regimen of nicotine in C3H/HeJ mice, and chronic nicotine administration and withdrawal in C57BL/6J mice. Isobaric labeling with a TMT 10-plex system, sample fractionation, and tandem mass spectrometry were used to quantify changes in protein abundance. In C3H/HeJ mice, similar numbers of proteins were differentially regulated between sexes at baseline compared with within each sex after sub-chronic nicotine administration. In C57BL/6J mice, there were significantly greater numbers of proteins differentially regulated between sexes at baseline compared with within each sex after chronic nicotine administration and withdrawal. Despite differences by sex, strain, and nicotine exposure parameters, glial fibrillary acidic protein (GFAP) and dopamine and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32, Ppp1r1b) were repeatedly identified as significantly altered proteins, especially in the VTA. Further, network analyses showed sex- and nicotine-dependent regulation of a number of signaling pathways, including dopaminergic signaling. Sub-chronic nicotine exposure in female mice increased proteins related to dopaminergic signaling in the NAc shell but decreased them in the VTA, whereas the opposite pattern was observed in male mice. In contrast, dopaminergic signaling pathways were similarly upregulated in both male and female VTA after chronic nicotine and withdrawal. Overall, this study identifies significant sex differences in the proteome of the mesolimbic system, at baseline and after nicotine reward or withdrawal, which may help explain differential trajectories and susceptibility to nicotine addiction in males and females.
Highlights
Smoking tobacco is responsible for more than 7 million deaths a year worldwide1 and nicotine is the primary psychoactive ingredient in tobacco (Picciotto and Kenny, 2013)
Sex differences in the mesolimbic system proteome are significant under baseline conditions as well as in response to nicotine
After a rewarding sub-chronic administration of nicotine, dopaminergic signaling pathways were altered in opposite directions in male and female mice, such that they were increased in the nucleus accumbens (NAc) and decreased in the ventral tegmental area (VTA) of female mice, and decreased in the NAc and increased in the VTA of male mice
Summary
Smoking tobacco is responsible for more than 7 million deaths a year worldwide and nicotine is the primary psychoactive ingredient in tobacco (Picciotto and Kenny, 2013). There are significant sex differences in many aspects of nicotine addiction, ranging from the cellular to behavioral levels. Nicotine interacts differentially with sex hormones in males and females to affect nicotine-induced dopamine release in striatal tissue in opposite directions (Dluzen and Anderson, 1997). Significant sex differences in baseline function of the mesolimbic dopamine system have been demonstrated, including the numbers of putative dopaminergic neurons in the VTA (McArthur et al, 2007), baseline VTA dopaminergic activity (Calipari et al, 2017), and D1 and D2-type dopamine receptor availability in the NAc shell and VTA (Pohjalainen et al, 1998; Bernardi et al, 2015)
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