Dissecting the Distinct Arrestin Signaling Capabilities of the Short and Long Dopamine D2 Receptors as a Paradigm for Psychostimulant Addiction Treatment

 描述（由申请人提供）：物质滥用障碍在美国产生巨大的经济和社会成本;因此，需要为这些疾病开发更好的治疗方法。药物替代疗法（即伐尼克兰和美沙酮）已成为减少某些类型成瘾药物使用的有效工具。然而，对于精神兴奋剂滥用（即可卡因和甲基苯丙胺），仍然需要有效的替代疗法。多巴胺（DA）受体部分激动剂已被提出作为一种策略，以取代减少DA的紧张度，基础上的负强化的精神兴奋剂成瘾，但调节DA系统是具有挑战性的，因为DA受体表达的各种细胞类型。更复杂的是，多巴胺D2受体（D2 R）表达为两种亚型，短型和长型，它们的差异在于29个氨基酸的插入。长的D2 R亚型被认为是负责DA对突触后中等多刺神经元（MSN）的作用，而短的D2 R亚型被认为主要作为突触前DA神经元上的自身受体起作用。最近，我们的实验室已经表明，MSN中的长D2 R亚型可以通过β-arrestin介导的途径发出信号，并且该途径在很大程度上负责苯丙胺的D2 R依赖性运动效应。相反，所有已知的D2 R自身受体（推测为短同种型）的功能可以单独归因于G蛋白信号传导。这是重要的，因为如果突触前和突触后D2 R功能可以由于两种D2 R同种型在与β-抑制蛋白偶联方面的根本差异而被完全分离，则可以选择性地增加作用于MSN上的突触后D2 R的DA张力，而不引起DA释放的同时减少。因此，本研究的目的是确定D2 R亚型表达模式和通过β-抑制蛋白的信号传导的差异是否可以用于实现突触后D2 R受体功能的选择性靶向。

 DESCRIPTION (provided by applicant): Substance abuse disorders exert large financial and social costs in the U.S.; therefore, better treatments for these disorders need to be developed. Pharmacological replacement therapies (i.e. varenicline and methadone) have become effective tools in reducing some types of addictive drug use. However, effective replacement therapies are still needed for psychostimulant abuse (i.e. cocaine and methamphetamine). Dopamine (DA) receptor partial agonists have been proposed as a strategy to replace the reduced DA tone that underlies the negative reinforcement of psychostimulant addiction, but modulating the DA system is challenging because DA receptors are expressed on a variety of cell types. Adding further complication, the dopamine D2 receptor (D2R) is expressed as two isoforms, short and long, which differ by a 29 amino acid insertion. The long D2R isoform is thought to be responsible for DA's effect on post-synaptic medium spiny neurons (MSNs), whereas the short D2R isoform is thought to function mainly as an autoreceptor on pre-synaptic DA neurons. Recently, our lab has shown that the long D2R isoform in MSNs can signal through a β-arrestin-mediated pathway and that this pathway is largely responsible for the D2R- dependent locomotor effects of amphetamine. In contrast, all of the known functions of D2R autoreceptors (presumably the short isoform) can be solely ascribed to G protein signaling. This is significant because if pre- and post-synaptic D2R function can be pharmacologically separated due to a fundamental difference between the two D2R isoforms in coupling to β-arrestin, then it may be possible to selectively increase DA tone acting upon post-synaptic D2Rs on MSNs without causing a simultaneous decrease in DA release. Thus, the objective of this fellowship will be to determine if differences in D2R isoform expression patterns and signaling through β-arrestin could be exploited to achieve selective targeting of post-synaptic D2R receptor function.