Mouse light/dark box test reveals anxiogenic-like effects by activation of histamine H 1 receptors

Abstract

Effects of substances that are able to alter the histamine level, a histamine H 1-receptor agonist and antagonist, and a histamine H 2-receptor agonist were investigated in an anxiety-like state in mice by means of the light/dark box test. Diazepam was used as positive control. The histamine H 3-receptor antagonist, thioperamide (2, 5, and 20 mg/kg sc), showed an anxiogenic-like effect that reached a maximum with the dosage of 5 mg/kg. The histamine- N-methyltransferase (HMT) inhibitor, metoprine (5 and 20 mg/kg sc), also decreased the time in the light at the highest dose used and, likewise, the highly selective histamine H 1-receptor agonist, 2-(3-trifluoromethylphenyl)histamine (FMPH) (2.65 and 6.5 μg/mouse, icv). On the contrary, the histamine H 2-receptor agonist, impromidine (3, 10, 20, and 30 μg/mouse, icv), dose-dependently showed an anxiolytic-like effect. The selective histamine H 1 antagonist, pyrilamine (20 mg/kg ip) was able to prevent the anxiogenic-like effect of FMPH significantly, and that of thioperamide partially, while the effect caused by metoprine remained unvaried. It is suggested that the histaminergic system modulates anxiety-like states via the activation of both postsynaptic receptors in a contrasting manner: activation of the H 1 receptor causes an anxiogenic-like effect, while that of the H 2 receptors reduces anxiousness. However, on the basis of effects observed with the substances capable of releasing endogenous histamine, it seems likely that the anxiogenic-like effect is prevalent.