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造成巨大的经济和社会成本；因此，需要开发更好的治疗这些障碍的方法。药物替代疗法(即伐伦克林和美沙酮)已成为减少某些类型成瘾药物使用的有效工具。然而，对于精神刺激性滥用(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)受体部分激动剂被认为是一种替代降低的DA张力的策略，而DA张力降低是精神刺激剂成瘾负面强化的基础，但调节DA系统是具有挑战性的，因为DA受体表达在各种类型的细胞上。更复杂的是，多巴胺D2受体(D2R)表达为两种不同的亚型，短和长，插入29个氨基酸。长D2R亚型被认为与DA对突触后中棘神经元(MSN)的影响有关，而短D2R亚型被认为主要作为突触前DA神经元的自身受体发挥作用。最近，我们的实验室已经证明，MSN中的长D2R亚型可以通过β-arrestin介导的途径发出信号，这一途径在很大程度上与苯丙胺的D2R依赖的运动效应有关。相比之下，D2R自身受体的所有已知功能(可能是短的异构体)都可以完全归因于G蛋白信号。这一点意义重大，因为如果由于与β-arrestin偶联的两种D2R亚型之间的根本差异，突触前和突触后的D2R功能在药物上可以分开，那么有可能选择性地增加作用于MSN上突触后D2R的DA音调，而不会导致DA释放的同时减少。因此，这项研究的目的将是确定是否可以利用D2R亚型表达模式和β-arrestin信号的差异来实现对突触后D2R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.