NORNICOTINE CONTRIBUTION TO THE CNS EFFECT OF NICOTINE

描述：(申请人摘要) 吸烟是头号健康问题，占比更大 疾病和死亡比任何其他单一因素都要多。的滥用责任 烟草中的主要生物碱尼古丁(NIC)源于其固有的 增强性能被认为是多巴胺激活的结果 (DA)大脑中的通路。阐明NIC的作用机制和 确定长期服药的效果对于 了解吸烟行为的开始/维持，并为 克服吸烟者在消除这种行为方面遇到的问题。 考虑到关于NIC外周代谢的过多信息， 对NIC在大脑中的新陈代谢及其潜在的作用知之甚少 NIC代谢物的药理活性。这样做的总体目标是 建议对NIC导致的CNS效应的假设进行检验 在使用烟草期间接触烟草并不完全是由于NIC，而是至少导致 部分来自NIC代谢物的作用。我们最近证明了 NIC代谢物(可替宁、去甲烟碱(NorNIC)、去甲可替宁和An迄今 未知的第四代谢物)在急性发作后4小时出现在大脑中 外设[2‘-14C]网卡管理。此外，我们还发现NorNIC 增加超融合大鼠纹状体脑片中DA的释放 依赖于浓度，依赖于钙离子，对甲基胺敏感， 二氢-β-红景天碱敏感和立体选择性方式，表明 烟碱受体调节。同样类似于NIC，重复S(-)或 R(+)NorNIC给药能够激活神经机制(S) 负责行为敏感化，即使R(+)NorNIC没有产生 反复给药后出现明显的行为效应。建议数 该项目将确定NIC代谢物在 脑，药理活性和 NIC代谢物的作用机制及其时间依赖行为 以及神经化学变化对重复使用NorNIC的反应。 建议的研究结果将增加我们对 神经行为效应的分子机制 由烟草使用和NIC暴露引起的。

DESCRIPTION: (Applicant's Abstract) Cigarette smoking is the number one health problem accounting for more illnesses and deaths than any other single factor. The abuse liability of the major tobacco alkaloid, nicotine (NIC), stems from its intrinsic reinforcing properties suggested to be the result of activation of dopamine (DA) pathways in brain. Elucidation of NIC's mechanism of action and determination of the effects of chronic administration are important for understanding the initiation/maintenance of smoking behavior, and for overcoming problems that smokers experience in extinguishing this behavior. Considering the plethora of information on the peripheral metabolism of NIC, little is known about NIC metabolism in brain and about the potential pharmacologic activity of NIC metabolites. The overall objective of this proposal is to test the hypothesis that CNS effects resulting from NIC exposure during tobacco usage are not solely due to NIC, but result at least in part from actions of NIC metabolites. We have recently demonstrated that NIC metabolites (cotinine, nornicotine (norNIC), norcotinine, and an as yet unidentified fourth metabolite) are present in brain 4 hours after acute peripheral [2'-14C]NIC administration. Also, we have found that norNIC increases DA release from superfused rat striatal slices in a concentration-dependent, Ca++ -dependent, mecamylamine-sensitive, dihydro-beta-erythroidine-sensitive, and stereo-selective manner, indicating nicotinic receptor mediation. Also similar to NIC, repeated S(-) or R(+)norNIC administration were capable of activating the neural mechanism(s) responsible for behavioral sensitization, even though R(+)norNIC produced no overt behavioral effects after its repeated administration. The proposed project will determine the kinetics of accumulation of NIC metabolites in brain, the pharmacological activity and mechanism of action of NIC metabolites, and the time-dependent behavioral and neurochemical changes in response to repeated norNIC administration. The results of the proposed studies will increase our knowledge of the molecular mechanisms that are involved in the neurobehavioral effects resulting from tobacco use and NIC exposure.