Evidence for the Role of Histamine H3 Receptor in Alcohol Consumption and Alcohol Reward in Mice

Abstract

Recent research suggests that histamine H3 receptor (H3R) antagonism may diminish motivational aspects of alcohol dependence. We studied the role of H3Rs in alcohol-related behaviors using H3R knockout (KO) mice and ligands. H3R KO mice consumed less alcohol than wild-type (WT) mice in a two-bottle free-choice test and in a 'drinking in the dark' model. H3R antagonist ciproxifan suppressed and H3R agonist immepip increased alcohol drinking in C57BL/6J mice. Impairment in reward mechanisms in H3R KO mice was confirmed by the lack of alcohol-evoked conditioned place preference. Plasma alcohol concentrations of H3R KO and WT mice were similar. There were no marked differences in brain biogenic amine levels in H3R KO mice compared with the control animals after alcohol drinking. In conclusion, the findings of this study provide evidence for the role of H3R receptor in alcohol-related behaviors, especially in alcohol drinking and alcohol reward. Thus, targeting H3Rs with a specific antagonist might be a potential means to treat alcoholism in the future.

Histamine H3 Receptor Regulates Sensorimotor Gating and Dopaminergic Signaling in the Striatum

“…All these findings together with our previous findings in addictive behaviors (Nuutinen et al, 2010(Nuutinen et al, , 2011aVanhanen et al, 2013Vanhanen et al, , 2015 indicate that histaminergic and dopaminergic systems are in close connection, mainly via receptor-level interaction of H3R with D1R and D2R in the striatum. These findings indicate that targeting H3R could offer treatment options for neuropsychiatric diseases where sensorimotor gating is disturbed and dopaminergic and/or glutamatergic neurotransmission is altered, such as GTS, motor function disorders, and alcoholism.…”

Histamine H3 receptor antagonist decreases cue-induced alcohol reinstatement in mice

“…We and others have shown previously that H3R antagonists inhibit alcohol drinking and alcohol-induced conditioned place preference (Galici et al, 2011;Nuutinen et al, 2011aNuutinen et al, , 2011b suggesting that antagonism of H3R could be a novel means to treat alcohol dependence. The reinstatement paradigm used operant alcohol administration in mice in a manner that to our knowledge has not been reported earlier.…”

“…However, C57BL/6 J mice have a genetically determined high preference for alcohol-containing solutions (Bachmanov et al, 2002;Crabbe et al, 2005) and are therefore widely used in other alcohol and reward-related studies. Although it is clear that H3R antagonists reduce alcohol drinking and place preference (Galici et al, 2011;Lintunen et al, 2001;Nuutinen et al, 2011aNuutinen et al, , 2011b, it is not known whether H3R antagonists are able to prevent alcohol seeking in animal models of relapse. Ciproxifan is an imidazole-based H3R antagonist widely used in behavioral studies.…”

“…Mice lacking histamine (histidine decarboxylase knock-out) display stronger alcohol-induced conditioned place preference (alcohol-CPP) than control animals (Nuutinen et al, 2010) further supporting the inhibitory role of histamine in reward. Also, the H3R knockout mice consume less alcohol in two different drinking paradigms and show a complete lack of alcohol-induced conditioned place preference (Nuutinen et al, 2011a). The H3R antagonist ciproxifan suppressed and the H3R agonist immepip increased alcohol drinking in C57BL/6 J mice (Nuutinen et al 2011b).…”

“…Manipulation of the brain histaminergic system via histamine H3 receptor (H3R) affects alcohol reward and abuse-related behaviors (Galici et al, 2011;Nuutinen et al, 2011aNuutinen et al, , 2011b. Brain histamine is elevated in an alcoholpreferring (AA) rat line compared with the alcohol non-preferring (ANA) line and they express lower levels of H3R binding (Lintunen et al, 2001).…”