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: 7257089
• 负责人: NEIL MARK RICHTAND
• 金额: $ 29.11万
• 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 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7257089
• 关键词: Affect; Agonist; Alternative Splicing; American; Amphetamines; Behavior; Behavioral; Biological Process; Brain region; Chronic; Condition; Development; Dimerization; Disease; Dopamine; Dopamine Agonists; Dopamine D1 Receptor; Dopamine Receptor; Drug Addiction; Drug Psychoses; Drug abuse; Drug usage; Feasibility Studies; Foundations; Functional disorder; Goals; Individual; Intervention; Length; Life; Ligands; Limbic System; Locomotion; Measures; Mediating; Messenger RNA; Neurotransmitters; Outcome; Pathway interactions; Pharmaceutical Preparations; Play; Protein Isoforms; Psychotic Disorders; RNA Splicing; Rattus; Receptor Activation; Research; Research Personnel; Rodent; Role; Substance abuse problem; System; Testing; behavior measurement; behavioral sensitization; desensitization; design; dopamine D3 receptor; neuropsychiatry; novel; prevent; programs; receptor; receptor expression; receptor function; receptor internalization; response; restoration; tool; trafficking

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，重复使用药物后某些行为的渐进性和持久增强，以长期的方式增强啮齿动物的运动。相同的多巴胺途径在药物依赖和精神病中起着重要作用，在致敏中也起着关键作用。然而，单个多巴胺受体亚型在敏化中的作用尚未清楚地鉴定出来。 D3多巴胺受体刺激抑制啮齿动物的运动。 D3受体活性可以通过表达替代剪接的，截断的受体同工型（称为“ D3NF”）来改变受体定位和通过全长亚基的二聚化来调节。我们研究的中心假设是1.）重复的D3受体刺激通过D3受体介导的运动抑制的反应性降低而导致致敏的发展；和2.）增加的D3NF表达指导受体定位改变，随后释放D3受体介导的抑制作用，导致敏化表达。我们将以以下特定目的测试这些假设。在特定的目标1中，我们确定了D3受体在行为敏化对苯丙胺中的作用。我们检验了以下假设：通过确定多巴胺受体激动剂和拮抗剂对敏化和D3受体同工型表达的发展，对D3受体刺激的反应有助于D3受体剪接的改变以及致敏的发展。在特定目标2中，我们将评估慢性药物给药后对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受体功能的工具来衡量对D3受体阻滞的行为反应。该目的检验了以下假设：敏化的表达部分是由于D3介导的抑制作用的释放而导致的，因此导致对D3受体拮抗剂的反应减少。在特定的目标3中，我们将确定慢性苯丙胺对D3多巴胺受体表达的后果。我们将测量全长D3受体和D3NF mRNA的表达，并测量D3受体内在化。该目标检验了以下假设：慢性苯丙胺给药增加了D3NF的表达，从而通过内在化全长受体来抑制全长D3受体功能。我们期望在致敏后证明D3NF表达增加，并显示D3受体内在化增加。这一发现将表明替代剪接途径是一种新的干预措施，以防止敏化，并恢复D3介导的抑制功能，并且还建议D3NF的生物学功能。集体这些研究提供了对边缘介导行为长期变化的机制的新假设进行的多方面检验。这些结果可能表明，众所周知，多巴胺在包括精神病和药物依赖性在内的神经精神疾病的新干预措施。值得注意的是，这些研究还可能阐明了先前未认识到的机制，该机制调节受体脱敏和与其他受体系统和病理条件相关的运输。

项目成果

Risperidone pretreatment prevents elevated locomotor activity following neonatal hippocampal lesions.

利培酮预处理可防止新生儿海马病变后运动活动升高。

• DOI: 10.1038/sj.npp.1300791
• 发表时间: 2006
• 期刊: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
• 作者: Richtand,NeilM;Taylor,Benjamin;Welge,JeffreyA;Ahlbrand,Rebecca;Ostrander,MichelleM;Burr,Jeffrey;Hayes,Scott;Coolen,LiqueM;Pritchard,LaurelM;Logue,Aaron;Herman,JamesP;McNamara,RobertK
• 通讯作者: McNamara,RobertK