NMDA Glutamate Receptor Transmission in Extinction of Cocaine-Seeking Behavior

NMDA 谷氨酸受体传递在可卡因寻求行为消失中的作用

• 批准号: 7851226
• 负责人: Richard W Foltin
• 金额: $ 18.78万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-15 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7851226
• 关键词: Agonist; Amygdaloid structure; Animal Model; Area; Behavior; Behavioral; Behavioral Mechanisms; Brain; Clinical; Clinical Trials; Cocaine; Cocaine Dependence; Cycloserine; Extinction (Psychology); FDA approved; Future; Glutamate Receptor; Glutamates; Goals; Guidelines; Human; Infusion procedures; Injection of therapeutic agent; Intravenous; Laboratory Animal Models; Laboratory Rat; Learning; Maps; Medial; Mediating; Memantine; Memory; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neurobiology; Nucleus Accumbens; Patients; Pharmaceutical Preparations; Prefrontal Cortex; Rattus; Role; Self-Administered; Sucrose; Testing; Time; Training; clinically relevant; craving; drug addiction pharmacotherapy; learning extinction; neural circuit; neurotransmission; public health relevance; reinforcer; skills training; transmission process

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.

描述（由申请人提供）：实验室动物模型已被证明可以有效地将可卡因成瘾理解为一种后天习得的异常行为。老鼠会自愿给自己注射可卡因。如果可卡因变得不可用，吸毒行为就会消失或消失。临床上成功的可卡因依赖疗法帮助患者学会在没有可卡因的情况下忍受可卡因的渴望，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不足。灭绝可以被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3个水平研究NMDA传递在可卡因消退中的作用。1.行为替代或技能培训是临床治疗的成功要素。我们建议评估学习新的行为，响应蔗糖，灭绝训练的效果。2.我们建议研究两种已经被FDA批准用于其他人类临床疾病的药物，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，以及药物是否在人类可卡因成瘾中具有药物治疗潜力。3.我们建议将d-环丝氨酸和美金刚胺注射到离散的脑区，以绘制NMDA受体介导的灭绝效应的神经回路。消退训练期间药物作用的时间过程可能会告知药物治疗的时间和类型，以优化未来临床试验中的消退训练。 公共卫生相关性：我们的提案“可卡因寻求行为消退中的NMDA谷氨酸受体传递”是对RFA-DA-08-025：“药物成瘾的消退和药物治疗，R 03”的应用。我们的建议密切遵循RFA的指导方针，研究药物化合物，NMDA药物d-环丝氨酸和美金刚，对实验室大鼠的消退学习的影响。我们进一步建议通过将NMDA药物微量注入离散的脑区来研究灭绝背后的神经回路。