Influence of the novel histamine H₃ receptor antagonist ST1283 on voluntary alcohol consumption and ethanol-induced place preference in mice

Rationale: Growing evidence supports a role for the central histaminergic system to have a modulatory influence on drug addiction in general and alcohol-use disorders in particular through histamine H₃ receptors (H₃R). Objective: In the present study, the effects of systemic injection of the newly synthesized H₃R antagonist ST1283 on ethanol (EtOH) voluntary intake and EtOH-conditioned reward in mice have been investigated. Methods: Oral EtOH, saccharin, and quinine intake was assessed in a two-bottle choice paradigm using escalating concentrations of alcohol or tastant solutions. EtOH-induced place preference (CPP), EtOH-induced locomotor activity, and blood ethanol concentration (BEC) were also measured. Results: Following administration of the H₃R antagonist (2.5, 5, and 10 mg/kg, i.p.), there was a significant dose-dependent decrease in alcohol consumption and preference. Importantly, vehicle- and ST1283 (5 mg/kg)-treated mice showed similar consumption and preference to increasing concentration of both sweet and bitter tastes. More interestingly, systemic administration of ST1283 inhibited EtOH-CPP and EtOH-enhanced locomotion. This inhibition was blocked when mice were pretreated with the selective H₃R agonist R-(alpha)-methyl- histamine (10 mg/kg). Finally, vehicle- and ST1283-treated mice had similar BECs. Conclusion: Our results show that ST1283 may decrease voluntary EtOH consumption and EtOH-CPP by altering its reinforcing effects, suggesting a novel role for histamine signaling in regulation of alcoholism. Lastly, the results add to the growing literature on H₃R modulation in the pharmacotherapy of EtOH addiction.