The novel non-imidazole histamine H₃ receptor antagonist DL77 reduces voluntary alcohol intake and ethanol-induced conditioned place preference in mice

It has become clear that histamine H₃ receptors (H₃R) have been implicated in modulating ethanol intake and preference in laboratory animals. The novel non-imidazole H₃R antagonist DL77 with excellent selectivity profile shows high in-vivo potency as well as in-vitro antagonist affinity with ED₅₀ of 2.1±0.2mg/kg and pK_i=8.08, respectively. In the present study, and applying an unlimited access two-bottle choice procedure, the anti-alcohol effects of the H₃R antagonist, DL77 (0, 3, 10 and 30mg/kg; i.p.), were investigated in adult mice. In this C57BL/6 line, effects of DL77 on voluntary alcohol intake and preference, as well as on total fluid intake were evaluated. Results have shown that DL77, dose-dependently, reduced both ethanol intake and preference. These effects were very selective as both saccharin and quinine, used to control for taste sensitivity, and intakes were not affected following DL77 pre-application. More importantly, systemic administration of DL77 (10mg/kg) during acquisition inhibited ethanol-induced conditioned-place preference (EtOH-CPP) as measured using an unbiased protocol. The anti-alcohol activity observed for DL77 was abrogated when mice were pretreated with the selective H₃R agonist R-(α)-methyl-histamine (RAMH) (10mg/kg), or with the CNS penetrant H₁R antagonist pyrilamine (PYR) (10mg/kg). These results suggest that DL77 has a predominant role in two in vivo effects of ethanol. Therefore, signaling via H₃R is essential for ethanol-related consumption and conditioned reward and may represent a novel therapeutic pharmacological target to tackle ethanol abuse and alcoholism.