TRIMIPRAMINE - PHARMACOLOGICAL REEVALUATION AND COMPARISON WITH CLOZAPINE

Trimipramine has been reported to differ from other typical tricyclic antidepressant drugs in several aspects, for instance it does not inhibit neuronal transmitter uptake and does not cause down-regulation of beta-adrenoceptors. Moreover, it may possess antipsychotic activity in schizophrenic patients. In the present investigation it was found that trimipramine did not alter the electrically-induced release of [H-3]noradrenaline and [H-3]5-hydroxytryptamine, from slices of the cerebral cortex of the rat, in concentrations of less than 1-mu-M. It did not antagonize the inhibitory effect of noradrenaline and 5-hydroxytryptamine on the release of transmitter, mediated by presynaptic autoreceptors. In radioligand binding studies, D,L-trimipramine showed fairly high affinities (K(I) 10-60 nM) for some dopamine (DA), noradrenaline and 5-hydroxytryptamine (5-HT) receptor subtypes (5-HT2 receptors = alpha-1A/B-adrenoceptors greater-than-or-equal-to D2 receptors), intermediate affinities (300-550 nM) for D1 receptors, alpha-2B-adrenoceptors and 5-HT1C receptors but only low affinities (> 1000 nM) for alpha-2A-adrenoceptors, 5-HT1A, 5-HT1D and 5-HT3 receptors. It may thus be classified as an atypical neuroleptic drug. Especially, its affinities for dopamine receptors, alpha-1-adrenoceptors and 5-HT2 receptors closely resembled the values measured for clozapine. The L-enantiomer of trimipramine showed higher affinities for these binding sites than D-trimipramine. The present findings may explain the mechanism of the potential antipsychotic action but not the antidepressant effect of trimipramine.