Modulation of the discriminative stimulus effects of cocaine by mu and kappa opioids.
The effects of cocaine alone and after pretreatment with selective mu and kappa opioids were determined in squirrel monkeys trained to discriminate i.m. injections of cocaine from vehicle in a two-lever discrimination procedure. Lever pressing was maintained under a fixed ratio schedule of food presentation. When administered alone, cocaine engendered dose-related increases in the proportion of cocaine-appropriate responding with an average ED50 of 0.19 mg/kg. Pretreatment with the mu agonists morphine (0.3 and 1.0 mg/kg), levorphanol (0.03 and 0.1 mg/kg) and methadone (0.1 and 0.3 mg/kg), as well as the mu partial agonist buprenorphine (3.0 and 5.6 micrograms/kg), potentiated the discriminative stimulus effects of cocaine such that the cocaine dose-effect functions were shifted to the left and the average ED50 for cocaine was reduced maximally by about one order of magnitude. None of the mu agonists consistently substituted for cocaine when administered alone, indicating that the observed interactions were not simply the result of additive discriminative stimulus effects. A similar potentiation by mu agonists was observed for the effects of cocaine on fixed ratio response rate. In contrast to the mu agonists, pretreatment with the kappa agonists N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4,5]dec-8-yll-4- benzofuranacetamide (CI 977; 3.0 and 5.6 micrograms/kg) and benzeneacetamide methane sulfonate (U 50,488; 0.3 and 1.0 mg/kg) attenuated the discriminative stimulus effects of cocaine in most monkeys, resulting in a modest (2- to 3-fold) increase in the average ED50 for cocaine.(ABSTRACT TRUNCATED AT 250 WORDS)
Spealman
R D
RD
Harvard Medical School, New England Regional Primate Research Center, Southborough, Massachusetts.
Bergman
J
J
D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D004193:Discrimination Learning / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D008297:Male; D009294:Narcotics / Q000494:pharmacology*; D011930:Reaction Time / Q000187:drug effects; D011957:Receptors, Opioid / Q000187:drug effects; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D012453:Saimiri
D009294:Narcotics; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D003042:Cocaine