Role of D3 dopamine receptor in behavioral sensitization

描述（由申请方提供）：行为致敏，重复使用药物后某些行为的渐进性和持久性增强，以长期的方式增强啮齿动物的运动。在药物依赖和精神病中起重要作用的相同多巴胺途径也在致敏中起关键作用。然而，单个多巴胺受体亚型在致敏中的作用尚未明确。D3多巴胺受体刺激抑制啮齿动物运动。D3受体活性可以通过表达可变剪接的截短受体同种型（称为“D3 nf”）来调节，所述受体同种型通过与全长亚基的二聚化改变受体定位和功能。我们研究的主要假设是：（1）重复的D3受体刺激通过降低D3受体介导的运动抑制的响应性来促进致敏的发展;和2.）增加的D3 nf表达指导改变的受体定位和随后的D3受体介导的抑制的释放，有助于敏化的表达。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受体在苯丙胺行为敏化中的作用。我们测试的假设，即一个稳态，代偿反应D3受体刺激有助于改变D3受体剪接和发展的致敏作用，通过确定多巴胺受体激动剂和拮抗剂对发展的致敏作用和D3受体亚型表达。在具体目标2中，我们将评估长期给药后对D3受体拮抗剂的行为反应。我们将测量对D3受体阻断的行为反应，使用D3选择性药物作为测量D3受体功能的工具。这一目的检验了以下假设：致敏的表达部分是由于D3介导的抑制作用的释放，因此导致对D3受体拮抗剂的反应降低。在具体目标3中，我们将确定慢性安非他明给药对D3多巴胺受体表达的影响。我们将测量全长D3受体和D3 nf mRNA的表达，并测量D3受体内化。这个目的测试的假设，慢性安非他明管理增加D3 nf的表达，从而抑制全长D3受体功能的内化全长受体。我们期望证明增加D3 nf的表达，并增加D3受体内化，敏化后。这一发现表明选择性剪接途径是一种新的干预措施，以防止致敏，以及恢复D3介导的抑制功能，也表明D3 nf的生物学功能。集体;这些研究提供了一个多方面的测试的一个新的假说的机制，潜在的长期变化的边缘介导的行为。这些结果可能表明，多巴胺在神经精神疾病中起着重要作用，包括精神病和药物依赖性。值得注意的是，这些研究还可能阐明一种以前未被认识到的调节受体脱敏和与其他受体系统和病理条件相关的贩运的机制。

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.