The objective of this application is to compare the neurochemical mechanisms mediating developmental differences to the behavioral effects of nicotine withdrawal. It is well established that adult smoking behavior is mediated in large part by avoiding the negative consequences of nicotine withdrawal. However, it is presently not clear how nicotine withdrawal contributes to smoking behavior during the adolescent period of development. This knowledge gap presents a problem because current smoking cessation strategies focus on alleviating withdrawal and these medications may be ineffective in treating adolescent smokers who may not experience withdrawal. This is supported by clinical studies showing that treatments such as the nicotine patch do not improve abstinence rates in young smokers. These findings along with the known health complications produced by long-term smoking underscore the importance of investigating the role of nicotine withdrawal in adolescent smoking behavior. Animal studies in our laboratory demonstrated that adolescent rats display less physical and negative affective properties of nicotine withdrawal relative to adults. However, the neurochemical mechanisms that mediate these behavioral differences are unclear. Neurochemical studies have shown that the mechanisms of withdrawal involve decreases in dopamine levels in the nucleus accumbens (NAcc), a terminal region of the mesolimbic dopamine pathway. This pathway originates in the ventral tegmental area (VTA) where dopamine cell bodies are tightly regulated by inhibitory gamma- aminobutyric acid (GABA) and excitatory glutamate neurotransmission. Several lines of research have suggested that inhibitory GABA systems are underdeveloped and excitatory glutamate systems are overdeveloped during adolescence. We propose that a lack of nicotine withdrawal in adolescents is related to fewer decreases in NAcc dopamine levels, and this will be due to reduced inhibitory (i.e., less GABA activity) and enhanced excitation (i.e., more glutamate activity) in the dopamine cell body region of the VTA relative to adult rats. Our hypothesis will be examined by using in vivo microdialysis and high performance liquid chromatography to compare NAcc dopamine and concomitant measures of VTA GABA and glutamate levels in adolescent and adult rats experiencing nicotine withdrawal. In addition, we will utilize pharmacological approaches to characterize the role of VTA GABA and glutamate in mediating the neurochemical effects of nicotine withdrawal in adolescent and adult rats. Collectively, these studies will provide a characterization of the mechanisms that mediate nicotine withdrawal at different stages of rodent development.
