Effect of Dipotassium Clorazepate on Ainygdaloid‐Kiiidling and Comparison Between Amygdaloid‐ and Hippocampal‐Kindled Seizures in Rats

Abstract

Purpose: We reportcd previously that dipotassium clorazcpate (potassium 7‐chloro‐2, 3‐dihydro‐2‐oxo‐S‐phcnyI‐ l H‐ l, 4‐bcnzodiazepinc‐3‐carboxylate potassium hydroxide: DC), an antianxiety drug, suppressed hippocampel kindled scizures in rats i n a dose‐dependent manner (Amano et al. Psychiatry Clin Neuroscienccs 1998; 52: 459–462). Its effect on kindling, howcver, has not been evaluated. Moreover, differcnces in the anticonvulsive effccts of conventional anticonvulsants bctween amygdaloid‐and hippocampal‐kindlcd seizures have becn reportcd (Kamci et al. Arch. Int. Pharmacodyn I98 1; 249: 164–176). To clarify the anticonvulsive propcrties of DC, we examined its effects on amygdaloid kindling and compared it for 7 succcssive days against amygdaloid‐ and hippocampal‐kindled seizures using thc rat kindling model of epilcpsy. Methods: Adult inale Wistar rata weighing 220–330 g werc used. Electrodes were implanted stereotaxically into thc left basoiatcfiil amygdala or the left dorsal hippocampus under pcntobarhital ancsthesia. Expcriment 1: Anticonvulsive effect on amygdaloid‐kindled seizurcs. Rats having >5 consecutive stage‐5 seimrcs were htimulated at the generalizcd seizure‐triggering threshold (GST) intensity 30 minutes after i.p. administration or DC or saline. Experiment 2: Effect on amygdala kindling. In other groups of Tiits, the amygdala was stimulated once daily following 30 minutes i.p. administration or DC at 5 mg/kg or saline until the first stage‐5 seizure was attained. Experimcnt 3: Comparison of anticonvulsive effect bctween amygdaloid‐ and hippocampal‐kindled scizures. In other groups of rats having 5 consecutive stage‐5 seizures, the GST was determined. Furthermorc, rats having >I0 stage‐5 scizures induced at thc GST intensity were testcd once a day for 7 consecutive days. Thc stimulation was delivercd 30 minutes aftcr i.p. administration of DC or saline. Results: Expcriment I: DC suppresscd amygdaloid‐kindled scizures in a dose‐depcndent manner. Significant reduction of aftcr‐discharge duration compared with the control group was observed at dosagcs of 2 mg/kg or more, hut complete suppression of after‐discharges was observed in only I of 7 sessions at the highcst dose. Expcriment 2: Thc number of stimulations rcquired for the first stage‐5 seiiurc in the 5 mg/kg dosage group was 14.1+1.4 stimulations, which was significantly greater than the 10.2+1.7 stimulations in the control group (P4.01). The contralateral cortical afterdischarge duration i n the DC treated group was signilicantly shortcr than thc afterdischarge duration in the amygdala at the first 7 stimulations, whereas it was significantly shorter only the first 3 stimulations i n the control group. Experiment 3: DC suppressed amygdaloid‐kindled seizures at 2 and 5 mg/kg, whcreas I mg/kg or morc suppresscd hippocampal‐kindlcd seizures. Conclusions: Thc result of the present study suggcst that thc principal anticonvulsive cffect of DC is likely to be relatcd mainly to attenuation of propagation of scizure activity rather than to an elevatcd seizure threshold, which may support our previously findings that increased stimulus intensity could not complctcly reverse thc anticonvulsive effects of DC. Thus, differences in effective dosages in both amygdaloid‐ and hippocampal‐kindled seizures may suggcst a difference in the neuronal mechanisms that arc cvolved in this kindling. The present study dcmonstratcd that DC has a modest anticonvulsive effect without serious adverse effccts, which indicates thc clinical uscfulness of DC for treatment intractable epilepsy.