An important scientific goal in attempting to address the problem of cocaine abuse is to gain a fuller understanding of the neural basis for the behavioral effects of cocaine that are relevant to its abuse. This project proposes to approach this question by examining the hypothesis that cocaine acts by binding to a site on the dopamine uptake transporter, increasing dopaminergic activation in critical brain regions leading to the production of psychomotor activation and cocaine-like intoxication and reinforcement. If this hypothesis is true, then other drugs which share these biochemical actions with cocaine should produce cocaine-like behavioral and pharmacological effects. Studies of biochemical and behavioral actions of cocaine and various cocaine analogues on measures relevant to this hypothesis are proposed to be carried out in rats. The methods to be employed are in vitro and in vivo binding to the cocaine site, quantitative autoradiographic determination of binding distribution, in vitro dopamine uptake, in vivo measurements of dopaminergic activation as revealed by increased metabolism and changes in extracellular dopamine concentrations as measured using microdialysis, the acoustic startle reflex to measure psychomotor activation, and drug discrimination as a model of cocaine-like subjective effects. Some of these methods will also provide information on drug effects on neurotransmitter systems other than the dopamine system. This will help determine how biochemical specificity of action alters the in vivo biochemical and behavioral expression of cocaine-like effects. Drugs to be tested include a) structural analogues of cocaine where the results can be related to other structure-activity and molecular modeling studies underway by our collaborator. When completed these studies will provide information on the precise structural requirements for actions at the cocaine site and on whether analogues may be found that bind to the site but lack a full-spectrum of cocaine-like effects. b) Other drugs structurally unrelated to cocaine that bind to the cocaine site will be evaluated for their profile of pharmacological effects. c) Finally, selected local anesthetics, which bind to the cocaine site and share some of the behavioral effects of cocaine, will also be tested. These studies will help determine if binding to the cocaine site on the dopamine transporter is sufficient to predict cocaine-like pharmacological effects and should lead to the identification of drugs that will share some but not all of the actions of cocaine and thus may be useful probes for further study of the neuropharmacology of cocaine and may modify the effects of cocaine in the therapeutically useful way.
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