NMDA Glutamate Receptor Transmission in Extinction of Cocaine-Seeking Behavior

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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.