This is a renewal application for grant R01 4137. The proposed research has two broad aims: first, in an animal model od drug liking, it will determine whether tolerance develops to the rewarding effects of cocaine, and in addition, it will examine neurochemical mechanisms that may be associated with tolerance; second, it will test various treatments for their ability to block the effects of cocaine in an animal model of subjective drug effects. The proposed experiments use rats as subjects. Behavioral experiments rely on two techniques. In one, subjects are trained to self-administer cocaine through a catheter that is implanted in the jugular vein. In the other, animals are taught to """"""""perceive"""""""" the effects of cocaine by use of drug discrimination methodology. For self- administration experiments, subjects are implanted with a catheter in the right jugular and subsequently are taught to press a lever to obtain an infusion of cocaine, 0.8 mg/kg. After training, tolerance will be established by infusion of cocaine, 20 mg/kg every 8-hours, for 7 days. Tolerance will be seen as a shift to the right in the cocaine dose-effect curve. The results of these experiments will establish whether tolerance occurs to the reinforcing properties of cocaine. If a positive answer is obtained, additional experiments will determine the role of dopamine neurotransmission in mediating this effect. For drug discrimination experiments, food is used as a reinforcer, and rats will be trained to press one lever when injected with cocaine, 10 mg/kg, and a different lever when injected with saline. After training the discrimination and establishing the dose-effect relationship for cocaine, these subjects will be tested to determine if lithium, a drug that is effective in controlling human mania, is also effective in blocking the discriminative stimulus effects of cocaine. These tests will occur with lithium given alone, as well as with lithium given in combination with various dopaminergic drugs. The answers to these questions are important, because tolerance to drugs is frequently cited as a reason for high-dose, chronic drug use. Cocaine has traditionally be associated with little or no tolerance, but this may not be the case. The drug discrimination method is frequently cited as a model of human subjective effects, and thus these experiments may have relevance for establishing new treatments that are capable of blocking the subjective effects of cocaine.
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