Adrenergic nonspecific potentiation of yohimbine toxicity in mice by antidepressants and related drugs and antiyohimbine action of antiadrenergic and serotonergic drugs.

Thirteen imipramine-like antidepressants and three anticholinergics potentiated yohimbine toxicity in mice. The strongest potentiation was observed after the nonantidepressant adrenergic compound AW 151129. Monomethyl derivatives were significantly stronger than their parent dimethyl compounds. Quaternary imipramine and amitriptyline, amphetamine, and inhibitors of monoamine oxidase were inactive. Pretreatment with an inhibitor of tyrosine hydroxylase (alpha-methyl-p-tyrosine) or the beta-adrenergic-blocking drug pindolol diminished lethality in mice treated with a combination of desmethylimipramine (AW 151129) and yohimbine. The inhibitor of brain serotonin synthesis p-chlorophenylalanine and a depletor of serotonin and catecholamine synthesis reserpine, enhanced yohimbine toxicity whereas serotonin and its precursors tryptophan and 5-hydroxytryptophan prolonged survival time. Thus, a test of yohimbine potentiation toxicity in mice reveals an adrenergic component of pharmacological activity of antidepressants. The predictive value of this test is limited similarly to antihypothermic tests of antagonism to reserpine and the related drugs apomorphine and 5-hydroxytryptophan.