SV2C: a novel target for inhibition of methamphetamine action

描述（由申请人提供）：甲基苯丙胺（METH）的成瘾性至少部分是由于细胞外多巴胺的急剧增加。虽然目前没有METH成瘾的治疗方法，但已经研究了许多化合物在METH成瘾恢复中的功效。治疗开发的困难在于找到一种既能调节多巴胺释放又能优先在多巴胺神经元内表达以限制治疗不良反应的分子靶点。突触糖蛋白2C（SV2C）的表达主要局限于多巴胺能神经支配丰富的区域，如中脑和纹状体。此外，申请人进行的初步实验证明了SV2C在正常多巴胺释放和储存中的重要性。SV2C的基因消融导致纹状体脑切片中囊泡释放减少50%，如通过快速扫描循环伏安法测量的，并且囊泡储存容量减少20%，如通过放射性多巴胺摄取测量的。SV2C的有限定位加上它在多巴胺神经传递中发挥的重要作用，将其确定为潜在治疗开发的主要候选者。本提案的目的是描述SV2C基因缺失对小鼠METH给药相关的神经化学和行为变化的影响。该项目是及时的和高度转化的，因为已经创建了选择性结合SV2C的化合物（UCB Pharma），尽管它们尚未被研究用于多巴胺信号传导的调节。

DESCRIPTION (provided by applicant): The addictive nature of methamphetamine (METH) is due, at least in part, to drastically increased extracellular dopamine. Though no current therapeutic for METH addiction is available, numerous compounds have been investigated for efficacy in METH addiction recovery. The difficulty in therapeutic development is finding a molecular target that both modulates dopamine release and is preferentially expressed within dopamine neurons to limit adverse effects of treatment. Expression of the synaptic glycoprotein 2C (SV2C) is largely restricted to areas rich in dopaminergic innervation, such as the midbrain and striatum. Additionally, preliminary experiments conducted by the applicant demonstrate the importance of SV2C in normal dopamine release and storage. Genetic ablation of SV2C results in a 50% reduction of vesicular release in striatal brain slices, as measured by fast scan cyclic voltammetry, and a 20% reduction in vesicular storage capacity, as measured by radioactive dopamine uptake. The restricted localization of SV2C coupled with the important role it plays in dopamine neurotransmission identify it as a prime candidate for potential therapeutic development. The purpose of this proposal is to delineate the effect of genetic deletion of SV2C on the neurochemical and behavioral changes associated with METH administration in mice. This project is both timely and highly translational, as compounds that selectively bind SV2C have been created (UCB Pharma), though they have not been investigated for modulation of dopamine signaling.