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

描述（由申请人提供）：目前，青少年滥用药物是一个严重的问题。最近对青少年人类和啮齿动物的研究表明，与成年人相比，可卡因的作用在某些方面相似，但在其他方面有所不同。有人提出，这些差异可能源于可卡因靶向的青少年中边缘和皮质纹状体多巴胺能和谷氨酸能系统的特定神经适应。此外，中枢神经系统的成熟变化可能会导致从青春期到成年期可卡因持续影响的独特脆弱性。我们实验室和其他实验室积累的证据也表明，氮系统（一氧化氮）与精神兴奋剂的成瘾性有关。具体来说，我们发现nNOS KO小鼠对精神兴奋剂的精神运动性、奖励性和神经毒性作用不太敏感。一氧化氮似乎也在青少年时期精神兴奋剂的作用中发挥作用。最近，我们发现青春期的nNOS KO小鼠，与WT小鼠不同，不能维持可卡因诱导的条件位置偏好（CPP），并且在成年期启动后不会恢复CPP。这些发现表明，nNOS在长期易受可卡因影响的机制中具有重要的发育作用。假设nNOS基因在青春期的表达对于维持从青春期到成年期的长期精神运动致敏反应是必要的。此外，我们预测，与多巴胺能神经元相关的氮能系统的成熟在形成可卡因精神运动致敏中起着关键作用。本项目将探讨nNOS在精神运动致敏中的发育和性别依赖作用。神经适应，例如蛋白质表达和结构变化，氮能细胞作为发育的功能以及可卡因暴露也将被调查并与行为研究相关联。该项目将有助于确定青少年的生物学特征，这些特征倾向于药物进展和持续的药物作用。

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.