The Roles of nNOS, Ontogeny, and Gender in Cocaine Sensitization

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DESCRIPTION (provided by applicant): Currently, substance abuse during adolescence is a serious problem. Recent studies in adolescent humans and rodents have revealed that the effects of cocaine are similar in some ways, but different in others, compared to the effects seen in adults. It has been proposed that these differences may arise from adolescent specific neural adaptations in the mesolimbic and corticostriatal dopaminergic and glutamatergic systems targeted by cocaine. Moreover, CNS maturational changes may impart a unique vulnerability to the persisting effects of cocaine from adolescence into adulthood. Accumulating evidence from our lab and others has also implicated the nitrergic system (nitric oxide) in the addictive properties of psycho stimulants. Specifically, we found that nNOS KO mice are less sensitive to the psychomotor, rewarding, and neurotoxic effects of psycho stimulants. Nitric oxide also appears to have a role in the effect of psycho stimulants during adolescence. Recently, we discovered that adolescent nNOS KO mice, unlike their WT counterparts, fail to maintain cocaine-induced conditioned place preference (CPP) and do not demonstrate reinstatement of CPP after priming in adulthood. These findings suggest nNOS has an important developmental role in the mechanisms underlying long-term vulnerability to cocaine. It is hypothesized that the expression of the nNOS gene in adolescence is necessary for the maintenance of long-term psychomotor sensitized response from adolescence through adulthood. In addition, we predict that maturation of the nitrergic system, in relation to the dopaminergic neurons, plays a critical role in shaping cocaine psychomotor sensitization. This project will address the developmental- and gender-dependent role of nNOS in psychomotor sensitization. The neural adaptations, e.g., protein expression and structural changes, of nitrergic cells as a function of development as well as cocaine exposure will also be investigated and correlated to the behavioral studies. This project will be helpful in identifying biological characteristics of adolescence which predispose towards drug progression and persisting drug effects.