ELECTORPHYSIOLOGY OF VTA PRE AND POSTSYNAPTIC NACHRS

描述：（申请人摘要） 烟草使用一直是疾病和过早死亡的主要原因， 我们社会有限的社会和经济资源。 尽管在了解基本方面取得了相当大的进展， 烟草/尼古丁成瘾，详细的细胞，分子， 缺乏尼古丁成瘾的生物物理机制。 如果不了解其精确位置、功能特性和 身份的受体介导尼古丁成瘾，有很少 希望开发具有潜在治疗价值的靶向试剂， 戒烟。 像其他滥用药物一样，尼古丁被认为会产生 其通过激活中脑边缘多巴胺系统的成瘾作用， 通常被认为是大脑“奖励”的关键神经回路 系统 尼古丁的成瘾作用是通过激活 神经元烟碱乙酰胆碱受体（nAChRs）在这个系统中，但 尼古丁成瘾的确切机制仍有争议。 研究 本提案中概述的将确定生理和 关键多巴胺能受体表达的nAChRs的药理学特性 “强化”回路中的神经元：腹侧被盖区 （VTA）。 突触前和突触后腹侧被盖区神经元nAChRs的性质 将通过电生理学方法确定。 的研究 腹侧被盖区体树突和轴突终末nAChRs的性质 神经元将集中在检查的影响“吸烟者的水平”， 尼古丁对内源性激动剂ACh的后续反应。 的 假设激活和失活特性的差异 突触前vs.突触后腹侧被盖区nAChRs（以及它们在成瘾中的作用， se）是由于在pre vs. 突触后nAChRs将直接通过使用基因工程 缺乏α 5 nAChR亚基基因表达的小鼠。 这些研究将提供 尼古丁成瘾的重要见解以及 中脑边缘奖励系统，并提供必要的信息， 尼古丁成瘾治疗剂的开发。

DESCRIPTION: (Applicant's Abstract) Tobacco use has been a major cause of diseases and premature death, draining the limited available social and economical resources of our society. Despite considerable progress in understanding fundamental aspects of tobacco/nicotine addiction, knowledge of the detailed cellular, molecular, and biophysical mechanisms that underlie nicotine addiction are lacking. Without understanding the precise location, functional properties, and identity of the receptors that mediate nicotine addiction, there is little hope of developing targeted reagents of potential therapeutic value for smoking cessation. Like other drugs of abuse, nicotine is thought to exert its addictive effects via activation on the mesolimbic dopamine system, commonly viewed as the key neuronal circuitry underlying the brain "reward" system. The addictive effects of nicotine are mediated by activation of neuronal nicotinic acetylcholine receptors (nAChRs) in this system, but the precise mechanism of addiction to nicotine is in dispute. The studies outlined in this proposal will determine the physiological and pharmacological properties of the nAChRs expressed by key dopaminergic neurons within the "reinforcement" circuitry: the ventral tegmental area (VTA). The properties of both the pre- and postsynaptic VTA neuronal nAChRs will be determined by electrophysiological methods. Studies on the properties of both the somatodendritic and axon terminal nAChRs of VTA neurons will focus on an examination of the effects of "smoker's levels" of nicotine on subsequent responses to the endogenous agonist, ACh. The hypothesis that differences in the activation and inactivation properties of pre- vs. postsynaptic VTA nAChRs (and their consequent role in addiction per se) are due to the inclusion, or lack thereof, of the a5 subunit in pre vs. postsynaptic nAChRs will be tested directly by using genetically engineered mice that lack a5 nAChR subunit gene expression. These studies will provide important insights into the nicotine addiction as well as the functioning of the mesolimbic reward system, and supply essential information toward development of therapeutic agents for nicotine addiction.