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（由申请人提供）：药物滥用疾病在美国造成巨大的经济和社会成本；因此，需要开发针对这些疾病的更好的治疗方法（即伐尼克兰和美沙酮）已成为减少某些类型的有效工具。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。作为替代减少 DA 音调的策略，DA 音调是精神兴奋剂成瘾负强化的基础，但调节 DA 系统具有挑战性，因为 DA 受体在多种细胞类型上表达，进一步增加了复杂性，即多巴胺 D2 受体 (D2R) 的表达。作为两种同工型，短和长，其不同之处在于插入了 29 个氨基酸。长 D2R 同工型被认为是 DA 对突触后中等刺的影响的原因。神经元（MSN），而短 D2R 异构体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，我们的实验室表明 MSN 中的长 D2R 异构体可以通过 β-抑制蛋白介导的途径发出信号。该途径主要负责苯丙胺的 D2R 依赖性运动作用，相反，D2R 自身受体的所有已知功能（大概是短的）。这很重要，因为如果由于两种 D2R 同工型与 β-arrestin 偶联的根本差异，突触前和后 D2R 功能可以在药理学上分开，那么这可能是可能的。选择性地增加作用于 MSN 上突触后 D2R 的 DA 音调，而不导致 DA 释放同时减少。因此，本研究的目的是确定 D2R 是否存在差异。可以利用 β-arrestin 的异构体表达模式和信号传导来实现突触后 D2R 受体功能的选择性靶向。