Psychopharmacological investigation of the monoamine oxidase inhibitory activity of molindone, a dihydroindolone neuroleptic
Balsara, J.J.; Gada, V.P.; Nandal, N.V.; Chandorkar, A.G.
Journal of Pharmacy and Pharmacology 36(9): 608-613
1984
ISSN/ISBN: 0022-3573 PMID: 6149285 Document Number: 230948
Pretreatment (24 h) with molindone enhanced the behavioral effects of L-dopa and 5-HTP [5-hydroxytryptophan], precursors of biogenic amines (catecholamines and 5-HT, respectively) preferentially deaminated by MAO-A [monoamine oxidase-A], confirming that a metabolite of molindone inhibits MAO-A. Pretreatment (24 h) with molindone enhanced the behavioral effects of tryptamine and antagonized reserpine-induced ptosis, and in molindone-pretreated rats L-Trp induced behavioral effects, probably because of the MAO-A inhibitory activity exerted by a metabolite of molindone. Since 24 h pretreatment with molindone, unlike 30 min pretreatment with clomipramine, failed to antagonize fenfluramine and p-chloramphetamine-induced behavioral syndromes, it suggests that molindone and/or its metabolites most probably do not exert 5-HT neuronal uptake blocking activity and the potential of 5-HTP-induced behavioral syndrome is due to a metabolite's MAO-A inhibitory activity. As 2 h pretreatment with molindone induced catalepsy and antagonized apomorphine-induced climbing behavior in mice and stereotypy in rats, while 24 h pretreatment failed to induce catalepsy and to antagonize apomorphine-induced behavior, it appears that, at 24 h, the tissue levels of molindone are inadequate to block postsynaptic striatal and mesolimbic DA receptors and that, though a metabolite of molindone is biologically active so far as inhibition of MAO-A is concerned, the metabolites are devoid of neuroleptic activity. Since 2 h pretreatment with molindone failed to enhance the behavioral effects of L-dopa, at 2 h the degree of MAO-A inhibition induced by molindone and/or the metabolite is apparently not sufficient to counteract the neuroleptic activity of the parent compound.