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

剖析短多巴胺 D2 受体和长多巴胺 D2 受体的独特抑制素信号传导能力，作为精神兴奋剂成瘾治疗的范例

• 批准号: 9252227
• 负责人: Thomas Franklin Pack
• 金额: $ 3.3万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9252227
• 关键词: Agonist; Amino Acids; Amphetamines; Arrestins; Autoreceptors; Behavioral; Binding; Biochemical; Biological; Cocaine; Complication; Coupling; Development; Disease; Dopamine; Dopamine D2 Receptor; Dopamine Receptor; Drug Addiction; Drug abuse; Drug usage; Epitopes; Fellowship; Fluorescence Polarization; G-substrate; GTP-Binding Proteins; In Vitro; Ligands; Locomotion; Measures; Mediating; Mediator of activation protein; Messenger RNA; Methadone; Methamphetamine; Molecular Conformation; Mus; Negative Reinforcements; Neurons; Pathway interactions; Pattern; Pharmacology; Property; Protein Isoforms; Psychostimulant dependence; Replacement Therapy; Reverse Transcriptase Polymerase Chain Reaction; Rewards; Role; Signal Pathway; Signal Transduction; Signaling Protein; Societies; Substance abuse problem; Synapses; Testing; Training; Viral; beta-arrestin; cell type; cost; dopamine system; dopaminergic neuron; experimental study; in vivo; mutant; negative affect; preference; protein B; psychostimulant; public health relevance; receptor expression; receptor function; reconstitution; social; stimulant abuse; tool; varenicline

 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.

 描述（由应用程序提供）：滥用药物疾病在美国施加巨大的财务和社会成本；因此，需要开发更好的这些疾病治疗方法。药理学替代疗法（即varenicline和Meadadone）已成为减少某些类型的添加剂使用的有效工具。但是，精神刺激滥用（即可卡因和甲基苯丙胺）仍然需要有效的替代疗法。已经提出了多巴胺（DA）受体部分激动剂，以替代降低的DA音调的策略，从而构成了心理刺激添加的负面增强的基础，但是调节DA系统是挑战的，因为DA受体在各种细胞类型上表达。增加并发症，多巴胺D2受体（D2R）表示为两种同工型，短而长，由29个氨基酸插入差异。长D2R同工型被认为是DA对突触后培养基神经元（MSN）的影响的原因，而短的D2R同工型被认为主要是在突触前DA神经元上起作用的自身受体。最近，我们的实验室表明，MSN中的长D2R同工型可以通过β-arrestin介导的途径发出信号，并且该途径在很大程度上是苯丙胺的D2R依赖性运动作用的主要原因。相比之下，D2R自身受体的所有已知功能（肯定是短同工型）都可以仅分配给G蛋白信号传导。这很重要，因为如果两种D2R同工型之间的基本差异与β-arrestin之间的基本差异，则可以在物理上分离出显着分离，那么可能会选择性地增加DA张力在MSN上的突触后D2RS上的DA态，而不会导致DA释放的简单降低。这是该团契的目的是确定可以探索D2R同工型表达模式的差异和通过β-arrestin的信号传导，以实现突触后D2R受体功能的选择性靶向。