GLUTAMATE AGONISTS AND ANTAGONISTS--ROLE IN ADDICTION

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The two overall objectives of this study are to evaluate the functional role of excitatory amino acid (glutamatergic) synapses in the rewarding (addicting) effects of psychostimulant and opioid drugs and to synthesize new drugs that attenuate the rewarding effects of these abused substances. The hypothesis is that a critical action in neuronal pathways that mediate the effects of these drugs is an increase in glutamate release in the nucleus accumbens (N.ACC), which activates the AMPA subtype of glutamate receptors. This hypothesis will be tested by determining 1) whether antagonists of AMPA receptors microinjected into the N.ACC attenuate the rewarding effects of psychostimulants and opioids as measured by conditioned place preference, 2) whether AMPA agonists microinjected into the N.ACC produce similar rewarding effects effects as the psychostimulant and opioid drugs, and 3) whether the responses to psychostimulant drugs and opioids involve an increase in the extracellular concentration of glutamic acid and aspartic acid in the N.ACC. A major limiting factor for such a study is the lack of selective antagonists of AMPA receptors. Therefore, we plan to synthesize new compounds and test them for AMPA antagonist activity. The strategy is to synthesize analogs based on two important lead compounds identified from the structure-activity studies that were done by ourselves and others. The two groups of compounds are: 1) substituted o-tyrosines and 2) hybrid molecules combining features of the quinoxalinedione compounds and the excitotoxin beta-oxalylaminoalanine. New compounds will be tested for their affinity and selectivity for excitatory amino acid receptors using radioligand binding techniques, and the cortical wedge procedure will be used to identify agonists and antagonists. The most potent and effective compounds will then be tested for their ability to antagonize the effects of amphetamine, cocaine, and morphine on locomotor activity and in the conditioned place preference paradigm. Thus, the proposed studies have a biological component that should provide greater understanding of neuronal circuits and mechanisms involved in drug addiction and and a chemical component that provides the possibility of a new pharmacological strategy for treating the problems associated with addicting drugs.