Dopamine D2/D3 Receptors in Compulsive Disorders

描述（由申请人提供）：强迫行为，包括过度饮食，赌博，购物，锻炼或吸毒，可以在没有其他精神病理学的个体中随着时间的推移而发展。虽然强迫行为的特征是过度参与特定的行为，但强迫行为的动物模型表明，另一个定义特征是行为与药物输送无关。因此，人们可能会强迫赌博，即使他们不经常赢，或过度购物，即使他们可能不会使用他们所购买的东西。我们的假设是，当操作性（工具性，目标跟踪）和应答性（巴甫洛夫，经典，符号跟踪）条件反射过程收敛于同一行为时，会导致这些类型的行为-断开行为。此外，个体必须对多巴胺敏感，并且在存在作用于敏感的多巴胺受体的D3/D2激动剂的情况下更可能发生强迫行为。我们将在三个行为模型中检验这一假设：1）喹吡罗诱导的对可卡因相关刺激的反应; 2）喹吡罗诱导的对水的反应; 3）喹吡罗作为可卡因或水强化行为的时机设定者。这些模型的行为药理学将用各种多巴胺激动剂和拮抗剂进行测试，并将研究致敏，目标跟踪和符号跟踪的作用。了解强迫症的环境、行为、神经化学和药理学方面将有望有助于开发这些使人衰弱的疾病的治疗方法。公共卫生相关性：这项提案的目的是确定各种环境和神经化学因素对强迫行为的贡献（例如，过度赌博、购物、饮食、性行为和吸毒）。我们的假设是，当在致敏多巴胺受体和多巴胺受体刺激的存在下建立相同的经典条件反射和操作性条件反射行为时，会产生强迫行为。在这项研究中，我们将在三种大鼠模型中进行测试。评价选择性多巴胺受体的能力，以及沉默D3受体的RNA，以改变强迫行为，应有助于指向这些疾病的可能的药物治疗，并了解设置条件将建议行为治疗和预防方法。

DESCRIPTION (provided by applicant): Compulsive behaviors, including excessive eating, gambling, shopping, exercising, or drug-taking, can develop over time in individuals without other psychopathology. Although compulsive behavior is marked by excessive engagement in a particular behavior, animal models of compulsive behavior suggest that another defining feature is behavior that is disconnected from reinforcer delivery. Thus, people may gamble compulsively even though they do not win often, or shop excessively even when they may not use what they have purchased. Our hypothesis is that these types of reinforcer- disconnected behaviors result when both operant (instrumental, goal-tracking) and respondent (Pavlovian, classical, sign-tracking) conditioning processes converge on the same behavior. In addition, individuals must be sensitized to dopamine, and the compulsive behavior is more likely to occur in the presence of a D3/D2 agonist acting on the sensitized dopamine receptors. We will test this hypothesis in three behavioral models: 1) quinpirole-induced responding for stimuli associated with cocaine; 2) quinpirole-induced responding for water in the presence of water; and 3) quinpirole as an occasion setter for either cocaine or water-reinforced behavior. The behavioral pharmacology of these models will be tested with various dopamine agonists and antagonists, and the roles of sensitization, goal-tracking, and sign-tracking will be studied. Understanding the environmental, behavioral, neurochemical, and pharmacological aspects of compulsive disorders will hopefully contribute to the development of treatments for these debilitating disorders. PUBLIC HEALTH RELEVANCE: The purpose of this proposal is to determine various environmental and neurochemical contributors to compulsive behavior (e.g., excessive gambling, shopping, eating, sexual behavior, and drug-taking). Our hypothesis, that compulsions result when the same classically conditioned and operantly conditioned behavior is established in the presence of sensitized dopamine receptors and stimulation of dopamine receptors, will be tested in three rat models in this research effort. Evaluation of the ability of selective dopamine receptors, as well as silencing the RNA for the D3 receptor, to modify the compulsive behavior should help point towards possible pharmacological treatment of these disorders, and understanding of the setting conditions will suggest behavioral therapy and prevention approaches.