Failure of cholecystokinin antagonists to modify the discriminative stimulus effects of cocaine

Abstract

Enhancement of brain dopamine (DA) activity is believed to be an important mechanism underlying the discriminative stimulus effects of cocaine in animals and the subjective effects of cocaine in people. Cholecystokinin (CCK) receptors, which are colocalized with DA receptors in several brain regions, have been implicated as modulators of DA activity, leading to speculation that CCK-based drugs might be developed as therapeutics for cocaine abuse. In the present study, the effects of cocaine alone and after pretreatment with the selective CCKA antagonist devazepide and the selective CCKB antagonist CI 988 were determined in squirrel monkeys trained to discriminate cocaine (1.0 mg/kg) from saline. When tested alone, cocaine engendered dose-related increases in the percentage of cocaine-appropriate responses, reaching virtually exclusive responding on the cocaine-associated lever after doses of 1.0 mg/kg or greater. Pretreatment with a wide range of doses of either devazepide (0.01–3.0 mg/kg) or CI 988 (0.3–30 mg./kg) did not systematically alter the discriminative stimulus effects of any dose of cocaine. The results do not support a role for CCK antagonists in the pharmacotherapy of cocaine abuse.