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

描述(申请人提供)：目前，青春期的药物滥用是一个严重的问题。最近对青春期人类和啮齿动物的研究表明，与成年人相比，可卡因的影响在某些方面相似，但在其他方面不同。有人提出，这些差异可能源于青少年对可卡因靶向的中脑边缘和皮质纹状体多巴胺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使人对可卡因从青春期到成年期的持久影响具有独特的脆弱性。来自我们实验室和其他实验室的越来越多的证据也表明，硝能系统(一氧化氮)与精神兴奋剂的成瘾特性有关。具体地说，我们发现nNOS KO小鼠对精神兴奋剂的精神运动、奖励和神经毒性作用不那么敏感。一氧化氮似乎也在青春期精神兴奋剂的影响中发挥了作用。最近，我们发现，与WT小鼠不同，青春期nNOSKO小鼠不能维持可卡因诱导的条件性位置偏爱(CPP)，并且在成年期启动后不表现出CPP的恢复。这些发现表明，nNOS在可卡因长期易感性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是维持从青春期到成年期的长期精神运动敏感化反应所必需的。此外，我们预测，与多巴胺能神经元相关的硝能系统的成熟，在形成可卡因精神运动敏化方面起着关键作用。本项目将探讨nNOS在精神运动敏感化中的发育和性别依赖作用。作为发育和可卡因暴露的函数的氮能细胞的神经适应，例如蛋白质表达和结构变化，也将被调查并与行为研究相关联。该项目将有助于确定青春期易导致药物进展和持久药物效应的生物学特征。

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.