title: Differential effects of ghrelin antagonists on alcohol drinking and reinforcement in mouse and rat models of alcohol dependence.
abstract: An effort has been mounted to understand the mechanisms of alcohol dependence in a way that may allow for greater efficacy in treatment. It has long been suggested that drugs of abuse seize fundamental reward pathways and disrupt homeostasis to produce compulsive drug seeking behaviors. Ghrelin, an endogenous hormone that affects hunger state and release of growth hormone, has been shown to increase alcohol intake following administration, while antagonists decrease intake. Using rodent models of dependence, the current study examined the effects of two ghrelin receptor antagonists, [DLys3]-GHRP-6 (DLys) and JMV2959, on dependence-induced alcohol self-administration. In two experiments adult male C57BL/6J mice and Wistar rats were made dependent via intermittent ethanol vapor exposure. In another experiment, adult male C57BL/6J mice were made dependent using the intragastric alcohol consumption (IGAC) procedure. Ghrelin receptor antagonists were given prior to voluntary ethanol drinking. Ghrelin antagonists reduced ethanol intake, preference, and operant self-administration of ethanol and sucrose across these models, but did not decrease food consumption in mice. In experiments 1 and 2, voluntary drinking was reduced by ghrelin receptor antagonists, however this reduction did not persist across days. Despite the transient effects of ghrelin antagonists, the drugs had renewed effectiveness following a break in administration as seen in experiment 1. The results show the ghrelin system as a potential target for studies of alcohol abuse. Further research is needed to determine the central mechanisms of these drugs and their influence on addiction in order to design effective pharmacotherapies.
authors.affiliation: Oregon Health & Science University, Department of Behavioral Neuroscience and Portland Alcohol Research Center, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA. Electronic address: GomezJ@ohsu.edu.
authors.forename: Juan L
authors.initials: JL
authors.lastname: Gomez
authors.affiliation: Oregon Health & Science University, Department of Behavioral Neuroscience and Portland Alcohol Research Center, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Cunningham
authors.affiliation: Oregon Health & Science University, Department of Behavioral Neuroscience and Portland Alcohol Research Center, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA; Portland VA Healthcare System, Department of Research, 3710 SW US Veterans Hospital Road, Portland, OR 97239, USA.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Finn
authors.affiliation: Oregon Health & Science University, Department of Behavioral Neuroscience and Portland Alcohol Research Center, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
authors.forename: Emily A
authors.initials: EA
authors.lastname: Young
authors.affiliation: Oregon Health & Science University, Department of Behavioral Neuroscience and Portland Alcohol Research Center, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
authors.forename: Lily K
authors.initials: LK
authors.lastname: Helpenstell
authors.affiliation: Oregon Health & Science University, Department of Behavioral Neuroscience and Portland Alcohol Research Center, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
authors.forename: Lindsey M
authors.initials: LM
authors.lastname: Schuette
authors.affiliation: Oregon Health & Science University, Department of Behavioral Neuroscience and Portland Alcohol Research Center, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
authors.forename: Tara L
authors.initials: TL
authors.lastname: Fidler
authors.affiliation: Baylor College of Medicine, Menninger Department of Psychiatry & Behavioral Sciences, Michael E Debakey VAMC, 2002 Holcombe Blvd, Houston, TX 77030, USA.
authors.forename: Therese A
authors.initials: TA
authors.lastname: Kosten
authors.affiliation: Oregon Health & Science University, Department of Behavioral Neuroscience and Portland Alcohol Research Center, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
authors.forename: Andrey E
authors.initials: AE
authors.lastname: Ryabinin
mesh_terms: D000428:Alcohol Drinking / Q000188:drug therapy* / Q000378:metabolism; D000437:Alcoholism / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D002491:Central Nervous System Agents / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000008:administration & dosage; D005518:Food Preferences / Q000187:drug effects / Q000502:physiology; D054439:Ghrelin / Q000378:metabolism*; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D008810:Mice, Inbred C57BL; D011897:Random Allocation; D017208:Rats, Wistar; D054440:Receptors, Ghrelin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012054:Reinforcement, Psychology; D012646:Self Administration; D014230:Triazoles / Q000494:pharmacology
chemical_list: D002491:Central Nervous System Agents; D054439:Ghrelin; C569751:N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-aminoacetamide; D054440:Receptors, Ghrelin; D014230:Triazoles; D000431:Ethanol; D005998:Glycine
keywords: Ethanol vapor; Ghrelin; Intragastric infusions; Self-administration; Two-bottle choice