Electronic Thesis/Dissertation


Sex Differences In Responses to Chronic Prenatal Nicotine Exposure in Rats Open Access

Cigarette smoking is one of the leading causes of preventable death and disease in developed countries. Despite the known risk, currently 19% of the adult population in the United States smoke cigarettes (Centers for Disease Control and Prevention, 2013). Early exposure to nicotine during development is associated with an increased risk of nicotine addiction in adults. Early exposure includes both initiation of smoking during adolescence and prenatal nicotine exposure. Adolescence is the most common period for the initiation of recreational drug use, and 88% of current adult smokers used their first cigarette before the age of 18 (Public Health Service 1994). Evidence also indicates differences between males and females in addiction rates and smoking behavior. Tobacco is also the most commonly abused substance during pregnancy: tobacco use occurs in an estimated 14% of pregnancies in the United States. Infants exposed to tobacco smoke in utero are more likely to be addicted to nicotine. In addition, females exposed to tobacco smoke through the mother appear to progress from initiation of tobacco smoking to addiction more quickly than non-exposed females. All of the pharmacological effects of nicotine are mediated by neuronal nicotinic acetylcholinergic receptors (nAChRs) , which are widespread throughout the autonomic and central nervous system. In the CNS, nAChRs are primarily presynaptic, and are involved in modulating the release of several neurotransmitters, including dopamine, norepinephrine, GABA, glutamate, and acetylcholine . The involvement of these receptors in the release of neurotransmitters suggests that nicotine use may have widespread effects on important neural pathways in the CNS. In order to help elucidate the underlying causes of sex differences in response to nicotine, we investigated nicotinic receptor regulation and genome expression differences in male and female rats following adolescent and prenatal nicotine exposure. To do this we exposed rats to nicotine under various treatment paradigms using subcutaneously implanted miniosmotic pumps containing either nicotine or saline. Using [3H]epibatidine to label assembled receptors and subunit specific antibodies to characterize receptors, we found sex differences in &alpha4;&beta2;* receptor regulation in the cerebral cortex at both early (PN28) and late (PN42) adolescence. These results imply sex differences in sensitivity to nicotine exposure in early and late adolescence. In addition, we found sex differences in &alpha4;β&alpha5; receptor regulation in the cerebral cortex following chronic prenatal nicotine exposure in rats at PN14. After using a fostering paradigm to isolate nicotine exposure to either in utero only or postnatal only exposure, we determined the sensitivity seen at PN14 in males required a combination of both in utero and postnatal exposure to manifest. Finally, in order to help clarify the underlying basis of behavioral differences in adolescents exposed to nicotine prenatally, we identified persistent alterations in genome expression in dopaminergic cell bodies using microarray analysis of the VTA of adolescent male and female rats following chronic prenatal nicotine exposure. With this method we identified dramatic differences in gene expression between males and females. These changes suggest that disruptions in circadian rhythm regulation may contribute to an increased risk of nicotine addiction in adolescent male rats, but not female rats, exposed to nicotine prenatally. Alterations in these associated genes were confirmed using qRT-PCR. These data suggest both differences in receptor regulation and genomic expression between males and females at ages of increased vulnerability to nicotine.

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