NOP Receptor Antagonists Decrease Alcohol Drinking in the Dark in C57BL/6J Mice.
Alcohol Deterrents
/ therapeutic use
Alcohol Drinking
/ genetics
Animals
Binge Drinking
/ drug therapy
Central Nervous System Depressants
/ blood
Cycloheptanes
/ pharmacology
Darkness
Dose-Response Relationship, Drug
Ethanol
/ blood
Indoles
/ pharmacology
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Motor Activity
/ drug effects
Narcotic Antagonists
/ therapeutic use
Piperidines
/ pharmacology
Receptors, Opioid
/ agonists
Nociceptin Receptor
Alcohol
Drinking in the Dark
N/OFQ
NOP Receptor
SB-612111
Journal
Alcoholism, clinical and experimental research
ISSN: 1530-0277
Titre abrégé: Alcohol Clin Exp Res
Pays: England
ID NLM: 7707242
Informations de publication
Date de publication:
10 2019
10 2019
Historique:
received:
21
01
2019
accepted:
25
07
2019
pubmed:
7
8
2019
medline:
29
9
2020
entrez:
7
8
2019
Statut:
ppublish
Résumé
The nociceptin/orphanin FQ opioid peptide (NOP) receptor and its endogenous ligand N/OFQ have been implicated in the regulation of drug and alcohol use disorders (AUD). In particular, evidence demonstrated that NOP receptor activation blocks reinforcing and motivating effects of alcohol across a range of behavioral measures, including alcohol intake, conditioned place preference, and vulnerability to relapse. Here, we show the effects of pharmacological activation and inhibition of NOP receptors on binge-like alcohol consumption, as measured by the "drinking in the dark" (DID) model in C57BL/6J mice. We found that 2 potent and selective NOP agonists AT-202 (0, 0.3, 1, 3 mg/kg) and AT-312 (0, 0.3, 1 mg/kg) did not affect binge alcohol drinking at doses that do not affect locomotor activity. AT-202 also failed to alter DID behavior when administered to mice previously exposed to chronic alcohol treatment with an alcohol-containing liquid diet. Conversely, treatment with either the high affinity NOP receptor antagonist SB-612111 (0, 3, 10, 30 mg/kg) or the selective antagonist LY2817412 (0, 3, 10, 30 mg/kg) decreased binge drinking. SB-612111 was effective at all doses examined, and LY2817412 was effective at 30 mg/kg. Consistently, NOP receptor knockout mice consumed less alcohol compared to wild type. SB-612111 reduced DID and increased sucrose consumption at doses that do not appear to affect locomotor activity. However, the high dose of SB-612111 (30 mg/kg) reduced alcohol intake but failed to inhibit preference in a 2-bottle choice DID model that can assess moderate alcohol intake. The present results suggest that NOP receptor inhibition rather than activation may represent a valuable approach for treatment of AUD characterized by excessive alcohol consumption such as binge drinking.
Sections du résumé
BACKGROUND
The nociceptin/orphanin FQ opioid peptide (NOP) receptor and its endogenous ligand N/OFQ have been implicated in the regulation of drug and alcohol use disorders (AUD). In particular, evidence demonstrated that NOP receptor activation blocks reinforcing and motivating effects of alcohol across a range of behavioral measures, including alcohol intake, conditioned place preference, and vulnerability to relapse.
METHODS
Here, we show the effects of pharmacological activation and inhibition of NOP receptors on binge-like alcohol consumption, as measured by the "drinking in the dark" (DID) model in C57BL/6J mice.
RESULTS
We found that 2 potent and selective NOP agonists AT-202 (0, 0.3, 1, 3 mg/kg) and AT-312 (0, 0.3, 1 mg/kg) did not affect binge alcohol drinking at doses that do not affect locomotor activity. AT-202 also failed to alter DID behavior when administered to mice previously exposed to chronic alcohol treatment with an alcohol-containing liquid diet. Conversely, treatment with either the high affinity NOP receptor antagonist SB-612111 (0, 3, 10, 30 mg/kg) or the selective antagonist LY2817412 (0, 3, 10, 30 mg/kg) decreased binge drinking. SB-612111 was effective at all doses examined, and LY2817412 was effective at 30 mg/kg. Consistently, NOP receptor knockout mice consumed less alcohol compared to wild type. SB-612111 reduced DID and increased sucrose consumption at doses that do not appear to affect locomotor activity. However, the high dose of SB-612111 (30 mg/kg) reduced alcohol intake but failed to inhibit preference in a 2-bottle choice DID model that can assess moderate alcohol intake.
CONCLUSIONS
The present results suggest that NOP receptor inhibition rather than activation may represent a valuable approach for treatment of AUD characterized by excessive alcohol consumption such as binge drinking.
Identifiants
pubmed: 31386211
doi: 10.1111/acer.14165
pmc: PMC6779486
mid: NIHMS1044886
doi:
Substances chimiques
AT-312
0
Alcohol Deterrents
0
Central Nervous System Depressants
0
Cycloheptanes
0
Indoles
0
Narcotic Antagonists
0
Piperidines
0
Receptors, Opioid
0
cis-1-methyl-7-((4-(2,6-dichlorophenyl)piperidin-1-yl)methyl)-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol
0
Ethanol
3K9958V90M
Nociceptin Receptor
0
Oprl1 protein, mouse
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2167-2178Subventions
Organisme : NIAAA NIH HHS
ID : R01 AA014351
Pays : United States
Organisme : NIDA NIH HHS
ID : R01 DA023281
Pays : United States
Organisme : Polish Ministry of Science and Higher Education
ID : 1662/1/MOB/V/17/2018/0
Pays : International
Informations de copyright
© 2019 by the Research Society on Alcoholism.
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