Effect of Mu Opioid Receptor Blockade on Alcohol Intake in Rats Bred for High Alcohol Drinking

Krishnan‐Sarin, Suchitra; Wand, Gary S.; Li, X. W.; Portoghese, Phillip; Froehlich, Janice C.

doi:10.1016/s0091-3057(97)00474-7

Cited by 101 publications

(60 citation statements)

References 58 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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“…Understanding the contribution of each opioid receptor to EtOH consumption could lead to the development of a more effective therapeutic by permitting more selective targeting of the appropriate receptor(s). For example, MOR selective antagonists reduce EtOH intake (Krishnan-Sarin et al, 1998) while KOR selective antagonists can increase EtOH intake (Mitchell et al, 2005; but see Walker and Koob, 2008) in rats. Therefore, antagonizing all opioid receptors simultaneously is not an optimal treatment strategy.…”

Section: Discussionmentioning

confidence: 99%

δ-Opioid Receptor Expression in the Ventral Tegmental Area Protects Against Elevated Alcohol Consumption

Margolis¹,

Fields²,

Hjelmstad³

et al. 2008

J. Neurosci.

106

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Alcoholism is a complex and debilitating syndrome affecting ϳ140 million people worldwide. However, not everyone who consumes ethanol develops abuse, raising the possibility that some individuals have a protective mechanism that inhibits elevated alcohol consumption. We tested the hypothesis that the ␦-opioid receptor (DOR) plays such a protective role. Here we show that DOR activity in the ventral tegmental area (VTA) robustly decreases ethanol consumption in rats and that these effects depend on baseline ethanol consumption. Intra-VTA microinjection of the DOR agonist DPDPE decreases drinking, particularly in low-drinking animals. Furthermore, VTA microinjection of the DOR selective antagonist TIPP-⌿ increases drinking in low, but not high, drinkers and this increase is blocked by comicroinjection of the GABA A antagonist bicuculline. Using electrophysiological techniques we found that in VTA brain slices from drinking rats DPDPE presynaptically inhibits GABA A receptor mediated IPSCs in low drinkers, but not in high drinkers or naive animals, most likely through activation of DORs on GABA terminals. This DOR-mediated inhibition of IPSCs also correlates inversely with behavioral correlates of anxiety measured in the elevated plus maze. In contrast, presynaptic inhibition of VTA GABA A IPSCs by theopioid receptor agonist DAMGO is significantly reduced in both high-and low-drinking rats (Ͻ30%) compared with age-matched nondrinking controls (Ͼ70%). Together, our findings demonstrate the protective nature of VTA DORs and identify an important new target for therapeutic intervention for alcoholism.

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“…Conversely, administration of opioid agonists (eg morphine) increased alcohol intake in rodents (Czirr et al, 1987;Hubbell et al, 1986;Linseman and Harding, 1990;Nichols et al, 1991;Reid et al, 1986). Antagonists that are selective for the m-ORs (Froehlich et al, 1991;Krishnan-Sarin et al, 1998) or d-ORs also can decrease alcohol drinking (Franck et al, 1998;Froehlich et al, 1991;June et al, 1999;Krishnan-Sarin et al, 1995a, b) (but cf. (Honkanen et al, 1996;Hyytia, 1993;Middaugh et al, 2000;Stromberg et al, 1998;).…”

Section: Introductionmentioning

confidence: 99%

Differences in δ- and μ-Opioid Receptor Blockade Measured by Positron Emission Tomography in Naltrexone-Treated Recently Abstinent Alcohol-Dependent Subjects

Weerts

Kim

Wand

et al. 2007

Neuropsychopharmacol

139

147

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Blockade of brain m-opioid receptor (m-OR) and d-opioid receptor (d-OR) was investigated in recently abstinent alcohol-dependent subjects (N ¼ 21) maintained on naltrexone. Subjects completed a 19-day inpatient protocol, which included alcohol abstinence followed by naltrexone treatment (50 mg) on days 15-19. Blood samples were collected after the first administration of naltrexone to evaluate serum levels of naltrexone and 6-b-naltrexol. Regional brain m-OR binding potential (BP) and d-OR K i was measured using [ 11 C]carfentanil (CAR) positron emission tomography (PET) and [11 C]methyl naltrindole ([ 11 C]MeNTI) PET, respectively, before (day 5) and during naltrexone treatment (day 18). Naltrexone inhibition of [ 11 C]CAR BP was near maximal across all brain regions of interest with little variability across subjects (mean + SD% inhibition ¼ 94.9 + 4.9%). Naltrexone only partially inhibited the [ 11 C]MeNTI K i and there was more variability across subjects (mean + SD% inhibition ¼ 21.1 + 14.49%). Peak serum levels of naltrexone were positively correlated with % inhibition of d-OR K i in neocortex and basal ganglia. Peak serum levels of naltrexone were not correlated with % inhibition of m-OR BP. Peak levels of 6-b-naltrexol were not significantly correlated with % inhibition of m-OR BP or d-OR K i . Thus, the FDA recommended therapeutic dose of naltrexone was sufficient to produce near complete inhibition of the m-OR in recently abstinent alcohol dependent subjects. The lower percent inhibition of d-OR and greater variability in d-OR blockade by naltrexone across subjects may contribute to individual differences in treatment outcomes to naltrexone. Further investigations on the relationship between individual differences in d-OR blockade by naltrexone and clinical outcomes should be explored.

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Effect of Mu Opioid Receptor Blockade on Alcohol Intake in Rats Bred for High Alcohol Drinking

Cited by 101 publications

References 58 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

δ-Opioid Receptor Expression in the Ventral Tegmental Area Protects Against Elevated Alcohol Consumption

Differences in δ- and μ-Opioid Receptor Blockade Measured by Positron Emission Tomography in Naltrexone-Treated Recently Abstinent Alcohol-Dependent Subjects

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