The research in this proposal focuses on the development and testing of a novel animal model of cocaine craving. The proposed model emphasizes cocaine-seeking rather than cocaine taking behavior in order to test the efficacy of potential treatment medications in decreasing cocaine craving. The model is based on the reinforcement schedule which will generate much behavior in the presence of cocaine cues, but in the absence of cocaine. In humans, the self-reported desire or craving for cocaine can be observed under three distinct environmental conditions: 1) in the absence of any external and internal cocaine stimuli, 2) in the presence of environmental cues associated with cocaine use, and 3) in the presence of cocaine itself. Rhesus monkeys will live in three-chambered residences. Cocaine-related cues and cocaine will be specific to one chamber, food-related cues and food will be specific to a second chamber, and no food cures or cocaine cues will be available in a third """"""""neutral"""""""" chamber. A two-component chain schedule of operant responding will provide a schedule appropriate for studying cocaine seeking behavior in non-human primates. The model is designed to provide the separate assessment of three types of craving using the following procedures: 1) Type #1 - the amount of time spent in a chamber out-of-session will provide a measure of craving in the absence of environmental stimuli associated with cocaine use. 2) Type #2 - during test probe sessions, responding in the presence of session lights, without illuminated lever light s will result in the presentation of the stimuli associated with drug delivery but drug will not be delivered. This will provide a model of craving in the presence of environmental cues associated with cocaine use. 3) Type #3 - responding following the administration of non-contingent cocaine immediately before a session, i.e., priming, will provide a model of drug craving in the presence of the cocaine cue. Craving for food will be assessed by 1) measuring changes in responding following delivery of large rations of food before the daily session, and 2) the effects of anorectic drug administration on responding for food. Food measures will provide information about specifity of interventions and will be a way of testing the validity of the model. The ultimate goal of the proposed animal model of cocaine craving is to test the efficacy of potential treatment medications in decreasing cocaine craving. This model should indicate at what point in the chain of cocaine seeking behavior a medication may be effective. Clearly the most desirable medications are those that decrease craving (and thus cocaine- seeking behavior) in the absence of cocaine itself (craving types #1, 2), prior to cocaine taking. Ritanserin, flupenthixol and other additional potential medications, as they are developed, will be tested.
