Effects of cholecystokinin antagonists on the discriminative stimulus effects 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 discriminate cocaine from saline. Lever pressing was maintained by food (all rats, two monkeys) or shock avoidance (one monkey). In rats, the CCKA antagonist 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 cocaine dose-response functions using a cumulative dosing method. In monkeys, CI-988 (8.0-32 mg/kg, i.m.) was administered 30, 60 or 120 min before the training dose of cocaine. In both species, cocaine produced dose-related increases in the percentage of responses emitted on the cocaine-appropriate lever. In rats, MK-329 shifted the cocaine dose-response function to the right in a dose-related manner. In contrast, CI-988 did not systematically alter the effects of cocaine in either rats or 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 CCKB antagonists will alter the subjective effects of cocaine.
Department of Pharmacological and Physiological Sciences, Pritzker School of Medicine, University of Chicago, IL 60637.
B W
BW
Massey
K E
KE
Vanover
W L
WL
Woolverton
D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology; D002766:Cholecystokinin / Q000037:antagonists & inhibitors / Q000502:physiology*; D003042:Cocaine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D020109:Devazepide; D004193:Discrimination Learning / Q000187:drug effects / Q000502:physiology*; D004298:Dopamine / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D007211:Indoles / Q000494:pharmacology; D008253:Macaca mulatta; D008297:Male; D008536:Meglumine / Q000031:analogs & derivatives / Q000494:pharmacology; D008636:Mesencephalon / Q000187:drug effects / Q000503:physiopathology; D009714:Nucleus Accumbens / Q000187:drug effects / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors / Q000502:physiology; D011954:Receptors, Dopamine / Q000187:drug effects / Q000502:physiology*; D019966:Substance-Related Disorders / Q000503:physiopathology*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
D001570:Benzodiazepinones; D007211:Indoles; D011949:Receptors, Cholecystokinin; D011954:Receptors, Dopamine; C065599:PD 134308; D008536:Meglumine; D002766:Cholecystokinin; D003042:Cocaine; D020109:Devazepide; D004298:Dopamine