Histamine and H3 receptor-dependent mechanisms regulate ethanol stimulation and conditioned place preference in mice

Neuronal histamine has a prominent role in sleep-wake control and body homeostasis, but a number of studies suggest that histamine has also a role in higher brain functions including drug reward. The present experiments characterized the involvement of histamine and its H3 receptor in ethanol-related behaviors in mice. Male histidine decarboxylase knockout (HDC KO) and control mice were used to study the role of histamine in ethanol-induced stimulation of locomotor activity, impairment of motor coordination, and conditioned place preference (CPP). Male C57BL/6Sca mice were used to study the effects of H3 receptor antagonist in the effects of ethanol on locomotor activity. The HDC KO mice displayed a weaker stimulatory response to acute ethanol than the wild-type (WT) mice. No differences between genotypes were found after ethanol administration on accelerating rotarod. The HDC KO mice showed stronger ethanol-induced CPP than the WT mice. Binding of the GABA(A) receptor ligand [H-3]Ro15-4513 was not markedly changed in HDC KO mouse brain and thus could not explain altered responses in KO mice. Ethanol increased the activity of C57BL/6Sca mice, and H3 receptor antagonist ciproxifan inhibited this stimulation. In CPP paradigm ciproxifan, an H3 receptor inverse agonist potentiated ethanol reward. Histaminergic neurotransmission seems to be necessary for the stimulatory effect of ethanol to occur, whereas lack of histamine leads to changes that enhance the conditioned reward by ethanol. Our findings also suggest a role for histamine H3 receptor in modulation of the ethanol stimulation and reward.