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Vol. 282, Issue 1, 44-55, 1997
Alcohol and Drug Abuse Research Center, Harvard Medical
School-McLean Hospital, Belmont, Massachusetts (S.S.N., N.K.M.), and
Department of Pharmacology, University of Minnesota, Minneapolis,
Minnesota (P.S.P., C.-E.L.)
Kappa opioid agonists attenuate some neurochemical and
behavioral effects of cocaine and are being considered as potential treatments for cocaine dependence. The present study examined the
effects of two kappa opioid agonists, the benzomorphan
ethylketocyclazocine (EKC) and the arylacetamide U50,488, on cocaine
self-administration in rhesus monkeys. Monkeys responded for 0.032 mg/kg/injection cocaine (i.v.) and 1 g banana-flavored food
pellets during alternating daily sessions of cocaine and food
availability. Chronic treatment for 10 consecutive days with EKC
(0.0032-0.032 mg/kg/hr) or U50,488 (0.032-0.1 mg/kg/hr)
dose-dependently decreased self-administration of cocaine unit doses at
the peak of the cocaine dose-effect curve (0.01 and 0.032 mg/kg/injection). These decreases in cocaine self-administration were
often sustained throughout the 10 days of treatment. Doses of EKC and
U50,488 that decreased cocaine self-administration usually decreased
food-maintained responding as well. In addition, EKC and U50,488 often
produced emesis and sedation during the first few days of treatment,
although tolerance appeared to develop rapidly to these effects. In
general, EKC produced fewer undesirable effects than U50,488 at doses
that decreased cocaine self-administration. The kappa
antagonist norbinaltorphimine (3.2 mg/kg) did not affect responding
maintained by cocaine or food. However, both norbinaltorphimine (3.2 mg/kg) and the opioid antagonist naloxone (1.0 mg/kg/hr) blocked the
effects of EKC and U50,488. These results indicate that chronic
administration of EKC and U50,588 produce a dose-dependent, kappa receptor-mediated and often sustained decrease in
cocaine self-administration. However, these kappa
agonists also produce undesirable behavioral effects that may
complicate their use as treatments for cocaine dependence.
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