Effects of kappa opioid agonists on cocaine- and food-maintained responding by rhesus monkeys.
There is accumulating evidence that kappa opioid agonists attenuate cocaine's behavioral effects, and we recently reported that the kappa opioid agonists ethylketocyclazocine (EKC) and U50-488 decreased cocaine self-administration by rhesus monkeys. In the present study, we first examined the effects of acute intramuscular administration of six kappa opioid agonists on responding maintained by food under an FR30 schedule. Each kappa agonist produced dose-dependent decreases in schedule controlled behavior, and the relative potencies were enadoline >/= bremazocine > Mr2033 >/= cyclazocine = spiradoline > PD117302. We then studied the effects of chronic administration of these kappa agonists in monkeys responding under a second order schedule of food delivery and cocaine self-administration. The effects of 10 days of intravenous treatment with three arylacetamides [enadoline (0.00032-0.0032 mg/kg/hr), (-) spiradoline (0.0032-0.018 mg/kg/hr), PD117302 (0.032-0.32 mg/kg/hr)] and three benzomorphans [bremazocine (0.00032-0.0032 mg/kg/hr), Mr2033 (0.0032-0.032 mg/kg/hr), cyclazocine (0.001-0.10 mg/kg/hr)] were compared with saline treatment. Enadoline (0.001 and 0.0032 mg/kg/hr), bremazocine (0.0032 mg/kg/hr) and Mr2033 (0.01 and 0.0032 mg/kg/hr) significantly decreased cocaine self-administration (0.01 mg/kg/injection) (P < .05-.01). Cyclazocine (0.001-0.10 mg/kg/hr), (-) spiradoline (0.0032-0.018 mg/kg/hr) and PD117302 (0.032-0.32 mg/kg/hr) had no significant effects on cocaine self-administration across the dose-range studied. When gradually increasing doses of enadoline (0.00032-0.01 mg/kg/hr) or Mr2033 (0.0032-0.032 mg/kg/hr) were administered over 28 consecutive days, cocaine self-administration was dose-dependently decreased in all monkeys. Food-maintained responding was usually decreased at doses that decreased cocaine self-administration. Adverse side effects (emesis and sedation) were transient, and laboratory indices of hematology and blood chemistry were normal throughout chronic enadoline and Mr2033 treatment. These data extend our earlier findings with EKC and U50,488 and suggest that kappa opioid agonists may be a useful approach to the development of new pharmacological treatments for cocaine dependence. The extent to which undesirable side effects may limit their clinical usefulness remains to be determined.
Mello
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Alcohol and Drug Abuse Research Center, McLean Hospital, Harvard Medical School, Belmont, Massachusetts 02178, USA.
Negus
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D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003042:Cocaine / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005502:Food; D008253:Macaca mulatta; D009294:Narcotics / Q000494:pharmacology*; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D012055:Reinforcement Schedule; D012054:Reinforcement, Psychology; D012646:Self Administration
D009294:Narcotics; D017473:Receptors, Opioid, kappa; D003042:Cocaine