The effects of 1,2-benzisoxazole-3-methanesulfonamide (zonisamide, AD-810, CI-912), an antiepileptic compound, on the central nervous system were compared with those of carbamazepine and acetazolamide in experimental animals. 1. Zonisamide at an oral dose of 100 mg/kg was without effect on general behavior in mice except lowerings of pelvic, tail and body positions and ptosis. In rats, zonisamide slightly decreased the body temperature at the same dose. 2. Zonisamide (50 mg/kg p.o.) did not affect spontaneous alteration behavior and active avoidance performance in mice, although it impaired the acquisition of step-down passive avoidance behavior in mice. Carbamazepine (50 mg/kg) deteriorated the spontaneous alternation behavior. 3. Zonisamide (40 mg/kg i.v.) did not affect the relative power of cortical EEGs in gallamine-immobilized cats. Caudate spindles and recruiting responses, induced by electrical stimulation of the head of the caudate nucleus and the ventralis anterior thalamus, respectively, were not affected with the same dose of zonisamide in cats. On the other hand, carbamazepine (5 mg/kg) decreased the beta 2 relative power in the cortex, and enhanced both caudate spindles and recruiting responses. 4. Zonisamide (10 mg/kg i.v.) and carbamazepine (3 mg/kg) showed a tendency to depress the flexor reflex without affecting the neuromuscular transmission in anesthetized cats. 5. The central effects of zonisamide clearly differed from those of acetazolamide. Namely, acetazolamide markedly decreased brain pH at 25 mg/kg i.v., and increased regional cerebral blood flow at 100 mg/kg p.o. in rats. Zonisamide at 50 mg/kg i.v. and 100 mg/kg p.o. did not affect brain pH and regional cerebral blood flow, respectively. In addition, zonisamide (100 mg/kg p.o.) decreased brain contents of dopamine metabolite, DOPAC, with slight increase of a serotonin metabolite, 5-HIAA, in mice, and decreased brain contents of dopamine metabolites, DOPAC and HVA, in rats.(ABSTRACT TRUNCATED AT 250 WORDS)