EFFECTS OF KAPPA-OPIOID AGONISTS ON COCAINE-MAINTAINED AND FOOD-MAINTAINED RESPONDING BY RHESUS-MONKEYS

There is accumulating evidence that kappa opioid agonists attenuate co caine's behavioral effects, and we recently reported that the kappa op ioid 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 kap pa opioid agonists on responding maintained by food under an FR30 sche dule. Each kappa agonist produced dose-dependent decreases in schedule controlled behavior, and the relative potencies-were enadoline greate r than or equal to bremazocine > Mr2033 greater than or equal to cycla zocine = spiradoline > PD117302. We then studied the effects of chroni c administration of these kappa agonists in monkeys responding under a second order schedule of food delivery and cocaine self-administratio n. The effects of 10 days of intravenous treatment with three arylacet amides [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 benzomorphan s [bremazocine (0.00032-0.0032 mg/kg/hr), Mr2033 (0.0032-0.032 mg/kg/h r), cyclazocine (0.001-0.10 mg/kg/hr)] were compared with saline treat ment. 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 coc aine self-administration (0.01 mg/kg/injection) (P < .05-.01). Cyclazo cine (0.001-0.10 mg/kg/hr), (-) spiradoline (0.0032-0.018 mg/kg/hr) an d PD117302 (0.032-0.32 mg/kg/hr) had no significant effects on cocaine self-administration across the dose-range studied. When gradually inc reasing 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 sel f-administration was dose-dependently decreased in all monkeys. Food-m aintained responding was usually decreased at doses that decreased coc aine self-administration. Adverse side effects (emesis and sedation) w ere transient, and laboratory indices of hematology and blood chemistr y were normal throughout chronic enadoline and Mr2033 treatment. These data extend our earlier findings with EKC and U50,488 and suggest tha t 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 rem ains to be determined.