Animal Models of Motivation for Drinking in Rodents with a Focus on Opioid Receptor Neuropharmacology

Koob, George F.; Roberts, Amanda J.; Kieffer, Brigitte L.; Heyser, Charles J.; Katner, Simon N.; Ciccocioppo, Roberto; Weiss, Friedbert

doi:10.1007/0-306-47939-7_19

Cited by 53 publications

(44 citation statements)

References 61 publications

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“…If the acute reinforcing properties of ethanol are in part mediated by the m-opioid receptor as suggested by the common effect of both nalmefene and naltrexone on nondependent ethanol self-administration, as well as the published literature (Hyytia, 1993;Krishnan-Sarin et al, 1998;Stromberg et al, 1998;Koob et al, 2003), then compensatory alterations in the dynorphin system would fit well with the opponent-process theory (Solomon and Corbit, 1974) and contemporary theories of allostasis Roberts et al, 2000;Koob and Le Moal, 2001) when applied to animals in an ethanol-dependent state. Thus, if m-opioid receptor stimulation produces positive hedonic states (Amalric et al, 1987), then one putative compensatory mechanism that could occur would be an increase in the function of dynorphin and/or the k-opioid receptors, stimulation of which produces negative hedonic states (Mucha and Herz, 1985).…”

Section: Discussionmentioning

confidence: 73%

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

Walker

Koob

2007

Neuropsychopharmacol

365

376

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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 animals suggests that opioid systems distinct from the m-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. INTRODUCTIONThe acute effects of ethanol have been shown to be both reinforcing and rewarding in animal models such as operant self-administration (Anderson and Thompson, 1974;Smith and Davis, 1974) and the conditioned place preference paradigm (Bozarth, 1990;Walker and Ettenberg, 2007). Ethanol produces its effects on the central nervous system via a variety of pharmacological mechanisms. These include alterations in the function of the cholinergic, dopaminergic, g-aminobutyric acid, glutamatergic, opioidergic, and serotonergic neurotransmitter systems (for review see Eckardt et al, 1998). In the case of the endogenous opioid system and its receptor subtypes (m, d, kFselective for the three main classes of endogenous opioids: b-endorphin, enkephalins, and dynorphins, respectively), acute ethanol has been shown to stimulate the release of b-endorphin...

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Section: Discussionmentioning

confidence: 73%

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

Walker

Koob

2007

Neuropsychopharmacol

365

376

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“…Opiate antagonists (Heinälä et al 2001;Litten and Allen 1998;O'Malley et al 1992;Monti et al 2001;Rubio et al 2001;Volpicelli et al 1992), acamprosate (Ansoms et al 2000;Besson et al 1998;Chick et al 2000;Lesch et al 2001;Rubio et al 2001;Sass et al 1996;Tempesta et al 2000;Litten and Allen 1998; see overview by Mason 2001) or a combination of these drugs (Kranzler and Van Kirk 2001) are currently prescribed to reduce alcohol consumption in alcoholics. In preclinical studies, opiate antagonists are capable of minimizing acute drinking of alcohol (Altshuler et al 1980;Badia-Elder et al 1999;Froehlich et al 1990;Heyser et al 2003;Hölter and Spanagel 1999;Hyytia and Sinclair 1993;Overstreet et al 1999;Samson and Doyle 1985), as well as reducing alcohol seeking by an alcohol conditioned stimulus (Liu and Weiss 2002a;Koob et al 2003). However, naltrexone's maintenance of abstinence in alcoholdependent patients was not remarkable in one study (Guardia et al 2002) and was absent in another (Krystal et al 2001).…”

Section: Future Directionsmentioning

confidence: 99%

Conceptual framework for the etiology of alcoholism: a ?kindling?/stress hypothesis

2004

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Rationale-The rationale for proposing the "kindling"/stress hypothesis is to provide a conceptual basis for the insidious development and maintenance of alcohol abuse.Objective and results-An objective of the hypothesis is to emphasize how continued alcohol abuse is linked to progressive neural adaptation. Work has shown that repeated withdrawals from chronic low levels of alcohol sensitize ("kindle") anxiety-like behavior ("anxiety") in rats, a finding consistent with multiple withdrawal kindling of seizure activity. Additionally, stress substitutes for initial cycles of the multiple withdrawal protocol to sensitize withdrawal-induced anxiety, which is indicative that stress is capable of facilitating neuroadaptive processes related to withdrawal. The persistence of adaptation caused by stress and multiple withdrawals is revealed by the appearance of withdrawal-induced anxiety following a future re-exposure to a single 5-day period of alcohol. This persisting adaptation also permits stress to induce anxiety during a period of abstinence-a response not observed in animals without previous exposure to alcohol. Furthermore, stress interacts with repeated withdrawals to enhance voluntary alcohol drinking. Results of other preclinical and clinical studies reported in the literature are integrated with these investigations in support of the proposed hypothesis.Conclusions-The "kindling"/stress hypothesis is based on the premise that repeated withdrawals from cycles of chronic alcohol exposure contribute to a progressive development of persisting adaptive change that sensitizes withdrawal-induced anxiety and allows stress to evoke symptoms associated with negative affect during abstinence. Thus, these consequences of repeated withdrawals account for the evolution of major characteristics of alcoholism, which include worsened acute withdrawal symptoms and increased stress-induced negative affect during abstinence, both of which enhance the likelihood of relapse-and with relapse an inability to limit an abusive pattern of alcohol intake. The "kindling"/stress hypothesis provides a clear strategy for future studies to explore the advancing neural adaptation proposed to contribute to the pathogenesis of alcoholism.

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“…Pharmacological and clinical studies have implicated the opioid system in various aspects of alcoholism (see Gianoulakis, 2004;Koob et al, 2003;Oswald & Wand, 2005 for rev.). There are three major groups of endogenous opioid peptides, each derived from a specific precursor hormone: the endorphins from the β-endorphin/ACTH precursor proopiomelanocortin (POMC) (Nakanishi et al, 1979); the enkephalins from the precursor proenkephalin ; and the dynorphins and neoendorphins from the precursor prodynorphin (Kakidani et al, 1982).…”

Section: Introductionmentioning

confidence: 99%

Reduced alcohol consumption in mice lacking preprodynorphin

Blednov

Walker

Martinez

et al. 2006

Alcohol

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Many studies suggest a role for endogenous opioid peptides and their receptors in regulation of ethanol intake. It is commonly accepted that the κ-opioid receptors and their endogenous ligands, dynorphins, produce a dysphoric state and therefore may be responsible for avoidance of alcohol. We used mutant mice lacking preprodynorphin in a variety of behavioral tests of alcohol actions. Null mutant female, but not male, mice showed significantly lower preference for alcohol and consumed lower amounts of alcohol in a two-bottle choice test as compared with wild-type littermates. In the same test, knockout mice of both sexes showed a strong reduction of preference for saccharin compared to control mice. In contrast, under conditions of limited (4 hours) access (light phase of the light/dark cycle), null mutant mice did not show any differences in consumption of saccharin but they showed significantly reduced intake of sucrose. To determine the possible cause for reduction of ethanol preference and intake, we studied other ethanol-related behaviors in mice lacking the preprodynorphin gene. There were no differences between null mutant and wild type mice in ethanol-induced loss of righting reflex, acute ethanol withdrawal, ethanol-induced conditioned place preference or conditioned taste aversion to ethanol. These results indicate that deletion of preprodynorphin leads to substantial reduction of alcohol intake in female mice, and suggest thath this is caused by decreased orosensory reward of alcohol (sweet taste and/or palatability).

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Animal Models of Motivation for Drinking in Rodents with a Focus on Opioid Receptor Neuropharmacology

Cited by 53 publications

References 61 publications

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

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

Conceptual framework for the etiology of alcoholism: a ?kindling?/stress hypothesis

Reduced alcohol consumption in mice lacking preprodynorphin

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