Mechanism of action of antihistamines in laboratory antidepressant tests

Dose-response curves for the prevention of tetrabenazine-induced ptosis in mice by antihistamines such as dexchlorpheniramine, are shifted to the right in parallel fashion by raising the dose of tetrabenazine, whereas the dose-response curves for imipramine-like antidepressants are relatively unaffected. Another difference between dexchlorpheniramine and imipramine is that the antihistamine reverses α-methyl-tyrosine-induced ptosis whereas imipramine is ineffective. In both procedures, methamphetamine produces effects similar to dexchlorpheniramine, suggesting that dexchlorpheniramine has a central sympathomimetic effect. Additional evidence for this hypothesis is that dexchlorpheniramine-indueed lethality is enhanced by aggregation (ten mice per cage vs. five mice per cage) and that this aggregate lethality can be prevented by phenoxybenzamine but not by α-methyl-tyrosine. The central sympathomimetic effect of dexchlorpheniramine may be similar to the direct effect of methamphetamine, which has been demonstrated in the present studies by reversal of both tetrabenazine- and α-methyl-tyrosine-induced ptosis. The present studies have not ruled out the possibility that antihistamines such as dexchlorpheniramine can antagonize ptosis in part by inhibition of norepinephrine uptake.