Dopamine D2/D3 Receptors in Compulsive Disorders

描述（由申请人提供）：强迫行为，包括暴饮暴食、赌博、购物、锻炼或吸毒，可以在没有其他精神病理的个体中随着时间的推移而发展。虽然强迫行为的特征是对某一特定行为的过度投入，但强迫行为的动物模型表明，另一个决定性特征是与强化物传递断开的行为。因此，人们可能会强迫性地赌博，即使他们不经常赢，或者过度购物，即使他们可能不会使用他们购买的东西。我们的假设是，当操作性条件反射过程（工具性、目标跟踪）和应答性条件反射过程（巴甫洛夫条件反射过程、经典条件反射过程、符号跟踪过程）收敛于同一行为时，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，当D3/D2激动剂作用于致敏的多巴胺受体时，强迫行为更有可能发生。我们将在三个行为模型中验证这一假设：1)喹匹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，喹匹罗诱导的对水的反应；3)喹匹罗作为可卡因或水增强行为的场合设置者。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，并研究致敏、目标跟踪和信号跟踪的作用。了解强迫性障碍的环境、行为、神经化学和药理学方面，有望有助于这些衰弱性障碍的治疗发展。公共卫生相关性：本提案的目的是确定各种环境和神经化学因素对强迫行为（如过度赌博、购物、饮食、性行为和吸毒）的影响。我们的假设是，当在敏化多巴胺受体和多巴胺受体的刺激下建立了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。我们将在三种大鼠模型中进行研究。评估选择性多巴胺受体的能力，以及沉默D3受体的RNA，来改变强迫行为，应该有助于指出这些疾病的可能的药物治疗，并了解环境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.