Role of Calcineurin in Nicotine Effects in Rats

描述（由申请人提供）：美国每年与吸烟相关的死亡人数超过440，000人，但仅在美国就有4620万吸烟者（CDC，2004）。尼古丁被认为是香烟的主要成瘾成分，因此更好地了解尼古丁奖励和强化机制至关重要。在动物中重复给予尼古丁会导致行为变化，如运动敏感化和条件性位置偏爱，这被认为反映了其强化特性。此外，尼古丁给药可调节中脑边缘多巴胺系统中的神经元活动、神经递质释放和下游信号传导，特别是腹侧被盖区（VTA）和丘脑核。钙依赖性蛋白磷酸酶，钙调神经磷酸酶，也调节许多涉及尼古丁成瘾的信号传导过程。因此，了解钙调神经磷酸酶在尼古丁介导的行为和神经化学可塑性中的作用是很重要的.拟定的实验将1）确定VTA中钙调磷酸酶活性对慢性尼古丁诱导的运动敏化的贡献，2）表征VTA钙调磷酸酶在尼古丁介导的信号传导途径中的作用。

DESCRIPTION (provided by applicant): Smoking related deaths in the US number over 440,000 per year and yet there are 46.2 million smokers in US alone (CDC, 2004). Nicotine is believed to be the primary addictive component of cigarettes, and thus it is critical to gain a better understanding of the mechanisms of nicotine reward and reinforcement. Repeated nicotine administration in animals leads to behavioral changes, such as locomotor sensitization and conditioned place preference, which are thought to reflect its reinforcing properties. In addition, nicotine administration modulates neuronal activity, neurotransmitter release and downstream signaling in the mesolimbic dopamine system, specifically in the ventral tegmental area (VTA) and nucleus accumbens. The calcium-dependent protein phosphatase, calcineurin, also modulates many of the signaling processes implicated in nicotine addiction. Thus, it is important to understand the role of calcineurin in nicotine- mediated behavioral and neurochemical plasticity. The proposed experiments will 1) determine the contribution of calcineurin activity in the VTA to chronic nicotine-induced locomotor sensitization and 2) characterize the role of VTA calcineurin in nicotine-mediated signaling pathways.