When administered orally to rodents, dogs and monkeys, molindone induces phenothiazine-like behavioural changes. In mice (CFl males) and rats (CFE females), molindone suppresses spontaneous locomotion, blocks a conditioned avoidance response and antagonizes stereotyped behaviour induced by amphetamine. Although less potent than chlorpromazine in mice, molindone is approximately two to three times more potent in rats (Table 1). Table 1. RELATIVE POTENCIES OF MOLINDONE AND CHLORPROMAZINE INRODENT NEUROLEPTIC TESTS Relative potencyTest Species (95 per cent confidence limits) molindone/chlorpromazine Locomotor suppression Avoidance blockade f Amphetamine antagonism JMouse RatMouse RatMouse Rat0-23 (0-13-0-46) 2-97 (2-19-3-89) 0-17 (0-12-0-24) 1-78 (0-92-3-58) 0-31 (0-23-0-44)2-38 (1-90-2-98) Determined during a 30 min period using four mice or one rat/photocell unib.t Animals trained to avoid a shock by jumping to a ledge at the sound of a buzzer. J Intensity of sniffing, licking and biting estimated 1 h after subcutaneous injections into mice and rats of 12 and 6 mg/kg, respectively, of rf-amphet-amine sulphate.Molindone was administered orally 1 h and chlorpromazine 2 h before each determination. In mongrel dogs or beagles, 1-2 mg/kg of molindone causes a behavioural depression for about 3 h, characterized by decreased locomotion, miosis and reduced arousability. Higher doses intensify and prolong these effects and simultaneously induce such others as catalepsy, palpebral closure and, in some dogs, tremors or motor restlessness. In cats, the oral administration of 5-10 mg/kg is necessary to suppress motor activity and arousability and to cause miosis. Palpebral closure was rarely observed in cats, even at 20 mg/kg, but staring, vocalization and emesis occurred in more than half the animals tested. ID rhesus monkeys, 0-5-1 mg/kg of molindone curtails aggressiveness for 2-3 h. With increasing dosage, the degree and duration of docility are correspondingly increased but more gradually than after similar increments in the dosage of chlorpromazine.Molindone also affects other responses frequently used to identify neuroleptics4. For example, the emesis induced in dogs by intravenous injections of 0-1 mg/kg of apomor-phine hydrochloride is antagonized by molindone, orally administered at 0-5-1 mg/kg. Catalepsy and hypothermia can be demonstrated in rats and mice at oral doses of about 5-15 mg/kg. Finally, molindone inhibits the pressor responses of epinephrine and 5-hydroxytryptamine in anaesthetized dogs, but at intravenous doses which are about ten times higher than equiactive doses of chlorpromazine. Table 2. EFFECTS OF MOLINDONE IN RODENT ANTIDEPRESSANT TESTSTest Tetrabenazine antagonism 5-HTP potentiation /-DOPA potentiationJZ>60, mg/kg (95 per cent Species confidence limits)Mouse 2-5 (1-5-4-1) Rat 2-6 (1-4-4-9)Mouse 10-0 (7-1-14-0) Rat 20-0 (14-1-28-2)Mouse 12-0 (8-6-16-8) Rat 8-8 (4-6-16-7)Estimated by the method of Litchfield and Wilcoxon5. Molindone was administered, orally, 1 h before intraperitoneal injections of 5-HTP and /-DOPA and 5 h before tetrabenazine. In addition to these characteristic neuroleptic actions, molindone modifies certain responses in rodents which are similarly affected by antidepressant agents (Table 2). The ptosis induced by intraperitoneal injections of 40 mg/kg of tetrabenazine methanesulphonate in mice or 15 mg/kg in rats is antagonized by oral pretreatment with molindone. Using 50 per cent lid closure as the criterion for ptosis, peak activity was observed at 3-5 h in mice and 24 h in rats. Molindone also produces tremors when administered up to 6 h before subthreshold intraperitoneal injections of 50 mg/kg (mice) and 25 mg/kg (rats) of 5-hydroxytryptophan (5-HTP), peak effects occurring after 1-3 h pretreatment. Finally, molindone potentiates certain effects induced by intraperitoneal injections of 100 and 25 mg/kg of 3,4-dihydroxyphenyl-alanine (DOPA) into mice and rats, respectively. The criterion for DOPA potentiation in mice was the presence of two or more of the following symptoms: pupillary dilatation, exophthalmos, Straub tail, salivation and aggressiveness. In rats, pupillary dilatation alone was used as the criterion for potentiation because most of the symptoms mentioned occur sporadically after independent .administration of either molindone or DOPA.The effects of molindone summarized in Table 2 are similar to those induced by antidepressants of the dibenzo-azepine class (for example, desmethylimipramine6) as well as by inhibitors of monoamine oxidase (MAO)7. Molindone scarcely affects rat brain MAO activity in vitro, however (50 per cent inhibition at 9-8 x 103 molar), using kynuramine as a substrate in the assay system of Krajl8; nor does this agent substantially inhibit kynuramine oxidation by brain MAO after oral doses of 20 mg/kg in rats (maximal inhibition of 30 per cent over a period of 24 h). The possibility that molindone is converted into an active metabolite, in vivo, which then competitively reduces enzyme activity cannot be discounted. Yet when molindone is administered orally to rats 30 min after intraperitoneal injections of 50 mg/kg of SKF 525A, the usual potentiation of 5-HTP and DOPA is unaffected while inhibition of a conditioned avoidance response is enhanced and prolonged. Work is now in progress to measure concentrations of amines in rat brain after treatment with molindone and to attempt to clarify the apparent paradox concerning tetrabenazine antagonism and 5-HTP and DOPA potentiation, on one hand, and antagonism to the effects of amphetamine, on the other. Although the ultimate clinical disposition of this unusual psychopharmaco-logical agent has not been determined, a recent preliminary investigation has demonstrated its antipsychotic activity9.