title: Histamine H3 receptor antagonist decreases cue-induced alcohol reinstatement in mice.
abstract: We have earlier found that the histamine H3 receptor (H3R) antagonism diminishes motivational aspects of alcohol reinforcement in mice. Here we studied the role of H3Rs in cue-induced reinstatement of alcohol seeking in C57BL/6J mice using two different H3R antagonists. Systemic administration of H3R antagonists attenuated cue-induced alcohol seeking suggesting that H3R antagonists may reduce alcohol craving. To understand how alcohol affects dopamine and histamine release, a microdialysis study was performed on C57BL/6J mice and the levels of histamine, dopamine and dopamine metabolites were measured in the nucleus accumbens. Alcohol administration was combined with an H3R antagonist pretreatment to reveal whether modulation of H3R affects the effects of alcohol on neurotransmitter release. Alcohol significantly increased the release of dopamine in the nucleus accumbens but did not affect histamine release. Pretreatment with H3R antagonist ciproxifan did not modify the effect of alcohol on dopamine release. However, histamine release was markedly increased with ciproxifan. In conclusion, our findings demonstrate that H3R antagonism attenuates cue-induced reinstatement of alcohol seeking in mice. Alcohol alone does not affect histamine release in the nucleus accumbens but H3R antagonist instead increases histamine release significantly suggesting that the mechanism by which H3R antagonist inhibits alcohol seeking found in the present study and the decreased alcohol reinforcement, reward and consumption found earlier might include alterations in the histaminergic neurotransmission in the nucleus accumbens. These findings imply that selective antagonists of H3Rs could be a therapeutic strategy to prevent relapse and possibly diminish craving to alcohol use. This article is part of the Special Issue entitled 'Histamine Receptors'.
authors.affiliation: Department of Anatomy, University of Helsinki, Finland; Neuroscience Center, University of Helsinki, Finland; Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Finland.
authors.forename: Saara
authors.initials: S
authors.lastname: Nuutinen
authors.affiliation: Department of Anatomy, University of Helsinki, Finland; Neuroscience Center, University of Helsinki, Finland.
authors.forename: Tiia
authors.initials: T
authors.lastname: Mäki
authors.affiliation: Department of Anatomy, University of Helsinki, Finland; Neuroscience Center, University of Helsinki, Finland.
authors.forename: Stanislav
authors.initials: S
authors.lastname: Rozov
authors.affiliation: Department of Pharmacology, University of Helsinki, Finland.
authors.forename: Pia
authors.initials: P
authors.lastname: Bäckström
authors.affiliation: Department of Pharmacology, University of Helsinki, Finland.
authors.forename: Petri
authors.initials: P
authors.lastname: Hyytiä
authors.affiliation: Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Finland.
authors.forename: Petteri
authors.initials: P
authors.lastname: Piepponen
authors.affiliation: Department of Anatomy, University of Helsinki, Finland; Neuroscience Center, University of Helsinki, Finland. Electronic address: pertti.panula@helsinki.fi.
authors.forename: Pertti
authors.initials: P
authors.lastname: Panula
mesh_terms: D000427:Alcohol Deterrents / Q000494:pharmacology*; D000428:Alcohol Drinking / Q000188:drug therapy / Q000378:metabolism; D019973:Alcohol-Related Disorders / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D001381:Azepines / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D003463:Cues; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D058999:Drug-Seeking Behavior / Q000187:drug effects* / Q000502:physiology; D005108:Extinction, Psychological / Q000187:drug effects / Q000502:physiology; D006632:Histamine / Q000378:metabolism; D054828:Histamine H3 Antagonists / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D008810:Mice, Inbred C57BL; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D018100:Receptors, Histamine H3 / Q000378:metabolism; D012646:Self Administration
chemical_list: C559587:(4-cyclobutyl-(1,4)diazepan-1-yl)-(6-(4-fluorophenoxy)pyridin-3-yl)methanone; D000427:Alcohol Deterrents; D001381:Azepines; D054828:Histamine H3 Antagonists; D007093:Imidazoles; D011725:Pyridines; D018100:Receptors, Histamine H3; C115705:ciproxifan; D006632:Histamine; D004298:Dopamine
keywords: Addiction; Alcohol; Cue-induced reinstatement; H3 receptor; Histamine; Microdialysis; Operant self-administration; Reward