Effects of Kappa Opioids on Cocaine Self-Administration by Rhesus Monkeys

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. Cocaine abuse continues to be a major public health concern in the United States (National Institutes of Health, 1996). Consequently, one goal of preclinical research has been to characterize the neurobiological and pharmacological determinants of cocaine’s high abuse potential and to identify drugs that could be used in the treatment of cocaine abuse. For example, cocaine has been shown to block the reuptake of the neurotransmitter dopamine (Koe, 1976; Taylor and Ho, 1978; Reith, 1988), and an extensive literature suggests that cocaine’s reinforcing effects are mediated by increases in extracellular dopamine levels in the terminal fields of the mesolimbic dopamine system, primarily the nucleus accumbens (Ritz et al., 1987; Koob and Bloom, 1988; Johanson and Fischman, 1989; Kuhar et al., 1991; Woolverton and Johnson, 1992). Dopamine receptor antagonists, which block the indirect dopamine agonist effects of cocaine, have been evaluated for their utility in treating cocaine abuse (see Mello and Negus, 1996, for review). However, dopamine antagonists also produce extrapyramidal motor effects and other unwanted effects that complicate their use in the treatment of cocaine dependence. In addition, the cocaine-antagonist effects of dopamine antagonists may not be sustained during chronic treatment (Kleven and Woolverton, 1990; Negus et al., 1996). Compounds acting on other receptor systems may provide an alternative means of modifying the neurobiological and behavioral effects of cocaine by indirectly modulating the activity of dopaminergic systems. For example, a growing body of evidence suggests that agonists and antagonists at kappa opioid receptors may modulate the activity of dopaminergic neurons and alter the neurochemical and behavioral effects of cocaine. The nucleus accumbens contains high levels of both kappa opioid receptors (Mansour et al., 1987, 1988, 1994) and dynorphin (Hokfelt et al., 1984), an endogenous opioid peptide with high affinity for kappa receptors (Chavkin et al., 1982). In contrast to cocaine, kappa agonists have been shown to decrease striatal dopamine levels in rats (Di Chiara and Imperato, 1988; Donzanti et al., 1992; Spanagel et al., 1992; Devine et al., 1993). Kappa agonists also Received for publication August 5, 1996. 1 This work was supported in part by grants DA 04059, R01-DA 02519, RO1-DA 01533 and KO5-DA 00101 from the National Institute on Drug Abuse, National Institutes of Health. Preliminary data were reported at the 1996 meeting of the College on Problems of Drug Dependence. ABBREVIATIONS: EKC, ethylketocyclazocine; FR, fixed ratio; nor-BNI, norbinaltorphimine; VR, variable ratio; ANOVA, analysis of variance. 0022-3565/97/2821-0044$03.00/0 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 282, No. 1 Copyright © 1997 by The American Society for Pharmacology and Experimental Therapeutics Printed in U.S.A. JPET 282:44–55, 1997 44 at A PE T Jornals on Jne 4, 2017 jpet.asjournals.org D ow nladed from attenuated cocaine-induced increases in dopamine levels in the nucleus accumbens (Maisonneuve et al., 1994) as well as cocaine-induced changes in the expression of immediate early oncogenes such as c-fos and zif 268 (Steiner and Gerfen, 1995; Crawford et al., 1995). Cocaine also appears to have a reciprocal action on kappa opioidergic systems. Cocaine administration has been found to up-regulate kappa receptors (Hurd and Herkenham, 1993; Unterwald et al., 1994) and increase levels of both dynorphin and dynorphin mRNA (Hurd and Herkenham, 1993; Daunais and McGinty, 1995; Daunais et al., 1995; Hanson et al., 1995). This cocaineinduced stimulation of kappa opioidergic systems may function as a form of negative feedback that opposes and limits the direct effects of cocaine (e.g., Hyman and Nestler, 1996). Kappa opioid agonists have also been found to attenuate many behavioral effects of cocaine. For example, the administration of kappa agonists in rodents has been reported to block or decrease cocaine-induced hyperactivity (Ukai et al., 1994; Crawford et al., 1995), sensitization to cocaine-induced hyperactivity and stereotypies (Heidbreder et al., 1995) and cocaine-induced place preferences (Suzuki et al., 1992; Crawford et al., 1995; Shippenberg et al., 1996). Kappa agonists also produced a surmountable antagonism of the discriminative stimulus effects of cocaine in squirrel monkeys (Spealman and Bergman, 1992, 1994). Taken together, these findings suggest that activation of kappa opioid receptors may functionally antagonize some effects of cocaine, possibly by inhibiting the release of dopamine from dopaminergic neurons. Although these studies suggest that kappa opioids modify some effects of cocaine that may contribute to its abuse, a direct examination of kappa opioid effects on the reinforcing effects of cocaine in drug self-administration procedures has only begun. Glick and co-workers (1995) recently reported that after acute administration, kappa agonists were slightly more potent in decreasing the self-administration of an intermediate unit dose of cocaine (0.4 mg/kg/injection) than in decreasing water-maintained responding in rats. In addition, the kappa antagonist nor-BNI (Portoghese et al., 1987) had no effect on cocaine self-administration but blocked the effects of the kappa agonists on cocaine self-administration (Glick et al., 1995). However, the effects of kappa agonists and antagonists on cocaine self-administration in primates are unknown, and there is some evidence which suggests that species may be an important determinant of the effects of kappa opioids (cf. Broadbear et al., 1994; Butelman et al., 1993a). In addition, pharmacotherapies for drug dependence are usually administered chronically, and the effects of chronic treatment with kappa opioids on cocaine self-administration have not been examined in any species. Consequently, the purpose of the present study was to evaluate the effects of chronic treatment with kappa opioids on the reinforcing effects of cocaine in rhesus monkeys trained to self-administer cocaine. Two kappa agonists, the arylacetamide U50,488 (VonVoigtlander et al., 1983) and the benzomorphan EKC (Martin et al., 1976), were selected for evaluation in this study. Both U50,488 and EKC produce qualitatively similar behavioral effects mediated by kappa opioid receptors in rhesus monkeys (e.g., Dykstra et al., 1987a,b; Gmerek et al., 1987; France et al., 1994). However, EKC may also produce agonist effects at mu opioid receptors (Gmerek et al., 1987; Butelman et al., 1993b). In addition, evidence from studies conducted both in vitro (Su, 1985; Zukin et al., 1988; Nock et al., 1990; Rothman et al., 1990) and in vivo (Horan et al., 1991; Butelman et al., 1993a, 1995) suggests that kappa receptor subtypes may exist, and the effects of U50,488 and EKC may be mediated by different kappa receptor subtypes in rhesus monkeys (Butelman et al., 1993a). The effects of the kappa antagonist nor-BNI (Portoghese et al., 1987; Butelman et al., 1993a) and the opioid antagonist naloxone on the behavioral effects of EKC and U50,488 were also examined.