title: The novel, selective, brain-penetrant neuropeptide Y Y2 receptor antagonist, JNJ-31020028, tested in animal models of alcohol consumption, relapse, and anxiety.
abstract: Neuropeptide Y (NPY) signaling has been shown to modulate stress responses and to be involved in regulation of alcohol intake and dependence. The present study explores the possibility that blockade of NPY Y2 autoreceptors using a novel, blood-brain barrier penetrant NPY Y2 receptor antagonist, JNJ-31020028 (N-(4-{4-[2-(diethylamino)-2-oxo-1-phenylethyl]piperazin-1-yl}-3-fluorophenyl)-2-pyridin-3-ylbenzamide), may achieve a therapeutically useful activation of the NPY system in alcohol- and anxiety-related behavioral models. We examined JNJ-31020028 in operant alcohol self-administration, stress-induced reinstatement to alcohol seeking, and acute alcohol withdrawal (hangover)-induced anxiety. Furthermore, we tested its effects on voluntary alcohol consumption in a genetic animal model of alcohol preference, the alcohol-preferring (P) rat. Neither systemic (0, 15, 30, and 40 mg/kg, subcutaneously [s.c.]) nor intracerebroventricular (0.0, 0.3, and 1.0 nmol/rat) administration of JNJ-31020028 affected alcohol-reinforced lever pressing or relapse to alcohol seeking behavior following stress exposure. Also, when its effects were tested on unlimited access to alcohol in P rats, preference for alcohol solution was transiently suppressed but without affecting voluntary alcohol intake. JNJ-31020028 (15 mg/kg, s.c.) did reverse the anxiogenic effects of withdrawal from a single bolus dose of alcohol on the elevated plus-maze, confirming the anxiolytic-like properties of NPY Y2 antagonism. Our data do not support Y2 antagonism as a mechanism for reducing alcohol consumption or relapse-like behavior, but the observed effects on withdrawal-induced anxiety suggest that NPY Y2 receptor antagonists may be a putative treatment for the negative affective states following alcohol withdrawal.
authors.affiliation: Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA. cippitellia@mail.nih.gov
authors.forename: Andrea
authors.initials: A
authors.lastname: Cippitelli
authors.forename: Amir H
authors.initials: AH
authors.lastname: Rezvani
authors.forename: J Elliott
authors.initials: JE
authors.lastname: Robinson
authors.forename: Lindsay
authors.initials: L
authors.lastname: Eisenberg
authors.forename: Edward D
authors.initials: ED
authors.lastname: Levin
authors.forename: Pascal
authors.initials: P
authors.lastname: Bonaventure
authors.forename: S Timothy
authors.initials: ST
authors.lastname: Motley
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Lovenberg
authors.forename: Markus
authors.initials: M
authors.lastname: Heilig
authors.forename: Annika
authors.initials: A
authors.lastname: Thorsell
mesh_terms: D000428:Alcohol Drinking / Q000188:drug therapy*; D000437:Alcoholism / Q000188:drug therapy; D000818:Animals; D001008:Anxiety Disorders / Q000139:chemically induced / Q000188:drug therapy; D001549:Benzamides / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects; D000431:Ethanol / Q000009:adverse effects; D007276:Injections, Intraventricular; D023421:Models, Animal; D009478:Neuropeptide Y / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors*; D012008:Recurrence; D012054:Reinforcement, Psychology; D012646:Self Administration; D013375:Substance Withdrawal Syndrome
chemical_list: D001549:Benzamides; C547250:JNJ-31020028; D009478:Neuropeptide Y; D010879:Piperazines; D017476:Receptors, Neuropeptide Y; C095889:neuropeptide Y2 receptor; D000431:Ethanol