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The behavioral effects of lopramine [N-methyl-N-(4-chlorobenzoyl-methyl)-3-(10, 11-dihydro-5H-dibenz (b,f) azepin-5-yl) propylamine hydrochloride] were investigated in mice and rats and compared with those of amitriptyline and imipramine. Lopramine inhibited reserpine hypothermia and haloperidol catalepsy in mice and tetrabenazine ptosis in rats. In addition the drug potentiated the effects of methamphetamine, and DOPA- or apomorphine-induced stereotypy in mice, whereas it suppressed muricide of the rat induced by either olfactory bulbectomy or delta9-tetrahydrocannabinol, similar to the responses seen with imipramine and amitriptyline. On the other hand,lopramine increased spontaneous motor activity and markedly potentiated methamphetamine hyperactivity. In contrast to imipramine and amitriptyline, lopramine failed to counteract both the lethal effect of physostigmine and oxotremorine tremor in mice, indicating that the drug had no central anticholinergic effect. Lopramine, even at such a large dose as 5,000 mg/kg p.o., caused neitherimpairment of coordinated motor activity nor muscle relaxation. It is concluded that lopramine is a new type of tricyclic antidepressant with extremely low toxicity and without central anticholinergic action.

Behavioral effects of amantadine, especially on abnormal behavior in mice and rats, were reevaluated, in comparison with those of tricyclic antidepressants, methamphetamine and L-DOPA. 1) Amantadine at 10 approximately 50 mg/kg, i.p., tended to decrease ambulation and rearing in rats and mice. The drug at 50 mg/kg, i.p., caused piloerection and hyperirritability and at doses over 80 mg/kg, i.p., it impaired coordinated motor activity in rats. 2) Amantadine inhibited methamphetamine-induced hyperactivity, but apomorphine-induced stereotyped behavior was unaffected in rats. 3) Amantadine was equipotent to imipramine in suppressing haloperidol-induced catalepsy in rats, but L-DOPA was without effect. On the other hand, amantadine was 40 and 400 times as potent as imipramine and L-DOPA, respectively, in suppressing delta 9-tetrahydrocannabinol (THC)-induced catalepsy in rats. 4) Amantadine was as potent as imipramine in suppressing the muricide of olfactory bulbectomized rats, but was 3.5, 8.8 and 225.5 times as potent as methamphetamine, imipramine and L-DOPA, respectively, in inhibiting THC-induced reversible muricide in rats. 5) Amantadine at 50 mg/kg did not elicit circling behavior in the rat with unilateral nigral lesion induced by 6-hydroxydopamine. 6) Amantadine at high doses caused irritable aggression characterized by squealing in rats pretreated with intraventricular 6-hydroxydopamine. The most important characteristic of amantadine is its prominent effect suppressing the THC-induced catalepsy and muricide. This may be a reflection of the feature of amantadine activating the dopaminergic as well as the serotonergic systems.

Central activity, antihypertensive action and antiulcerogenic actions of Neurotropin (NSP), an extract isolated from vaccinia virus-innoculated skin or tissues of rabbits were investigated herein. When actions of NSP were examined in isolated muscle preparations by the Magnus-method, peristalsis and ACh-induced contraction in the small intestine isolated from crayfish were not influenced, peristalsis and ACh-induced contraction in the small intestine from mice were slightly accelerated, but adrenaline-induced relaxation in the small intestine from mice was not affected. Histamine-induced contraction in the small intestine and tracheal muscles isolated from guinea pigs was antagonized slightly, or not at all by NSP in a high concentration. NSP had no direct action nor anti-ACh action on abdominal muscles from frogs. NSP had no influence on E1-mice-convulsions. Both spontaneous motor activities and exploratory movements in mice were depressed. Sleeping time induced by hexobarbital-Na was prolonged in mice. Tremorine-induced tremor in mice was inhibited by NSP, while perphenazine-induced catalepsy in rats was not. Normal blood pressure in Wistar rats was not influenced, but high blood pressure in SHR (spontaneously hypertensive rats) decreased close to normal levels after NSP. NSP had antiulcerogenic effects on Takagi's restraint-plus-water-immersing ulcers in rats and histamine-induced duodenal ulcers in guinea pigs, but no influence on Shay ulcers in Wistar rats. From the data obtained herein, it may be concluded that NSP has many central depressant-like activities.

N-[(1-butyl-2-pyrrolidinyl)methyl]-2-methyl-5-sulfamoyl-2,3- dihydrobenzofuran-7-carboxamide hydrochloride (Y-20024) was synthesized in our laboratories in anticipation of developing a new psychotropic drug. In the present study, the pharmacological properties of Y-20024 were compared with those of sulpiride (SPR) and haloperidol (HPD). Administered orally, Y-20024 was 10 times stronger than SPR in inhibiting apomorphine (0.5 mg/kg, s.c.)-induced hyperactivity in mice; administered intravenously or intracerebroventricularly, it was 2 times or one third as strong, respectively. Y-20024 was almost equipotent to SPR in antagonizing apomorphine (0.1 mg/kg, s.c.)-induced vomiting in dogs. Combined with methamphetamine (5 mg/kg, i.p.), Y-20024 and SPR induced mortality dose-dependently in rats, but HPD did not. The mammotropic activity of Y-20024 administered orally once a day for 5 days was almost equipotent to that of SPR. From these results, Y-20024, pharmacologically similar to SPR, but superior in bioavailability and penetration through the blood brain barrier, may have potential usefulness as an antipsychotic drug.