Central histaminergic transmission modulates the ethanol induced anxiolysis in mice

•Biphasic role of endogenous histamine in the ethanol induced anxiolysis is proposed.•Low dose of histamine attenuates while high dose enhances the ethanol induced anxiolysis.•Histamine H1 receptor stimulation counteracts the ethanol induced anxiolysis.•Histamine H2 receptor stimulation potentiates the ethanol induced anxiolysis. Intrigued by the report demonstrating an increase in brain histamine levels by ethanol administration and central histamine transmission to affect the anxiety related behaviors, the present study examined the permissive role of central histaminergic transmission in the acute anxiolytic-like effect of the ethanol on elevated plus maze (EPM) in mice. Results demonstrated that prior administration of the agents that are known to enhance the brain histamine transmission, i.e. low dose of histamine (0.1μg/mouse, i.c.v.) or histamine precursor, l-histidine (500, 1000mg/kg, i.p.) or low dose of histamine releasing agent (H3 receptor inverse agonist), thioperamide (2μg/mouse) attenuated the acute anitanxiety-like effect of ethanol (2g/kg, i.p, 8% w/v) in mice on EPM. However, pre-treatment with the H1 receptor antagonist, cetirizine (0.1μg/mouse, i.c.v.) or H2 receptor antagonist, ranitidine (50μg/mouse, i.c.v.) failed to affect the attenuating effect of low dose of histamine on ethanol induced anxiolysis. On the other hand, only H1 receptor antagonist, cetirizine (0.1μg/mouse, i.c.v.) was able to partially reverse the attenuation of ethanol induced anxiolysis by l-histidine (1000mg/kg, i.p.). Surprisingly, in mice pre-treated with the higher dose of histamine (50μg/mouse, i.c.v.) or thioperamide (10μg/mouse, i.c.v.), the ethanol (2g/kg, i.p.) induced antianxiety-like effect was further enhanced on EPM. Furthermore, this potentiating effect of high dose of histamine on the ethanol (2g/kg, i.p.) was exacerbated on pre-treatment with the H1 receptor antagonist, cetirizine, while H2 receptor antagonist, ranitidine completely reversed this action of high dose of histamine on ethanol. Supportive to these results, i.c.v. pre-treatment with H1 receptor agonist, FMPH (2, 6.5μg/mouse, i.c.v.) attenuated while H2 receptor agonist, amthamine (0.1, 0.5μg/mouse, i.c.v.) enhanced the ethanol induced anxiolysis in mice. Thus, it is reasonable to contemplate that central histaminergic transmission functions to negatively modulate the acute ethanol-induced anxiolysis probably via stimulation of postsynaptic H1 receptor and histamine might contribute to th