Crack cocaine use continues to be a major public health problem with consequent legal, social and personal costs. In spite of this major concern over the use of smoked cocaine, limited human laboratory and systematic research has been conducted on examining pharmacological agents that may reduce cocaine self-administration or relapse. The development of human laboratory models of cocaine self-administration, relapse and withdrawal so that potentially effective pharmacological agents for the treatment of various aspects of cocaine abuse can be tested is very important. The use of these models will provide: (a) a better understanding of whether a particular drug affects the reinforcing effects from cocaine, may prevent relapse and/or affects withdrawal symptoms from cocaine, (b) a measure of the safety of the drug when used in conjunction with cocaine, (c) and a cost effective method for making these determinations. The primary purpose of the proposed studies are to test various medications using models of self-administration, relapse and acute withdrawal. The medications that we would like to test are ritanserin, a 5-HT2 antagonist, and nifedipine, a calcium ion channel inhibitor. These drugs were chosen because: (a) they have different mechanisms of action; (b) animal or human studies indicate that they may affect the reinforcing effects of cocaine; and (c) each appears to minimize the toxic effects of cocaine. In addition, ritanserin is attractive because of the potential specificity of its selective 5HT2 receptor blockade. Five studies are proposed. The purpose of the first experiment will be to determine the effects of escalating doses of ritanserin on cocaine self-administration. We hypothesize that increasing doses of ritanserin will result in greater decreases in the self-administration of cocaine. The second experiment will examine the effects of ritanserin on relapse to cocaine in the presence of cocaine- related and neutral stimuli. The hypothesized result is that subjects randomly assigned to the placebo condition will show a greater probability of and extent of self-administering cocaine in the presence of cocaine-related stimuli compared to those assigned in the ritanserin condition. The third experiment will examine the effects ritanserin on the disruptions due to acute withdrawal from cocaine. We hypothesize that the subtle signs of acute withdrawal observed in previous studies will be reduced with ritanserin. The fourth and fifth experiments and hypotheses will be the same as the first two except nifedipine will be the medication under investigation. The effects of nifedipine on acute cocaine withdrawal symptoms will be pursued in the future.
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