Non-transporter cocaine mechanisms in dopamine system

描述（由申请人提供）：可卡因通常被认为通过抑制单胺转运蛋白，特别是多巴胺转运蛋白（DAT）来诱导其精神兴奋和行为作用。在自我管理的动物和人类成瘾者的大脑中，可卡因水平可以在5 ？除了单胺转运蛋白外，还可能影响神经元靶点。研究还表明，可卡因抑制克隆的神经元烟碱乙酰胆碱受体（nAChRs）。更重要的是，最近的报道表明，nAChR的活性调节多巴胺（DA）的释放并影响可卡因的行为效应，这表明可卡因和DA系统中nAChR之间可能存在相互作用。我们的初步数据支持我们的假设，即除了DAT抑制外，可卡因可能抑制纹状体中DA末端的突触前nachr，并降低初始DA释放概率。因此，可卡因可减少单脉冲诱发的强直性多巴胺释放，促进与奖励相关的阶段性多巴胺释放。因此，这种新的可卡因机制可能会增加阶段性DA与强直性DA的比例，潜在地增强可卡因相关奖励信号的显著性和动机价值。我们的初步结果表明，在低水平(<2 ？M)，可卡因主要通过众所周知的摄取抑制机制增强DA信号。在可卡因滥用者达到较高水平时，新的机制开始发挥作用。特别重要，在2-10 ？在滥用者中，可卡因可抑制突触前nachr，降低初始DA释放概率，增强奖励相关的相性DA信号与进行性DA信号的比值。总的来说，这些拟议的项目将描绘新的，突触前nachr介导的可卡因机制，有利于奖励相关的阶段性DA释放。这些新颖的非转运体可卡因机制，与单胺转运体依赖机制一致，可能有助于可卡因的成瘾特性。这些结果也将为我们未来使用体内动物模型的项目提供指导，并有助于我们阐明可卡因和尼古丁滥用的神经元机制，可能导致更有效的预防和治疗这些问题的策略。

DESCRIPTION (provided by applicant): Cocaine is commonly believed to induce its psychostimulant and behavioral effects through inhibition of monoamine transporters, dopamine transporters (DAT) in particular. Brain cocaine levels in self- administering animals and human addicts can be around 5 ?M and may affect neuronal targets besides monoamine transporters. Studies also show that cocaine inhibits cloned neuronal nicotinic acetylcholine receptors (nAChRs). More important, recent reports indicate that nAChR activity regulates dopamine (DA) release and affects cocaine's behavioral effects, suggesting potential interactions between cocaine and nAChRs in the DA system. Our preliminary data support our hypothesis that, in addition to DAT inhibition, cocaine may inhibit the presynaptic nAChRs on DA terminals in the striatum and reduce initial DA release probability. Consequently, cocaine may reduce single pulse-evoked tonic DA release and favor the reward-related phasic DA release. This novel cocaine mechanism may thus increase the phasic to tonic DA ratio, potentially enhancing the saliency and motivational value of cocaine-related reward signals. Our preliminary results indicate that at low levels (<2 ?M), cocaine primarily enhances the DA signal through the well known uptake inhibition mechanism. At higher levels attained in cocaine abusers, novel mechanisms come into play. Of particular importance, at 2-10 ?M attained in abusers, cocaine may inhibit presynaptic nAChRs and decrease the initial DA release probability, and enhance the reward-related phasic to tonic DA signal ratio. Overall, these proposed projects will delineate novel, presynaptic nAChR-mediated cocaine mechanisms that favor reward-related phasic DA release. These novel, non-transporter cocaine mechanisms, in concert with monoamine transporter-dependent mechanisms, are likely to contribute to cocaine's addictive properties. These results will also provide guidance to our future projects using in vivo animal models, and contribute to our long term goals to elucidate the neuronal mechanisms of cocaine and nicotine abuse, potentially leading to more effective prevention and treatment strategies for these problems.