Project Abstract Tobacco use remains a major public health problem, particularly in women who are more vulnerable to the long-term consequences of smoking. Unfortunately, there is a critical knowledge gap regarding the underlying mechanisms by which stress promotes the behavioral effects of nicotine in females. The objective of this fellowship application is to investigate the role of stress systems in promoting nicotine reward and withdrawal in female rats. Our central hypothesis is that sex differences in the behavioral effects of nicotine are modulated via stress systems in the local circuits of the nucleus accumbens (NAc), a terminal region of the mesolimbic dopamine pathway. The rationale for our hypothesis is based on our preliminary studies showing that viral- mediated over-expression of corticotrophin-releasing factor (CRF) in the NAc selectively enhances the rewarding effects of nicotine in female versus male rats. Our mechanistic hypothesis is that sex differences in the behavioral effects of nicotine are modulated via inhibitory (GABA) and excitatory (glutamate) amino acids that regulate dopamine release in the NAc. Thus, the proposed studies will examine sex differences in the neurochemical effects of nicotine in female and male rats that received over-expression of CRF in the NAc (Aim 1). We predict that activation of CRF1 receptors following CRF over-expression produces a decrease in GABA transmission that results in enhanced dopamine release in the NAc of female versus male rats. We will examine whether these effects are CRF1 receptor mediated by infusing the CRF1 receptor antagonist, antalarmin into the NAc during our dialysate collections. Subsequent studies will examine sex differences in the neurochemical effects of nicotine withdrawal in female and male rats that received over-expression of CRF in the NAc (Aim 2). We predict that CRF over-expression will exacerbate the neurochemical effects of nicotine withdrawal via the emergence of large increases in glutamate release onto GABAergic interneurons. We expect that this effect will lead to a larger increase in GABA release that will contribute to a larger decrease in NAc dopamine release in female versus male rats. The project will provide important information regarding the role of stress systems in the behavioral effects of nicotine.