The CCKA receptor antagonist devazepide does not modify opioid self-administration or drug discrimination: comparison with the dopamine antagonist haloperidol.
We previously reported that the selective cholecystokininA (CCKA) receptor antagonist, devazepide, blocked the acquisition of a morphine conditioned place preference (ref 28). An interpretation of this finding is that devazepide may either affect an opioid discriminative stimulus and/or modify the rewarding properties of opioids. The present study was designed to investigate these issues by determining the effect of equivalent doses of devazepide in a morphine drug discrimination paradigm and a model of heroin self-administration. In each case, devazepide (0.001-1 mg/kg) was ineffective, i.e there was no antagonism of a morphine discriminative cue, and in a separate group of rats trained to self-administer heroin (0.03 mg/kg/infusion, FR5 schedule, 1h per day), devazepide did not alter the pattern of heroin responding. Because of evidence implicating an interaction between accumbens CCK and dopamine (DA) systems and evidence suggesting an apparent differential involvement of DA in opioid place conditioning, self-administration and drug discrimination behaviour, the effect of the DA antagonist haloperidol was examined in the latter two paradigms. In each test, haloperidol produced an effect inconsistent with a direct DAergic involvement. In a final study the CCKB antagonist L365-260 was also found not to affect an opioid discriminative cue. The present results therefore cast doubt on the potential utility of selective CCKA antagonists as treatments for opioid abuse, and further suggest that CCKB antagonists may not potentiate the subjective effects of opioids, an important finding considering that such drugs have been proposed as adjuncts to opioid therapy for the treatment of pain relief.
Higgins
G A
GA
Addiction Research Foundation, University of Toronto, Ont., Canada.
Joharchi
N
N
Wang
Y
Y
Corrigall
W A
WA
Sellers
E M
EM
D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology*; D002766:Cholecystokinin / Q000037:antagonists & inhibitors*; D003042:Cocaine / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects; D003463:Cues; D020109:Devazepide; D004192:Discrimination, Psychological / Q000187:drug effects*; D018492:Dopamine Antagonists; D005502:Food; D006220:Haloperidol / Q000494:pharmacology*; D003932:Heroin / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology; D009294:Narcotics / Q000008:administration & dosage / Q000494:pharmacology*; D010671:Phenylurea Compounds; D051381:Rats; D017208:Rats, Wistar; D011949:Receptors, Cholecystokinin / Q000187:drug effects*; D012646:Self Administration / Q000523:psychology
D001570:Benzodiazepinones; D018492:Dopamine Antagonists; D009294:Narcotics; D010671:Phenylurea Compounds; D011949:Receptors, Cholecystokinin; C058121:L 365260; D003932:Heroin; D009020:Morphine; D002766:Cholecystokinin; D003042:Cocaine; D006220:Haloperidol; D020109:Devazepide