NORNICOTINE CONTRIBUTION TO THE CNS EFFECT OF NICOTINE

描述：（申请人摘要） 吸烟是头号健康问题， 疾病和死亡比任何其他单一因素。 滥用责任 主要的烟草生物碱尼古丁（NIC）源于其内在的 强化特性被认为是多巴胺激活的结果 (DA)大脑中的路径 阐明NIC的作用机制， 确定长期给药的效果对于 了解吸烟行为的开始/维持，以及 克服了吸烟者在消除这种行为时遇到的问题。 考虑到NIC外周代谢的过多信息， 关于NIC在大脑中的代谢以及其潜在的 NIC代谢物的药理活性。 本报告的总体目标 一个建议是测试假设，中枢神经系统的影响，导致从NIC 烟草使用期间的暴露不仅是由于NIC，但至少 部分来自NIC代谢物的作用。 我们最近已经证明， NIC代谢物（可替宁、去甲烟碱（norNIC）、去甲可替宁和一种 未鉴定的第四种代谢物）在急性给药后4小时存在于脑中。 外围设备[2 '-14C]NIC管理。 此外，我们还发现， 增加多巴胺释放从灌流大鼠纹状体切片在一个 浓度依赖性、Ca++依赖性、美加明敏敏感性， 二氢-β-赤霉素敏感的和立体选择性的方式，表明 烟碱受体介导。 也类似于NIC，重复的S（-）或 R（+）norNIC给药能够激活神经机制 负责行为敏化，即使R（+）norNIC产生不 重复给药后的明显行为效应。 拟议 该项目将确定NIC代谢物的累积动力学， 脑，药理活性和 NIC代谢物的作用机制，以及时间依赖性行为 和神经化学变化的反应，反复norNIC管理。 拟议研究的结果将增加我们对 参与神经行为效应的分子机制 吸烟和NIC暴露。

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.