EFFECTS OF KAPPA-OPIOIDS ON COCAINE SELF-ADMINISTRATION BY RHESUS-MONKEYS

Kappa opioid agonists attenuate some neurochemical and behavioral effe cts of cocaine and are being considered as potential treatments for co caine dependence. The present study examined the effects of two kappa opioid agonists, the benzomorphan ethylketocyclazocine (EKC) and the a rylacetamide U50,488, on cocaine self-administration in rhesus monkeys . Monkeys responded for 0.032 mg/kg/injection cocaine (i.v.) and 1 g b anana-flavored food pellets during alternating daily sessions of cocai ne and food availability. Chronic treatment for 10 consecutive days wi th EKC (0.0032-0.032 mg/kg/hr) or U50,488 (0.032-0.1 mg/kg/hr) dose-de pendently decreased self-administration of cocaine unit doses at the p eak of the cocaine dose-effect curve (0.01 and 0.032 mg/kg/injection). These decreases in cocaine self-administration were often sustained t hroughout the 10 days of treatment. Doses of EKC and U50,488 that decr eased cocaine self-administration usually decreased food-maintained re sponding as well. In addition, EKC and U50,488 often produced emesis a nd sedation during the first few days of treatment, although tolerance appeared to develop rapidly to these effects. In general, EKC produce d fewer undesirable effects than U50,488 at doses that decreased cocai ne self-administration. The kappa antagonist norbinaltorphimine (3.2 m g/kg) did not affect responding maintained by cocaine or food. However , both norbinaltorphimine (3.2 mg/kg) and the opioid antagonist naloxo ne (1.0 mg/kg/hr) blocked the effects of EKC and U50,488. These result s indicate that chronic administration of EKC and U50,588 produce a do se-dependent, kappa receptor-mediated and often sustained decrease in cocaine self-administration. However, these kappa agonists also produc e undesirable behavioral effects that may complicate their use as trea tments for cocaine dependence.