Nicotinic Receptor Regulation of Dopamine Transporter

描述（由申请人提供）：烟草使用是美国头号可预防的死亡原因。烟草中含量最多的生物碱尼古丁（NIC）的补强作用在维持吸烟行为中起着重要作用。此外，烟草使用和抑郁症是高度共病的，NIC可能在一定程度上缓解了这一临床人群的抑郁症。奖励和药物成瘾的神经生物学研究主要集中在中皮质边缘和黑质纹状体多巴胺（DA）通路上。NIC激活烟碱受体，增加这些通路末端和细胞体区域的胞外DA浓度。细胞外DA浓度是突触前末端神经递质释放和细胞外间隙神经递质清除的净结果。多巴胺清除主要由质膜多巴胺转运蛋白（DAT）介导。尽管有大量关于NIC刺激的DA释放的信息，但NIC调节DAT功能的能力和负责这种影响的潜在机制尚未得到详细研究。初步数据显示，在前额皮质，急性NIC增加突触体对DA的摄取，体内伏安法研究中的DA清除和细胞表面的数据运输。因此，NIC对DAT功能的增强似乎增强了NIC诱导的前额皮质细胞外DA浓度增加的动力学。提出的研究将开始阐明负责nic诱导的DAT功能增强的潜在机制。在当前的应用中需要测试的假设是，NIC通过尼古丁受体激活，介导DAT的贩运。这一假设将以大鼠为动物模型进行验证，并将确定(1)急性体内给药NIC对纹状体、伏隔核、前额皮质和杏仁核中数据传输的剂量相关影响；(2)尼古丁受体是否介导NIC对数据传输的影响；(3)间歇性和连续的NIC管理对数据传输的影响。这些实验的结果将开始阐明NIC和尼古丁受体调节DAT功能的细胞机制，从而有助于调节细胞外DA浓度。因此，将提供有关NIC对与药物滥用相关的脑区DA神经传递的影响的见解。

DESCRIPTION (provided by applicant): Tobacco use is the number one preventable cause of death in the US. The reinforcing efficacy of nicotine (NIC), the most abundant alkaloid in tobacco, plays a major role in the maintenance of tobacco smoking. Furthermore, tobacco use and depressive disorders are highly comorbid, and NIC maybe be used in part to alleviate depression in this clinical population. Research on the neurobiology of reward and drug addiction has focused on mesocorticolimbic and nigrostriatal dopamine (DA) pathways. NIC activates nicotinic receptors which increases extracellular DA concentrations at both terminal and cell body regions of these pathways. Extracellular DA concentration is the net result of neurotransmitter release from the presynaptic terminal and neurotransmitter clearance from the extracellular space. DA clearance is mediated primarily by the plasma membrane dopamine transporter (DAT). Although there is a wealth of information on NIC stimulated DA release, the ability of NIC to modulate DAT function and the underlying mechanisms responsible for this effect have not been studied in detail. Preliminary data show that in prefrontal cortex, acute NIC increases DA uptake into synaptosomes, DA clearance in in vivo voltammetry studies and DAT trafficking to the cell surface. Thus, NIC augmentation of DAT function appears to sharpen the kinetics of the NIC-induced increase in extracelluar DA concentration in prefrontal cortex. The proposed study will begin to elucidate the underlying mechansims responsible for the NIC-induced enhancement of DAT function. The hypothesis to be tested in the current application is that NIC, via nicotinic receptor activation, mediates the trafficking of DAT. This hypothesis will be tested using the rat as the animal model, and will determine (1) the dose-related effects of acute in vivo administration of NIC on DAT trafficking in striatum, nucleus accumbens, prefrontal cortex and amygdala; (2) if nicotinic receptors mediate the effect of NIC on DAT trafficking; and (3) the effect of intermittent and continuous NIC administration on DAT trafficking. Results of these experiments will begin to elucidate the cellular mechanisms by which NIC and nicotinic receptors modulate DAT function, and thereby, contribute to the regulation of extracellular DA concentration. Thus, insight will be provided with respect to the effect of NIC on DA neurotransmission in brain regions associated with drug abuse.