Kappa-opioid receptors and relapse-like drinking in long-term ethanol-experienced rats

Hölter, Sabine M.; Henniger, M. S. H.; Lipkowski, Andrzej W.; Spanagel, Rainer

doi:10.1007/s002130000601

Cited by 91 publications

(109 citation statements)

References 38 publications

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“…Chronic administration of naltrexone alone or in combination with acamprosate eliminated this deprivation-induced increase in drinking. These results confirm previous reports that opiate antagonists and acamprosate reduce the alcohol deprivation effect (Hölter et al, 1997;Spanagel et al, 1996a;Heyser et al, 1998;Hölter and Spanagel, 1999;Hölter et al, 2000). In the present study, the effects of drug administration had no effects on responding for water.…”

Section: Discussionsupporting

confidence: 93%

“…These results confirm previous reports that opioid receptor antagonists reduce ethanol intake (Samson and Doyle, 1985;Hubbell et al, 1986;Froehlich et al, 1990;Weiss et al, 1990;Hyytia and Sinclair, 1993;June et al, 1999) and attenuate the ethanol deprivation effect (Hölter and Spanagel, 1999;Hölter et al, 2000). The reduction in responding for ethanol below baseline observed after administration of the higher doses (0.125 and 0.25 mg/kg) of naltrexone was specific to the first day after ethanol deprivation.…”

Section: Discussionsupporting

confidence: 91%

See 1 more Smart Citation

Effects of Naltrexone Alone and In Combination With Acamprosate on the Alcohol Deprivation Effect in Rats

Heyser

Moc

Koob

2003

Neuropsychopharmacol

101

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Previous research in our laboratory has shown that responding for ethanol increases after a period of imposed deprivation during which no ethanol is available (the alcohol deprivation effect). This selective increase in responding for ethanol was blocked by chronic administration of acamprosate. In the present study the effects of naltrexone and the combination of naltrexone+acamprosate on oral ethanol self-administration were examined following an imposed period of abstinence. Male Wistar rats were trained to respond for ethanol (10% w/v) or water in a two-lever free-choice condition. After training, separate groups of rats received chronic injections (2 Â /day) of saline, naltrexone, or naltrexone+acamprosate during a 5-day period of abstinence. Ethanol self-administration was tested in all groups of rats on the last day of abstinence, 30 min after the last drug injection. Responding for ethanol increased significantly following the deprivation period in animals treated with saline. Chronic administration of naltrexone and the combination naltrexone+acamprosate blocked the increased ethanol consumption following the imposed abstinence period on post-deprivation Day 1. On post-deprivation Day 2, the combination of acamprosate with naltrexone blocked the rebound increase in ethanol consumption observed in animals treated with a low dose of naltrexone. These results support the hypothesis that naltrexone and acamprosate are effective in modulating aspects of alcohol-seeking behavior, and under certain situations may be more effective in combination.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 91%

Effects of Naltrexone Alone and In Combination With Acamprosate on the Alcohol Deprivation Effect in Rats

Heyser

Moc

Koob

2003

Neuropsychopharmacol

101

View full text Add to dashboard Cite

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“…Natural and synthetic kappaopioid receptor agonists directly infused into the striatum or administered systemically to rodents will both attenuate cocaine-induced dopamine surges in the nucleus accumbens and block cocaine-induced conditioned place preference (Maisonneuve et al, 1994;Zhang et al, 2004a, b). Centrally penetrating kappa-opioid receptor agonists can be aversive in rodents, so studies showing a reduction in alcohol intake but an increased alcohol deprivation effect and a decrease in morphine and cocaine self-administration may be difficult to interpret (Glick et al, 1995;Hölter et al, 2000;Lindholm et al, 2001). Studies of kappa-opioid receptor antagonists have not found an effect of these agents on alcohol, morphine, or cocaine administration (Glick et al, 1995;Hölter et al, 2000).…”

Section: Mu-and Kappa-opioid System and Addictionmentioning

confidence: 99%

“…Centrally penetrating kappa-opioid receptor agonists can be aversive in rodents, so studies showing a reduction in alcohol intake but an increased alcohol deprivation effect and a decrease in morphine and cocaine self-administration may be difficult to interpret (Glick et al, 1995;Hölter et al, 2000;Lindholm et al, 2001). Studies of kappa-opioid receptor antagonists have not found an effect of these agents on alcohol, morphine, or cocaine administration (Glick et al, 1995;Hölter et al, 2000). Acute administration of cyclazocine or butorphanol, compounds with mixed activity at mu-and kappa-opioid receptors, in human cocaine users did not alter the effects of investigator-administered intranasal cocaine or reduce intravenous cocaine self-administration (Walsh et al, 2001;Preston et al, 2004).…”

Section: Mu-and Kappa-opioid System and Addictionmentioning

confidence: 99%

Nalmefene Induced Elevation in Serum Prolactin in Normal Human Volunteers: Partial Kappa Opioid Agonist Activity?

Bart

Schluger

Borg

et al. 2005

Neuropsychopharmacol

126

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In humans, mu-and kappa-opioid receptor agonists lower tuberoinfundibular dopamine, which tonically inhibits prolactin release. Serum prolactin is, therefore, a useful biomarker for tuberoinfundibular dopamine. The current study evaluated the unexpected finding that the relative mu-and kappa-opioid receptor selective antagonist nalmefene increases serum prolactin, indicating possible kappa-opioid receptor agonist activity. In all, 33 healthy human volunteers (14 female) with no history of psychiatric or substance use disorders received placebo, nalmefene 3 mg, and nalmefene 10 mg in a double-blind manner. Drugs were administered between 0900 and 1000 on separate days via 2-min intravenous infusion. Serial blood specimens were analyzed for serum levels of prolactin. Additional in vitro studies of nalmefene binding to cloned human kappa-opioid receptors transfected into Chinese hamster ovary cells were performed. Compared to placebo, both doses of nalmefene caused significant elevations in serum prolactin (po0.002 for nalmefene 3 mg and po0.0005 for nalmefene 10 mg). There was no difference in prolactin response between the 3 and 10 mg doses. Binding assays confirmed nalmefene's affinity at kappa-opioid receptors and antagonism of mu-opioid receptors. [ 35 S]GTPgS binding studies demonstrated that nalmefene is a full antagonist at mu-opioid receptors and has partial agonist properties at kappa-opioid receptors. Elevations in serum prolactin following nalmefene are consistent with this partial agonist effect at kappa-opioid receptors. As kappaopioid receptor activation can lower dopamine in brain regions important to the persistence of alcohol and cocaine dependence, the partial kappa agonist effect of nalmefene may enhance its therapeutic efficacy in selected addictive diseases.

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“…Even though there is no report regarding the effects of prenatal alcohol exposure on kappa mRNA level in fetal animal models, experimental animal data have documented significant interactions between the kappa opioid receptor and alcohol use in adulthood. [36][37][38][39] Prenatal alcohol exposure in humans has in fact been shown to be most predictive of adolescent alcohol use even after adjusting for family history and other prenatal and environmental variables, 40 which suggests that modification of the kappa system by prenatal alcohol exposure could have a long-lasting effect on behavior that enhances the vulnerability to alcoholism. It is interesting to note that alcohol-related changes on the kappa opioid receptor mRNA were not mimicked by alterations in the PDYN mRNA expression.…”

Section: Discussionmentioning

confidence: 99%

Discrete opioid gene expression impairment in the human fetal brain associated with maternal marijuana use

et al. 2006

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Fetal development is a period sensitive to environmental influences such as maternal drug use. The most commonly used illicit drug by pregnant women is marijuana. The present study investigated the effects of in utero marijuana exposure on expression levels of opioid-related genes in the human fetal forebrain in light of the strong interaction between the cannabinoid and opioid systems. The study group consisted of 42 midgestation fetuses from saline-induced voluntary abortions. The opioid peptide precursors (preprodynorphin and preproenkephalin (PENK)) and receptor (mu, kappa and delta) mRNA expression were assessed in distinct brain regions. The effect of prenatal cannabis exposure was analyzed by multiple regression controlling for confounding variables (maternal alcohol and cigarette use, fetal age, sex, growth measure and post-mortem interval). Prenatal cannabis exposure was significantly associated with increased mu receptor expression in the amygdala, reduced kappa receptor mRNA in mediodorsal thalamic nucleus and reduced preproenkephalin expression in the caudal putamen. Prenatal alcohol exposure primarily influenced the kappa receptor mRNA with reduced levels in the amygdala, claustrum, putamen and insula cortex. No significant effect of prenatal nicotine exposure could be discerned in the present study group. These results indicate that maternal cannabis and alcohol exposure during pregnancy differentially impair opioid-related genes in distinct brain circuits that may have long-term effects on cognitive and emotional behaviors.

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Kappa-opioid receptors and relapse-like drinking in long-term ethanol-experienced rats

Cited by 91 publications

References 38 publications

Effects of Naltrexone Alone and In Combination With Acamprosate on the Alcohol Deprivation Effect in Rats

Effects of Naltrexone Alone and In Combination With Acamprosate on the Alcohol Deprivation Effect in Rats

Nalmefene Induced Elevation in Serum Prolactin in Normal Human Volunteers: Partial Kappa Opioid Agonist Activity?

Discrete opioid gene expression impairment in the human fetal brain associated with maternal marijuana use

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