Dopamine D2/D3 Receptors in Compulsive Disorders

强迫症中的多巴胺 D2/D3 受体

• 批准号: 7728111
• 负责人: james H Woods
• 金额: $ 39.98万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7728111
• 关键词: Agonist; Animal Model; Behavior; Behavior Therapy; Behavioral; Behavioral Model; Cocaine; Data; Disease; Dopamine; Dopamine Agonists; Dopamine Receptor; Eating; Elements; Evaluation; Exercise; Gambling; Goals; Home environment; Individual; Intervention; Modeling; Nature; Obsessive compulsive behavior; Operant Conditioning; Organism; Pharmaceutical Preparations; Pharmacological Treatment; Positioning Attribute; Prevention approach; Procedures; Process; Psychopathology; Quinpirole; RNA Interference; Rattus; Research; Respondent; Rodent; Role; Sex Behavior; Stimulus; Testing; Thinking; Time; Water; behavioral pharmacology; chemical synthesis; conditioning; design; excessive behavior; neurochemistry; programs; public health relevance; receptor; reinforced behavior; reinforcer; sex; therapy development

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.

描述（由申请人提供）：随着时间的推移，没有其他精神病理学的个体可能会出现强迫行为，包括过度饮食、赌博、购物、锻炼或吸毒。尽管强迫行为的特点是过度参与特定行为，但强迫行为的动物模型表明，另一个定义特征是与强化物传递无关的行为。因此，人们可能会强迫性赌博，即使他们不经常赢钱，或者过度购物，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）和反应性（巴甫洛夫式、经典性、符号跟踪）条件反射过程收敛于相同行为时，就会产生这些类型的强化物断开行为。此外，个体必须对多巴胺敏感，并且当D3/D2激动剂作用于敏感的多巴胺受体时，更容易发生强迫行为。我们将在三种行为模型中测试这一假设：1）喹吡罗诱导的对可卡因相关刺激的反应； 2) 在有水存在的情况下，喹吡罗诱导的水响应； 3) 喹吡罗作为可卡因或水强化行为的场合设置者。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，并将研究敏化、目标跟踪和体征跟踪的作用。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：本提案的目的是确定导致强迫行为（例如过度赌博、购物、饮食、性行为和吸毒）的各种环境和神经化学因素。我们的假设是，当在敏化多巴胺受体存在和刺激多巴胺受体的情况下建立相同的经典条件反射和操作性条件反射行为时，就会产生强迫行为，我们将在本研究工作中的三个大鼠模型中进行测试。评估选择性多巴胺受体以及沉默 D3 受体 RNA 改变强迫行为的能力应有助于指出这些疾病的可能药物治疗方法，而对环境条件的了解将建议行为治疗和预防方法。