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Pharmacological Evidence for a Motivational Role of К-Opioid Systems in Ethanol Dependence

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Pharmacological Evidence for a Motivational Role of К-Opioid Systems in Ethanol Dependence Neuropsychopharmacology (2008) 33, 643–652 & 2008 Nature Publishing Group All rights reserved 0893-133X/08 $30.00 www.neuropsychopharmacology.org Pharmacological Evidence for a Motivational Role of k-Opioid Systems in Ethanol Dependence ,1 1 Brendan M Walker* and George F Koob 1Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA, USA The purpose of this study was to test the hypothesis that activation of the dynorphin/kappa (k)-opioid system has a role in the increased consumption of ethanol in dependent animals. The effects of three opioid receptor antagonists with different effects on opioid receptors, naltrexone, nalmefene, and nor-binaltorphimine (nor-BNI), were compared in their ability to decrease ethanol self-administration in nondependent and ethanol-dependent male Wistar rats. Nalmefene and naltrexone are both opioid receptor ligands with comparable molecular weights and pharmacokinetic profiles, but differing specificity for the three opioid receptor subtypes at low doses, while nor- BNI is a selective k-opioid receptor antagonist. Dependence was induced in half the animals by subjecting them to a 4-week intermittent vapor exposure period in which animals were exposed to ethanol vapor for 14 h per day. Subsequent to dependence induction, nalmefene, naltrexone, and nor-BNI were tested for their ability to modulate self-administration of ethanol in vapor-exposed and control rats. The results indicated that both nalmefene and naltrexone induced a significant dose-dependent decrease in the number of lever presses for ethanol in both groups of animals. However, in ethanol-dependent animals, nalmefene was significantly more effective in suppressing ethanol intake than naltrexone. Nor-BNI selectively attenuated ethanol-dependent self-administration while leaving nondependent ethanol self-administration intact. Because naltrexone is primarily selective for the m-opioid receptor, and nalmefene is primarily selective for the m- and k-opioid receptor subtypes, the fact that nalmefene demonstrates more suppression in dependent m animals suggests that opioid systems distinct from the -regulated portion may be involved in the increased drinking seen during withdrawal in dependent animals. The results with nor-BNI confirm that k-opioid receptor antagonism selectively decreases dependence-induced ethanol self-administration, which supports the hypothesis that dynorphin/k-opioid systems are dysregulated in dependence and contribute to the increased drinking seen during acute withdrawal in dependent rats. Neuropsychopharmacology (2008) 33, 643–652; doi:10.1038/sj.npp.1301438; published online 2 May 2007 Keywords: alcoholism; alcohol self-administration; reinforcement; dependence; opioids; dynorphin INTRODUCTION opioids: b-endorphin, enkephalins, and dynorphins, re- spectively), acute ethanol has been shown to stimulate the The acute effects of ethanol have been shown to be both release of b-endorphin, enkephalins, and dynorphin in reinforcing and rewarding in animal models such as humans and rats (Gianoulakis et al, 1996; Marinelli et al, operant self-administration (Anderson and Thompson, 2003, 2004; Dai et al, 2005; Marinelli et al, 2005, 2006). 1974; Smith and Davis, 1974) and the conditioned place Blockade of the receptors for these endogenous ligands by preference paradigm (Bozarth, 1990; Walker and Ettenberg, naltrexone and naloxone has been shown to reliably 2007). Ethanol produces its effects on the central nervous decrease ethanol consummatory behaviors (Gonzales and system via a variety of pharmacological mechanisms. These Weiss, 1998; Stromberg et al, 2001; Coonfield et al, 2002; include alterations in the function of the cholinergic, Shoemaker et al, 2002). In fact, evidence has led researchers dopaminergic, g-aminobutyric acid, glutamatergic, opio- to postulate that a surfeit of opioidergic activity enhances idergic, and serotonergic neurotransmitter systems (for the rewarding properties of ethanol (Hubbell et al, 1988; review see Eckardt et al, 1998). In the case of the Marglin et al, 1988; Reid, 1996) and may be related to endogenous opioid system and its receptor subtypes (m, d, continuing ethanol intake once it has begun (ie binge kFselective for the three main classes of endogenous drinking). Furthermore, b-endorphins and enkephalins have themselves been shown to be rewarding (ie produce a positive hedonic state) and reinforcing in that they *Correspondence: Dr BM Walker, Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, 10550 N. Torrey produce place preferences (Amalric et al, 1987; Agmo and Pines Rd, SP30-1501, La Jolla, CA 92037, USA, Tel: + 858 784 7240, Gomez, 1991) and support self-administration behavior Fax: + 858 784 7475, E-mail: [email protected] (Belluzzi and Stein, 1977; Goeders et al, 1984). Received 28 November 2006; revised 21 March 2007; accepted 30 In contrast, k-opioid receptor agonists produce place March 2007 aversions (Mucha and Herz, 1985) and are morphologically Motivational role of j-opioid systems in ethanol dependence BM Walker and GF Koob 644 in a spatial location that enables them to oppose the effects increased ethanol self-administration observed during acute of m-opioid receptor agonists (Di Chiara and Imperato, withdrawal, central k-opioid receptors were selectively 1988b) and directly inhibit motivationally relevant dopa- targeted for antagonism in nondependent and ethanol- mine neurons at both the somatic and terminal regions dependent rats. Therefore, in one experiment, nalmefene within the mesocorticolimbic dopamine system (Di Chiara and naltrexone were peripherally administered, and in the and Imperato, 1988a; Margolis et al, 2003, 2006). second, the selective k-opioid receptor antagonist nor-BNI An important question is how opioidergic systems change was administered intracerebroventricularly (ICV) immedi- with the development of dependence when there is an ately before operant ethanol self-administration sessions in increase in the motivation to consume ethanol. Aside from nondependent rats and ethanol vapor-exposed rats during the ability of acute ethanol to activate endogenous opioids, acute withdrawal. numerous investigations have evaluated the effects of chronic ethanol on opioid peptide systems. In both humans and animals, chronic ethanol exposure has induced changes METHODS in opioid peptide systems that generally reflect down- Animals regulation of the positive and upregulation of the negative hedonic portion of the systems. These changes range from Twenty-eight male Wistar rats (Charles River Laboratory, alterations in the levels of the peptides themselves Kingston, NY) weighing approximately 200 g upon arrival (Gianoulakis et al, 1996; Lindholm et al, 2000), changes in were communally housed (2–3 per cage) with food and receptor densities and effector systems (Turchan et al, 1999; water available ad libitum. The animals were housed within Chen and Lawrence, 2000), as well as modifications of a temperature-controlled (21.51C) vivarium that was main- mRNA coding for both the peptides and receptors tained on a 12 h light/dark cycle (lights on at 0800). On their (Przewlocka et al, 1997; Rosin et al, 1999; Cowen and arrival in the vivarium, animals were gently handled daily Lawrence, 2001). Therefore, the purpose of the present over a 1-week period (until the onset of operant condition- series of experiments was to test the hypothesis that ing). The work described herein adheres to the guidelines alterations in k-opioid-regulated systems have a role in stipulated in the NIH Guide for the Care and Use of mediating the increased ethanol consumption associated Laboratory Animals and was reviewed and approved by The with dependence. Scripps Research Institute’s Institutional Animal Care and To evaluate ligands with differential affinity for the opioid Use Committee. receptor subtypes for their ability to attenuate ethanol self- administration, the present experiment compared the Operant Chambers effects of three opioid receptor antagonists (ie naltrexone, nalmefene, and nor-binaltorphimine (nor-BNI)) on non- The operant chambers (Coulbourn Instruments, Allentown, dependent and ethanol-dependent self-administration of PA) utilized in the present study had two retractable levers ethanol during acute withdrawal. Naltrexone is now an located 4 cm above a grid floor and 4.5 cm to each side of a approved drug for the treatment of alcoholism based on its two-well acrylic drinking cup that allowed for up to two efficacy in reducing craving for and consumption of ethanol solutions to be administered upon the pressing of the (Volpicelli et al, 1992), and nalmefene has shown clinical appropriate lever. Recording of operant responses and utility in the treatment of alcoholism (Mason et al, 1994; subsequent fluid delivery were controlled by custom soft- Anton et al, 2004). However, naltrexone, although classified ware running on a PC computer. A lever press resulted in as a general opioid receptor antagonist, actually has a the activation of a 15 r.p.m. Razel syringe pump (Stanford, higher affinity for the m-opioid receptor subtype than the d CT) which delivered 0.1 ml of fluid to the appropriate well and k subtypes at low doses (Abbott et al, 1986; Millan, over 0.5 s. During the 0.5 s of pump activation, no responses 1989; Millan et al, 1989; Walker et al, 1994; Stromberg et al, were recorded. Operant chambers were individually housed 1998). Nalmefene is also classified as a general opioid in ventilated,
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