Decreased Oral Self-Administration of Alcohol In ??-Opioid Receptor Knock-Out Mice

Kovacs, Krisztina M.; Szakall, Istvan; O’Brien, Danielle; Wang, Ray; Vinod, K. Yaragudri; Saito, Mariko; Simonin, Frédéric; Kieffer, Brigitte L.; Vadász, Csaba

doi:10.1097/01.alc.0000164361.62346.d6

Cited by 109 publications

(111 citation statements)

References 57 publications

(77 reference statements)

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“…36 A complete knockout of OPRK1 significantly reduced alcohol preference and consumption in mice. 39 Alteration of the k-opioid system expression was further investigated in Withdrawal Seizure-Prone (WSP) and Withdrawal Seizure-Resistant (WSR) mice, 68 using in situ hybridization (ISH) and KOR autoradiography. Ethanol withdrawal increased PDYN mRNA in multiple brain regions of WSP, but not WSR mice; 68 basal KOR binding was higher in WSR mice than in WSP mice.…”

Section: Discussionmentioning

confidence: 99%

“…38 OPRK1 knockout mice demonstrate an increased ethanol-evoked dopamine response in the nucleus accumbens 37 and show less oral alcohol self-administration than wild-type mice. 39 The OPRK1 gene is located on human chromosome 8. The 22 kb OPRK1 gene contains four exons, including a newly identified exon that encodes the 5 0 untranslated region.…”

Section: Introductionmentioning

confidence: 99%

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Association of the κ-opioid system with alcohol dependence

et al. 2006

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Opioid receptors and their endogenous peptide ligands play important roles in the reward and reinforcement of drugs such as heroin, cocaine, and alcohol. The binding of dynorphins to the j-opioid receptor has been shown to produce aversive states, which may prevent the development of reinforcement. We genotyped SNPs throughout OPRK1, encoding the j-opioid receptor, and PDYN, which encodes its ligand prodynorphin, in a group of 1860 European American individuals from 219 multiplex alcohol dependent families. Family-based analyses demonstrated associations between alcohol dependence and multiple SNPs in the promoter and 3 0 end of PDYN, and in intron 2 of OPRK1. Haplotype analyses further supported the association of PDYN. Thus, variations in the genes encoding both the j-opioid receptor and its ligand, OPRK1 and PDYN, are associated with the risk for alcohol dependence; this makes biological sense as variations in either should affect signaling through the j-opioid system.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Association of the κ-opioid system with alcohol dependence

et al. 2006

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“…A similar relationship may also exist with the drinking of ethanol. There is evidence that ethanol intake is stimulated by peripheral injection of opioid agonists, and it is decreased by an opioid receptor antagonist (Hubbell et al, 1986;Messiha, 1989;Oswald and Wand, 2004) or by deletion of the k-opioid receptor gene (Kovacs et al, 2005). Also, 2 recent studies from our laboratories show that PVN or i.c.v.…”

Section: Functional Consequences Of Increased Peptide Expressionmentioning

confidence: 96%

Effect of Ethanol on Hypothalamic Opioid Peptides, Enkephalin, and Dynorphin: Relationship With Circulating Triglycerides

Chang

Karatayev

Ahsan

et al. 2007

Alcoholism Clin & Exp Res

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Background: Recent evidence has demonstrated that ethanol intake can stimulate the expression and production of the feeding-stimulatory peptide, galanin (GAL), in the hypothalamic paraventricular nucleus (PVN), and that PVN injection of this peptide, in turn, can increase the consumption of ethanol. To test the hypothesis that other feeding-related systems are involved in ethanol intake, this study examined the effect of ethanol on the hypothalamic opioid peptides, enkephalin (ENK), and dynorphin (DYN).Method: Adult, male Sprague-Dawley rats were trained to voluntarily drink increasing concentrations of ethanol, up to 9% v/v, on a 12-hour access schedule or were given a single injection of ethanol (10% v/v) versus saline vehicle. The effect of ethanol on GAL, ENK, and DYN mRNA was measured using real-time quantitative polymerase chain reaction and radiolabeled in situ hybridization, while radioimmunoassay was used to measure peptide levels. In addition to blood alcohol, circulating levels of triglycerides (TG), leptin, and insulin were also measured.Results: The data demonstrated that: (1) rats voluntarily drinking 9% v/v ethanol (approximately 2.0 g/kg/d) show a significant increase in GAL, ENK, and DYN mRNA in the PVN compared with water-drinking rats; (2) voluntary consumption of ethanol also increases peptide levels of ENK and DYN in the PVN; (3) acute injection of 10% ethanol (1.0 g/kg of 10% v/v) similarly increases the expression of GAL, ENK, and DYN in the PVN; and (4) ethanol consumption and injection, while having little effect on leptin and insulin, consistently increase circulating levels of TG as well as alcohol, both of which are strongly, positively correlated with peptide expression in the PVN.Conclusions: These findings, together with published studies, suggest a possible role for hypothalamic opioid peptides in the drinking of ethanol. Based on evidence that dietary fat and lipid injections stimulate the PVN peptides and injection of the opiates and GAL increase ethanol intake, it is proposed that both TG and alcohol in the circulation, which are elevated by the ingestion or injection of ethanol, are involved in stimulating these peptides in the PVN, which in turn promote further consumption of ethanol.

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“…The results of this gene-mapping study suggested that genetic polymorphisms in kappa opioid receptors may contribute to genetic predisposition to voluntary alcohol-drinking behavior. Our follow-up studies on opioid receptor kappa 1 knock-out mice indicated that complete constitutional dysfunction of the Oprk1 gene can reduce alcohol consumption (20), however chromosome position of microsatellite marker " D1Mit167" in the MIT database was assigned incorrectly, and the proposed chr. 1 region was not associated with genetic variation in alcohol consumption (21).…”

Section: Introductionmentioning

confidence: 94%

Mapping of QTLs for Oral Alcohol Self-Administration in B6.C and B6.I Quasi-Congenic RQI Strains

et al. 2007

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One strategy to identify neurochemical pathways of addiction is to map the relevant genes. In the present study we used 43 B6.C and 35 B6.I inbred RQI mouse strains, carrying <3% donor genome on C57BL/6ByJ background, for gene mapping. The strains were phenotyped for consumption of alcohol (12% v/v) in a two-bottle-choice paradigm, and genotyped for 396 microsatellite markers. The current mapping study extends our earlier experiment scanning five mouse chromosomes (1) to a whole-genome study, and discusses the differences and limitations. Data were analyzed with composite interval (CIM) and multiple interval (MIM) QTL mapping methods. CIM of B6.C strains detected significant QTLs on chrs. 6 and 12. A suggestive, but not significant, locus was detected in the B6.I strains on chr. 12. The best MIM model for B6.C strains confirmed one QTL on chr. 6 and one QTL on chr. 12., while the MIM model for the B6.I strains confirmed the suggestive locus on chr. 12. Some of the QTLs for alcohol consumption are new, while others confirm previously reported QTLs for alcohol preference, and alcohol acceptance.

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Decreased Oral Self-Administration of Alcohol In ??-Opioid Receptor Knock-Out Mice

Cited by 109 publications

References 57 publications

Association of the κ-opioid system with alcohol dependence

Association of the κ-opioid system with alcohol dependence

Effect of Ethanol on Hypothalamic Opioid Peptides, Enkephalin, and Dynorphin: Relationship With Circulating Triglycerides

Mapping of QTLs for Oral Alcohol Self-Administration in B6.C and B6.I Quasi-Congenic RQI Strains

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