This proposal continues ongoing research into the mechanisms of action of anorectic drugs and the possible relationship between the effects of these drugs on food intake and the ability of some of these drugs to function as reinforcers. Recent studies using an economic model of operant behavior have shown that acute administration of anorectic drugs produced dose-dependent decreases in food intake that were unaffected by food cost. In contrast, when baboons could self-administer anorectic drugs, and the cost for food was increased, food intake decreased more quickly. The finding that self-administered anorectic drugs substitute for food, while experimenter-administered anorectic drugs do not, serves as the starting point for the research in this proposal. The first goal of the proposed research is to investigate the generality of drugs of abuse to substitute for food. Cost for food will be systematically varied, with 5 costs each examined for 10 consecutive days: six days with oral drug available for self-administration, two days with only food available and two days with experimenter-given drug in doses matched to those self-administered. Specifically, we are asking whether the short-acting, dissociative anesthetic phencyclidine, the calorie-containing drug ethanol, and the food-intake increasing drug pentobarbital can function as substitutes for food. The second goal of the proposed research is to investigate the neuropharmacological mechanisms by which a self-administered drug serves as a substitute for food using cocaine and phencyclidine. In order to determine the influence of dopaminergic or serotonergic systems, specific uptake blockers will be given either before or spaced throughout the session. Specifically, will the dopamine uptake blocker GBR-12909 or the serotonin uptake blocker citalopram affect the substitution for food by self-administered cocaine or PCP? Once a predominant role for dopamine or serotonin is established, additional studies will be undertaken using antagonists for specific receptor types. These studies will involve either the dopamine D1, antagonist SCH-39166 and the D2 antagonist raclopride, or the 5HT2 antagonist ritanserin and the 5HT3 antagonist ondansetron. Studies involving both acute and repeated dosing regimens are planned. The manipulation of specific dopamine receptors that are putatively related to drug-maintained behavior, and serotonin receptors that are putatively related to food intake (and to a lesser extent drug-maintained behavior), will allow a possible pharmacological dissection of a drug's 1) effect on feeding behavior, 2) reinforcing effects and 3) ability to substitute for food. The possibility that these three drug effects can be differentiated pharmacologically holds promise for understanding drug self-administration, food intake and the complex interaction between behavior maintained by these commodities.
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