Histamine is required for H3 receptor mediated alcohol reward inhibition, but not for alcohol consumption or stimulation.

BACKGROUND AND PURPOSE: Histamine and especially H3R regulate drug dependence related behaviors. Conflicting data has 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 histamine in the addictive effects of alcohol. EXPERIMENTAL APPROACH: 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. KEY RESULTS: Low doses of H3R antagonists (JNJ-10181457 and JNJ-39220675) inhibited alcohol reward in WT mice. However, H3R antagonists did not inhibit alcohol reward in HDC KO mice and lack of histamine did not alter alcohol consumption. H3R antagonists thus inhibit alcohol reward in a histamine dependent manner. Furthermore, WT and HDC KO mice were similarly stimulated by alcohol. Dopamine D1 and D2 receptors, STEP61 and DARPP-32 mRNA expression levels in striatal subregions were unaltered in HDC KO mice. No differences were seen in alcohol kinetics in HDC KO versus WT control animals. In addition, JNJ-39220675 had no effect on alcohol kinetics in WT mice. CONCLUSIONS AND IMPLICATIONS: These data suggest that histamine is required in the H3R-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 H3R blockade could therefore be a novel means to treat alcohol dependence. © 2013 The Authors. British Journal of Pharmacology © 2013 The British Pharmacological Society.