title: Histamine is required for H₃ receptor-mediated alcohol reward inhibition, but not for alcohol consumption or stimulation.
abstract: OBJECTIVE
  Conflicting data have been published on whether histamine is inhibitory to the rewarding effects of abused drugs. The purpose of this study was to clarify the role of neuronal histamine and, in particular, H₃ receptors in alcohol dependence-related behaviours, which represent the addictive effects of alcohol.
  
  
  METHODS
  Alcohol-induced conditioned place preference (alcohol-CPP) was used to measure alcohol reward. Alcohol-induced locomotor stimulation, alcohol consumption and kinetics were also assessed. mRNA levels were quantified using radioactive in situ hybridization.
  
  
  RESULTS
  Low doses of H₃ receptor antagonists, JNJ-10181457 and JNJ-39220675, inhibited alcohol reward in wild-type (WT) mice. However, these H₃ receptor antagonists did not inhibit alcohol reward in histidine decarboxylase knock-out (HDC KO) mice and a lack of histamine did not alter alcohol consumption. Thus H₃ receptor antagonists inhibited alcohol reward in a histamine-dependent manner. Furthermore, WT and HDC KO mice were similarly stimulated by alcohol. The expression levels of dopamine D₁ and D₂ receptors, STEP61 and DARPP-32 mRNA in striatal subregions were unaltered in HDC KO mice. No differences were seen in alcohol kinetics in HDC KO compared to WT control animals. In addition, JNJ-39220675 had no effect on alcohol kinetics in WT mice.
  
  
  CONCLUSIONS
  These data suggest that histamine is required for the H₃ receptor-mediated inhibition of alcohol-CPP and support the hypothesis that the brain histaminergic system has an inhibitory role in alcohol reward. Increasing neuronal histamine release via H₃ receptor blockade could therefore be a novel way of treating alcohol dependence.
authors.affiliation: Neuroscience Center and Institute of Biomedicine, University of Helsinki, Finland.
authors.forename: J
authors.initials: J
authors.lastname: Vanhanen
authors.forename: S
authors.initials: S
authors.lastname: Nuutinen
authors.forename: M
authors.initials: M
authors.lastname: Lintunen
authors.forename: T
authors.initials: T
authors.lastname: Mäki
authors.forename: J
authors.initials: J
authors.lastname: Rämö
authors.forename: K
authors.initials: K
authors.lastname: Karlstedt
authors.forename: P
authors.initials: P
authors.lastname: Panula
mesh_terms: D000428:Alcohol Drinking / Q000378:metabolism; D000818:Animals; D001381:Azepines / Q000008:administration & dosage / Q000494:pharmacology; D003213:Conditioning, Psychological / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D006632:Histamine / Q000378:metabolism*; D054828:Histamine H3 Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D006636:Histamine Release / Q000502:physiology; D006640:Histidine Decarboxylase / Q000235:genetics*; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000378:metabolism; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D018100:Receptors, Histamine H3 / Q000187:drug effects / Q000378:metabolism*; D012201:Reward
chemical_list: C559587:(4-cyclobutyl-(1,4)diazepan-1-yl)-(6-(4-fluorophenoxy)pyridin-3-yl)methanone; C515396:4-(3-(4-piperidin-1-ylbut-1-ynyl)benzyl)morpholine; D001381:Azepines; D054828:Histamine H3 Antagonists; D009025:Morpholines; D010880:Piperidines; D011725:Pyridines; D012333:RNA, Messenger; D018100:Receptors, Histamine H3; D000431:Ethanol; D006632:Histamine; D006640:Histidine Decarboxylase
keywords: H3 receptor antagonist; alcohol; dopamine; histamine; reward