NMDA Glutamate Receptor Transmission in Extinction of Cocaine-Seeking Behavior

描述(由申请人提供)：实验动物模型已被证明有效地将可卡因成瘾理解为一种习得性行为，尽管是异常行为。老鼠会自愿给自己注射可卡因。如果没有可卡因，吸毒行为就会消失或消失。临床上成功的可卡因依赖治疗方法帮助患者学会在不接触可卡因的情况下耐受可卡因的渴望，这种情况与灭绝条件相似。尽管有明确的临床相关性，但在动物模型中对物种灭绝的研究还不够深入。灭绝可以看作是对新行为的学习和记忆。NMDA谷氨酸受体参与学习和记忆。我们建议从行为学、药理学和神经生物学三个水平研究NMDA传递在可卡因消退中的作用。1.行为选择或技能培训是临床治疗的一个成功因素。我们建议评估学习新的行为，对蔗糖的反应，对消退训练的影响。2.我们建议研究FDA已经批准用于其他人类临床疾病的两种药物--NMDA受体激动剂d-环丝氨酸和NMDA拮抗剂美金刚对消退的影响。我们将评估NMDA受体是否以及如何参与灭绝，以及这些药物是否对人类可卡因成瘾具有药物治疗潜力。3.我们建议将d-环丝氨酸和美金胺注射到不同的脑区，以定位NMDA受体介导的消退效应背后的神经回路。在未来的临床试验中，消退训练中药物作用的时间进程可能会为谷氨酸能药物的使用时机和类型提供信息，以优化消退训练。 公共卫生相关性：我们的建议“NMDA谷氨酸受体在寻求可卡因行为的灭绝中的传递”是对RFA-DA-08-025：“吸毒成瘾的灭绝和药物疗法，R03”的应用。我们的建议紧跟着RFA的指南，研究药理化合物，NMDA试剂d-环丝氨酸和美金刚，对实验室大鼠灭绝学习的影响。我们进一步建议研究通过将NMDA药物微量注入离散的大脑区域而导致灭绝的神经回路。

Description (provided by applicant): Laboratory animal models have proven validity for understanding cocaine addiction as a type of learned, albeit abnormal behavior. Rats will voluntarily self-administer cocaine. Drug-taking behavior will disappear or extinguish if cocaine becomes unavailable. Clinically successful therapies for cocaine dependence help patients learn to tolerate cocaine cravings without access to cocaine, a situation not unlike extinction conditions. Despite clear clinical relevance, extinction has been understudied in animal models. Extinction can be seen as the learning of and memory for new behavior. The NMDA glutamate receptor is involved in learning and memory. We propose to study the role of NMDA transmission in cocaine extinction at 3 levels: behavioral, pharmacological and neurobiological. 1. Behavioral alternatives or skills training are a successful ingredient of clinical therapies. We propose to assess the effect of learning new behavior, responding for sucrose, on extinction training. 2. We propose to study the effects on extinction of two medications already FDA approved for other human clinical conditions, the NMDA receptor agonist d-cycloserine and the NMDA antagonist memantine. We will assess if and how NMDA receptors are involved in extinction and if the medications have pharmacotherapeutical potential in human cocaine addiction. 3. We propose to inject d-cycloserine and memantine into discrete brain areas to map the neural circuitry underlying NMDA receptor-mediated effects on extinction. The time course of medication effects during extinction training may inform the timing and type of glutamatergic medications to optimize extinction training in future clinical trials. Public Health Relevance: Our proposal "NMDA Glutamate Receptor Transmission in Extinction of Cocaine-Seeking Behavior" is an application to RFA-DA-08-025: "Extinction and pharmacotherapies for drug addiction, R03". Our proposal closely follows the RFA's guidelines to study the effects of pharmacological compounds, the NMDA agents d- cycloserine and memantine, on extinction learning in laboratory rats. We further propose to study the neural circuitry underlying extinction by micro-infusion of NMDA agents into discrete brain areas.