Molecular and Functional Analysis of Age and Sex Differences in Nicotine-induced Cellular Signaling and Synaptic Plasticity



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Nicotine addiction is the most common form of chemical dependence in the United States and leads to almost 500,000 deaths each year. Adolescents and females have been shown to be particularly vulnerable to the addictive properties of nicotine and other drugs. We measured multiple proteins and phosphorylation events involved in drug addiction and synaptic plasticity in three brain areas closely linked to drug addiction: the ventral striatum (VS), ventral tegmentum (VT), and the medial prefrontal cortex (mPFC). We found sex- and age-dependent CDK5 signaling, including lower levels of p25 in adult females, particularly in the VS. This has important implications for synaptic plasticity and drug addiction. A single nicotine injection (as a model of the first reaction to nicotine), caused a larger increase in VS BDNF signaling in adolescent than in adults. Conversely, we found that both single and repeated nicotine injections (the latter as a model of nicotine dependence) caused adolescent-specific increases in DARPP-32 Thr34 phosphorylation (which would increase cyclic AMP signaling). We also found decreases in VS GLUR1 phosphorylation (which would reduce the strength of glutamatergic signaling). In the VT, a single nicotine injection caused a female-specific increase in GLUR1 phosphorylation and BDNF signaling. Repeated nicotine injections caused an adolescent-specific increase in VT DARPP-32 Thr34 phosphorylation. In the mPFC, repeated nicotine injections caused an adolescent specific decrease in BDNF signaling, as well as a female-specific decrease in the inferred CDK5 activity. Due to the importance of the CDK5 regulator p25 in a form of synaptic plasticity known as "long-term depression” (LTD), and the low production of p25 in adult females, we measured the magnitude of LTD in the core of the nucleus accumbens. We found a significant deficit in LTD specifically during proestrus in females (the time of peak estrogen levels), compared to males and estrus females. Moreover, we found p25 levels were significantly lower in proestrus females than estrus females or ovariectomized females. We present a proposed molecular mechanism for this hormonal effect on LTD in the nucleus accumbens, which is a key step in the physiology of drug addiction. More broadly, our results show an adolescent-specific response to nicotine in the VS, but a female-specific response to nicotine in the VT. These responses would increase the vulnerability of adolescents and females, respectively, to nicotine dependence.