GLUTAMATERIC MECHANISMS OF DRUG-CONDITIONED BEHAVIOR

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DESCRIPTION (provided by applicant) It is well established that learning plays an important role in the development and maintenance of drug addictions. Animal models have been successfully used to isolate and study these learning phenomenon using principles of operant and classical conditioning. This project is focused on developing a better understanding of the neurobehavioral basis for classically conditioned behavioral effects of drugs of abuse. We hypothesize that glutamatergic neurotransmission plays a key role in these conditioned processes. Conditioning models developed by scientists at Pavlov Medical University in St. Petersburg will be used in their laboratories to conduct research to evaluate this hypothesis and evaluate glutamate antagonists as possible pharmacotherapies for drug dependence. Specifically, the ability of glutamate receptor antagonists to affect behaviors conditioned with drugs of abuse (morphine, cocaine) will be assessed in rodents. Antagonists acting at N-methyl-D-aspartate (NMDA) subtypes of glutamate receptors will be tested. The specific aims are to: 1) study effects of site-selective NMDA receptor antagonists on extinction of drug- vs. non-drug conditioned behaviors; and 2) estimate the role of NMDA receptors for the development and expression of post-abstinent increase in drug consumption. The proposed studies will complement work done in earlier years of this project with various site-selective glutamate receptor antagonists in a wide range of experimental models encompassing different aspects of drug conditioning such as: 1) the drug-conditioned activation of locomotor activity, 2) the facilitation of intracranial self-stimulation induced by conditioned stimuli associated with abused drugs or rewarding electrical brain stimulation, 3) the responding maintained by conditioned reinforcers using intravenous drug self-administration procedures; 4) conditioned components of drug tolerance and dependence; and 5) post-abstinent increase in drug consumption.