Effect of nomifensine (Hoe 984), a new antidepressant, on uptake of noradrenaline and serotonin and on release of noradrenaline in rat brain synaptosomes

Abstract

Nomifensine (8-amino-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline hydrogen maleate) is a thymoleptic drug with a moderate centrally stimulating component. Its effects on noradrenaline (NA) and serotonin (5-HT) uptake by crude synaptosome preparations from both whole rat brain and from hypothalamus have been studied and compared with those of several tricyclic antidepressants and d-amphetamine. Nomifensine inhibition of NA uptake by synaptosomal fractions from rat hypothalamus (IC 50 = 7.0 × 10 −7 M) was similar to that of nortriptyline and protriptyline. In contrast to tricyclic antidepressants, nomifensine was found to be a powerful inhibitor of NA uptake in synaptosomes obtained from whole brain (IC 50 = 9.0 × 10 −8 M). Nomifensine had only a moderate effect on 5-HT accumulation (IC 50 = 2.8 × 10 −5 M), comparable with that of desipramine. The inhibition of uptake of both NA and 5-HT by nomifensine was of a competitive type. It is suggested that the centrally stimulating component of nomifensine, which is lacking in most thymoleptic drugs, is based upon its strong inhibition of catecholamine re-uptake into noradrenergic as well as dopaminergic nerve endings. Nomifensine has no releasing effects on the efflux of NA from rat brain synaptosomes, thus differing clearly from d-amphetamine and other indirectly acting sympathicomimetic agents.