NMDA Glutamate Receptor Transmission in Extinction of Cocaine-Seeking Behavior

描述（由申请人提供）：实验动物模型已经证明了将可卡因成瘾理解为一种习得的，尽管是异常的行为的有效性。老鼠会自愿给自己注射可卡因。如果无法获得可卡因，吸毒行为就会消失或消失。临床成功的可卡因依赖疗法帮助患者在没有可卡因的情况下学会忍受可卡因的渴望，这种情况与灭绝条件没有什么不同。尽管有明确的临床相关性，但在动物模型中对灭绝的研究还不够充分。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。我们拟从行为学、药理学和神经生物学三个层面研究NMDA传递在可卡因消失中的作用。1. 行为替代或技能训练是临床治疗的成功组成部分。我们建议评估学习新行为，对蔗糖的反应，对灭绝训练的影响。2. 我们建议研究FDA已经批准用于其他人类临床条件的两种药物，NMDA受体激动剂d-环丝氨酸和NMDA拮抗剂美金刚对灭绝的影响。我们将评估NMDA受体是否以及如何参与灭绝，以及药物是否具有药物治疗人类可卡因成瘾的潜力。3. 我们建议将d-环丝氨酸和美金刚注射到离散的大脑区域，以绘制NMDA受体介导的灭绝效应背后的神经回路。消除训练期间药物作用的时间过程可以为谷氨酸能药物的时间和类型提供信息，以便在未来的临床试验中优化消除训练。

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.