EFFECTS OF CHOLECYSTOKININ ANTAGONISTS ON THE DISCRIMINATIVE STIMULUSEFFECTS OF COCAINE IN RATS AND MONKEYS

Cholecystokinin (CCK) has been implicated as a modulator of dopamine ( DA) neurotransmission in the mesolimbic DA pathway, a primary pathway implicated in the effects of cocaine related to its abuse. The present experiment was designed to examine whether an antagonist that acts at either CCKA or CCKB receptors can modify the discriminative stimulus effects of cocaine in animals. Rats (N = 9) and rhesus monkeys (N = 3) were trained in two-lever drug discrimination paradigms to discrimina te cocaine from saline. Lever pressing was maintained by food (all rat s, two monkeys) or shock avoidance (one monkey). In rats, the CCKA ant agonist MK-329 (1.0-32 mg/kg, i.p.) or the CCKB antagonist CI-988 (1.0 -32 mg/kg, i.p.) were administered 30 min before determination of coca ine dose-response functions using a cumulative dosing method. In monke ys, CI-988 (8.0-32 mg/kg, i.m.) was administered 30, 60 or 120 min bef ore the training dose of cocaine. In both species, cocaine produced do se-related increases in the percentage of responses emitted on the coc aine-appropriate lever. In rats, MK-329 shifted the cocaine dose-respo nse function to the right in a dose-related manner. In contrast, CI-98 8 did not systematically alter the effects of cocaine in either rats o r monkeys. Since drug discrimination serves as an animal model of the subjective effects of drugs in humans, these results suggest that CCKA antagonists may decrease the subjective effects of cocaine. It seems unlikely that CCK, antagonists will alter the subjective effects of co caine.