The central effects of a new tremorgenic drug, 2(p-nitrobenzylthio)-imidazoline '(3H) 9 HC1 (NBTI) were studied. This compound, first synthesized by EASTON et al. 2, caused marked tremors in rats (Sprague-Dawley male, 160-210 g) and mice (Swiss male, 22-30 g) in doses above 40 mg/kg, and in doses above 60 mg/kg a majority of the animals also showed clonic convulsions. All of the anticholinergic antiparkinsonism agents (atropine sulfate, (5 mg/kg), scopolamine like HBr (5 mg/kg), orphenadrine citrate (10 mg/kg) and biperiden (10 mg/kg)) f ailed to block the NBTI-induced tremors in mice. d-Amphetamine sulfate (10 mg/kg), L-dopa methyl ester. HC1 (400 mg/kg base), diphenhydramine 9 HC1 (40 mg/kg) and benztropine mesylate (20 mg/kg) enhanced the excitation and lethality of NBTI (50 mg/kg).In rats a dose even as small as 15 mg/kg of NBTI produced stereotyped movements of the head and sniffing at the sides and corners of the cage. This effect started within 3 rain, and lasted for 30 rain. Pretreatment with chlorpromazine 9 HC1 (10 mg/kg), perphenazine (115 mg/kg) and haloperidol (20 mg/kg) blocked the stereotyped behavior, but not the tremors. Treatment with p-chlorophenylalanine methyl ester 9 ItC1 (400 mg/kg base given 72 h before NBTI) or phenoxybenzamine (15 mg/kg given 4 h before NBTI) did not modify the effects of NBTI (50 mg/kg). This drug was very effective in antagonizing the marked depression produced in rats by treatment with reserpine (5 mg/kg) and ~-methyltyrosine methyl ester 9 HC1 (c~-MT) (250 mg/kg base given 20 h after reserpine and 4 h before NBTI (30 mg/kg).The influence of NBTI (50 mg/kg) on the monoamines of whole brain of rats was studied using the single extraction procedure of FLEMING et al. a. The only significant change seen was a 55% depletion of noradrenaline (NA) seen 1 h after treatment. Changes in NA, dopamine (DA) and serotonin (5 HT) levels were not appreciable at 30, 120 and 240 rnin after NBTI treatment. The turnover rates of brain NA and DA were estimated by the method of ANDI~N et al. 4. It was found that 50 mg/kg dose of NBTI decreased the turnover rates of both DA and NA, the former being more affected.The in vitro uptake of NA and-DA by slices of hypothalamus (NA) and caudate (DA) of rats was estimated by the method of DENGLER et al. 5. When compared with the catecholamine uptake inhibitor desipramine (DMI) it was found that the NBTI concentration required for blocking the uptake of DL-14C-NA by hypothalamus slices was 0.01 times the required concentration of DMI and 200 times the DMI concentration required for blocking 14C-DA uptake by caudate slices.Studies are in progress to evaluate the effects of NBTI on the in vivo uptake of catecholamines, and also its behavioral, antidepressant and antiparkinsonism effects. The latter experiments are being performed on rhesus monkeys. Dyskinesias are being produced by various methods including those which involve pharmacological depletion of brain DA and also by means of appropriate lesions of brain areas. In a preliminary experiment, on...
