Role of D3 dopamine receptor in behavioral sensitization

D3 多巴胺受体在行为敏化中的作用

• 批准号: 6862693
• 负责人: NEIL MARK RICHTAND
• 金额: $ 30.7万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6862693
• 关键词: RNA splicing; amphetamines; behavioral /social science research tag; behavioral habituation /sensitization; chordate locomotion; dopamine agonists; dopamine antagonists; dopamine receptor; in situ hybridization; laboratory rat; male; neuropharmacology; polymerase chain reaction; protein isoforms; protein localization; psychomotor function; receptor expression

DESCRIPTION (provided by applicant): Behavioral sensitization, the progressive and enduring enhancement of certain behaviors following repetitive drug use, augments rodent locomotion in a long-standing fashion. The same dopamine pathways playing an important role in drug dependence and psychosis also play a critical role in sensitization. The role of individual dopamine receptor subtypes in sensitization, however, has not been clearly identified. D3 dopamine receptor stimulation inhibits rodent locomotion. D3 receptor activity may be regulated through expression of an alternatively spliced, truncated receptor isoform (termed "D3nf") altering receptor localization and function via dimerization with the full-length subunit. The central hypotheses for our research are that 1.) repetitive D3 receptor stimulation contributes to development of sensitization through decreased responsivity of D3 receptor-mediated locomotor inhibition; and 2.) increased D3nf expression directs altered receptor localization and subsequent release of D3-receptor mediated inhibition, contributing to expression of sensitization. We will test these hypotheses with the following Specific Aims. In Specific Aim 1,we identify the role of D3 receptors in behavioral sensitization to amphetamine. We test the hypothesis that a homeostatic, compensatory response to D3 receptor stimulation contributes to altered D3 receptor splicing and the development of sensitization by determining the effect of dopamine receptor agonists and antagonists on development of sensitization and D3 receptor isoform expression. In Specific Aim 2, we will evaluate behavioral response to D3 receptor antagonists following chronic drug administration. We will measure the behavioral response to D3 receptor blockade, using D3-selective drugs as a tool to measure D3 receptor function. This aim tests the hypothesis that expression of sensitization results in part from release of D3-mediated inhibition, therefore resulting in decreased response to D3 receptor antagonist. In Specific Aim 3, we will determine the consequences of chronic amphetamine administration on D3 dopamine receptor expression. We will measure expression of both full-length D3 receptor and D3nf mRNA, and also measure D3 receptor internalization. This aim tests the hypothesis that chronic amphetamine administration increases D3nf expression, thereby inhibiting full-length D3 receptor function by internalizing the full-length receptor. We expect to demonstrate increased D3nf expression, and increased D3 receptor internalization, following sensitization. This finding would suggest alternative splicing pathways as a novel intervention to prevent sensitization, as well as restore D3-mediated inhibitory function, and would also suggest a biological function for D3nf. Collectively; these studies provide a multi-faceted test of a novel hypothesis of the mechanism underlying long-standing changes in limbic-mediated behaviors. These outcomes may suggest new interventions for neuropsychiatric conditions in which dopamine is known to play an important role, including psychosis and drug dependence. Significantly, these studies may also elucidate a previously unrecognized mechanism regulating receptor desensitization and trafficking relevant to other receptor systems and pathological conditions.

描述（由申请人提供）：行为敏化，即重复吸毒后某些行为的渐进和持久增强，以长期存在的方式增强啮齿动物的运动能力。在药物依赖和精神病中发挥重要作用的相同多巴胺途径也在致敏中发挥着关键作用。然而，单个多巴胺受体亚型在致敏中的作用尚未明确确定。 D3 多巴胺受体刺激可抑制啮齿动物的运动。 D3受体活性可以通过表达选择性剪接、截短的受体亚型（称为“D3nf”）来调节，通过与全长亚基的二聚化改变受体定位和功能。我们研究的中心假设是 1.) 重复的 D3 受体刺激通过降低 D3 受体介导的运动抑制的反应性而促进敏化的发展； 2.) D3nf 表达增加导致受体定位改变，随后释放 D3 受体介导的抑制作用，从而促进敏化的表达。我们将通过以下具体目标来检验这些假设。在具体目标 1 中，我们确定了 D3 受体在安非他明行为敏感性中的作用。我们通过确定多巴胺受体激动剂和拮抗剂对致敏发生和 D3 受体亚型表达的影响，检验了对 D3 受体刺激的稳态补偿反应有助于改变 D3 受体剪接和致敏发生的假设。在具体目标 2 中，我们将评估长期用药后对 D3 受体拮抗剂的行为反应。我们将使用 D3 选择性药物作为测量 D3 受体功能的工具，测量对 D3 受体阻断的行为反应。该目的检验了这样的假设：敏化的表达部分是由于 D3 介导的抑制作用的释放导致的，因此导致对 D3 受体拮抗剂的反应降低。在具体目标 3 中，我们将确定长期服用安非他明对 D3 多巴胺受体表达的影响。我们将测量全长 D3 受体和 D3nf mRNA 的表达，并测量 D3 受体内化。该目的测试了以下假设：长期服用安非他明会增加 D3nf 表达，从而通过内化全长受体来抑制全长 D3 受体功能。我们期望证明致敏后 D3nf 表达增加，D3 受体内化增加。这一发现表明替代剪接途径可以作为一种新的干预措施来防止致敏，以及恢复 D3 介导的抑制功能，并且还表明 D3nf 的生物学功能。集体；这些研究为边缘系统介导的行为长期变化的潜在机制的新假设提供了多方面的检验。这些结果可能建议对神经精神疾病采取新的干预措施，其中多巴胺在其中发挥重要作用，包括精神病和药物依赖。值得注意的是，这些研究还可能阐明以前未被认识的调节与其他受体系统和病理状况相关的受体脱敏和运输的机制。