DOPAMINERGIC SENSITIZATION AND DRUG SELF ADMINISTRATION

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The experiments proposed in this application are part of a continuing research effort by the applicant aimed at determining the neural basis of drug-induced sensitization in mesolimbic dopamine (DA) neurons and at understanding the nature and significance of its behavioral expression. Psychomotor stimulant and opiate drugs, both of which are self- administered by man and laboratory animals, increase the DA released by these neurons and produce locomotor activation. Repeated exposure to these drugs enhances or sensitizes both of these responses so that subsequent reexposure to the drug produces both greater behavioral activation and greater DA release than seen initially. Considerable evidence implicates mesolimbic DA neurons in the mediation of the rewarding properties of stimulant and opiate drugs. Changes in the functioning of these neurons may therefore be important in the initiation and maintenance of drug taking. Recently. a number of reports have appeared suggesting that exposure to drug regimens that produce behavioral sensitization also facilitates the acquisition of drug self-administration behavior. I propose, therefore, to investigate whether this facilitation is linked to sensitization in mesolimbic DA neurons. If it is, then facilitation should be accompanied by sensitized mesolimbic DA neuron responsivity to drug during acquisition and similarly influenced by the same manipulations that influence the induction of sensitization in these neurons. By studying the acquisition of self-administration of low doses of amphetamine in the rat, I will seek to answer three questions: A. Is facilitation of the acquisition of self-administration behavior accompanied by sensitized levels of DA overflow, as measured by in vivo microdialysis, in the terminal regions of mesolimbic DA neurons during acquisition? B. Does prior exposure to sensitizing injections of amphetamine into the cell body region of mesolimbic DA neurons facilitate the acquisition of self-administration behavior? C. Do manipulations that block the induction of sensitization to amphetamine, such as preceding injections with the D-1 DA receptor antagonist, SCH-23390, also block the facilitation of acquisition of self- administration behavior produced by prior exposure to the drug? The possibility of a link between sensitized DA function and liability to drug abuse could provide important insights into the neurobiology of drug dependence.