The primary long-term goal of this project is to employ behavioral pharmacological methods to investigate neura1 substrates underlying the self-administration of opiate and stimulant drugs of abuse. Toward this end, three specific aims are described each of which is intended to build upon and extend the work completed during the first nine years of this project. These are; 1) to continue investigations of the putative reward-attenuating actions of dopamine antagonist drugs on opiate- and stimulant-reinforced behaviors; 2) to further examine the role of drug-paired stimuli in drug self-administration and drug relapse; and 3) to continue investigations of the anxiogenic side effects of chronic cocaine. The hypothesis driving this work is that central dopaminergic (DA) systems are responsible for the reinforcing properties of both opiate and stimulant drugs. While this position is hardly unique, the methodological approach taken in this project is novel in a number of ways: I) while traditional lever-press procedures examine the behavior of drugged animals working to maintain their drug plasma levels, the current project examines IV drug reinforcement using an operant runway where animals received only one drug injection per day. In this context, the speed with which Ss traverse the alley for drug reinforcement has operationally provided a reliable index of the undrugged animals' motivation to obtain the reinforcer; ii) by testing only one trial per day, the resulting data are devoid of potential confounding and nonspecific effects produced by the drug reinforcers themselves; iii) a response reinstatement test is used to examine the factors that result in the reinstatement of operant runway behavior after a prolonged period of abstinence, and hence serves as a viable model of human drug relapse; and iv) in each of the studies, the putative reinforcement-attenuating actions of antagonist drugs are assessed at a time when the drug's direct pharmacological effects are no longer present (i.e., on the first post-treatment trial 24 hrs post-injection). This permits conclusions about antagonist effects on operant behavior that are not confounded by the sedative arrd motoric side-effects of these test agents. In summary, the work proposed in this application is intended to provide important new information about the nature and neurobiology of both the positive and negative factors that together determine the nature and extent of human drug self-administration behaviors.
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