The general significance of the proposed research is that it may have relevance to the development of dependence on cocaine. Cocaine use and dependence remain significant health issues in the United States. For example, recent surveys indicated that more than 5.6 million Americans had used cocaine within the past year, and that more than 23 million have taken the drug at some time in their lifetimes. Interestingly, estimates indicate that only about 5 to 10% of those who use cocaine eventually become dependent on it. It appears, therefore, that cocaine tends not to be immediately addictive. The factors that lead to dependence have not been identified, but clinical evidence suggests that a prolonged period of intermittent use of the drug often precedes the development of dependence. The proposed research is aimed at furthering our knowledge concerning behavioral effects of relatively long-term intermittent exposure to cocaine. Laboratory study of effects of long-term intermittent exposure to cocaine has yielded a puzzling array of results. Sometimes tolerance is observed, sometimes sensitization. Previous investigations, however, have indicated that experiential/behavioral factors can determine whether or not tolerance or sensitization occurs to cocaine's effects. The proposed research is aimed at adding to our knowledge of how experiential factors interact with repeated cocaine exposure. The specific research aims of this application are to: 1.) Expand our analyses of the interaction between explicitly conditioned operant behavior (as a model of purposive behavior) and general activity during repeated exposure to cocaine. Our recent finding that presence of an operant contingency prevented the observation of sensitization to the drug's effects on general activity has set the basis for this aim. 2.) Continue to examine the role of alterations in rate of reinforcement as a predictor of tolerance to effects of cocaine. 3) Continue analyses of reinforcement-schedule-parameter dependent tolerance. We plan to determine if such tolerance is """"""""contingent,"""""""" if and how it is related to behavioral economic factors, and how rate of reinforcement and ratio contingencies interact. This application is to provide support for the PI so that he may devote at least 75% of his time to research on the foregoing issues. The study of long-term, intermittent exposure to cocaine has potential relevance to the genesis of cocaine dependence. Understanding of the processes that occur under long-term, intermittent exposure should facilitate the development of effective treatment and, especially, prevention programs.
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