Psychopharmacological investigation of the monoamine oxidase inhibitory activity of molindone, a dihydroindolone neuroleptic.
24 h pretreatment with molindone enhanced the behavioural effects of L-dopa and 5-HTP, precursors of biogenic amines (catecholamines and 5-HT respectively) preferentially deaminated by MAO-A, confirming that a metabolite of molindone inhibits MAO-A. 24 h pretreatment with molindone enhanced the behavioural effects of tryptamine and antagonized reserpine-induced ptosis, and in molindone-pretreated rats L-tryptophan induced behavioural 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 behavioural syndromes, it suggests that molindone and/or its metabolites most probably do not exert 5-HT neuronal uptake blocking activity and the potentiation of 5-HTP-induced behavioural syndrome is due to a metabolite's MAO-A inhibitory activity. As 2 h pretreatment with molindone induced catalepsy and antagonized apomorphine-induced climbing behaviour in mice and stereotypy in rats, while 24 h pretreatment failed to induce catalepsy and to antagonize apomorphine-induced behaviour, 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. Further, since 2 h pretreatment with molindone failed to enhance the behavioural effects of L-dopa, it suggests that at 2 h the degree of MAO-A inhibition induced by molindone and/or the metabolite is not sufficient to counteract the neuroleptic activity of the parent compound.
D006916:5-Hydroxytryptophan / Q000494:pharmacology; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects*; D001763:Blepharoptosis / Q000139:chemically induced; D002375:Catalepsy / Q000139:chemically induced; D010134:Fenclonine / Q000494:pharmacology; D005277:Fenfluramine / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D007980:Levodopa / Q000494:pharmacology; D008297:Male; D051379:Mice; D008972:Molindone / Q000494:pharmacology*; D008996:Monoamine Oxidase Inhibitors; D051381:Rats; D012110:Reserpine / Q000494:pharmacology; D013239:Stereotyped Behavior / Q000187:drug effects; D014363:Tryptamines / Q000494:pharmacology; D014364:Tryptophan / Q000494:pharmacology; D010133:p-Chloroamphetamine / Q000494:pharmacology
D007211:Indoles; D008996:Monoamine Oxidase Inhibitors; D014363:Tryptamines; D005277:Fenfluramine; D007980:Levodopa; D010133:p-Chloroamphetamine; D012110:Reserpine; D014364:Tryptophan; D006916:5-Hydroxytryptophan; D001058:Apomorphine; D010134:Fenclonine; D008972:Molindone