Characterization of the behavioral and neurochemical effects of nicotine withdrawal in adolescent and adult rats.

Previous studies have demonstrated that the behavioral effects of nicotine withdrawal are lower in adolescent versus adult rats. However, the neurochemical mechanisms that mediate these developmental differences are presently unclear. Much work has shown that nicotine reward is mediated via enhanced dopamine neurotransmission in the mesolimbic pathway which originates in the ventral tegmental area (VTA) and terminates in several forebrain structures including the nucleus accumbens (NAcc). More recently, studies have shown that nicotine withdrawal produces a decrease in NAcc dopamine transmission, an effect that is believed to serve as a neurochemical marker of withdrawal in adult rodents. The goal of this project was to understand whether developmental sensitivity to nicotine withdrawal is mediated via dopaminergic mechanisms in adolescent versus adult rats. Thus, extracellular levels of dopamine in the NAcc were compared in adolescent and adult rats experiencing nicotine withdrawal. Following 13 days of nicotine exposure, the rats were implanted unilaterally with microdialysis probes into the NAcc and the ipsilateral VTA. The next day, dialysate samples were collected following administration of the nicotinic-receptor antagonist mecamylamine to precipitate withdrawal. The physical signs of withdrawal were also examined in the same animals during baseline and then following systemic mecamylamine administration. The results revealed that mecamylamine precipitated the physical signs of withdrawal in both age groups; however, the total number of physical signs was larger in nicotine-dependent adult versus adolescent rats. The microdialysis results revealed that mecamylamine produced a decrease in extracellular levels of dopamine in the NAcc that was larger in adults (44% decrease) versus adolescents (20%). A similar pattern of developmental differences was observed with the dopaminergic metabolites (3,4-dihydroxyphenlyacetic acid and homovanillic acid). However, an assessment of the serotonergic metabolite (5-hydroxyindoleacetic acid) revealed that there were no developmental differences in this measure during nicotine withdrawal. A follow-up study compared extracellular levels of NAcc dopamine in adolescent and adult rats receiving intra-VTA administration of bicuculline, which reduces gamma-aminobutyric acid (GABA) inhibition of dopamine neurotransmission. The results revealed that blockade of GABA receptors in the VTA produced a 2-fold increase in NAcc dopamine of adult, but not adolescent rats. The results of these studies provide a potential mechanism involving dopamine that mediates developmental differences in nicotine withdrawal. Specifically, they suggest that GABAergic systems are underdeveloped during adolescence, and this reduced inhibition of dopamine neurons in the VTA may lead to reduced decreases in NAcc dopamine of adolescent versus adult rats during nicotine withdrawal