Influence of the novel histamine H^sub 3^ receptor antagonist ST1283 on voluntary alcohol consumption and ethanol-induced place preference in mice

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 H^sub 3^ receptors (H^sub 3^R). In the present study, the effects of systemic injection of the newly synthesized H^sub 3^R antagonist ST1283 on ethanol (EtOH) voluntary intake and EtOH-conditioned reward in mice have been investigated. 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. Following administration of the H^sub 3^R 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 H^sub 3^R agonist R-(alpha)-methyl-histamine (10 mg/kg). Finally, vehicle- and ST1283-treated mice had similar BECs. 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 H^sub 3^R modulation in the pharmacotherapy of EtOH addiction.[PUBLICATION ABSTRACT]