Combined Study of the Pattern of Spontaneous Activity of Cerebellar Purkinje Cells and Phenytoin Serum Levels in the Rat

Abstract

The effects of phenytoin (PHT) on the spontaneous activity of cerebellar Purkinje cells and the drug serum levels have been examined following both intravenous and intraperitoneal administration in rats. Purkinje cell activity was assessed by on-line computer analysis of interspike interval distributions. PHT levels were assayed in blood samples taken at the end of the electrophysiological experiments and in successive samples obtained in parallel experiments over periods corresponding to when electrophysiological recordings were made. Single intravenous doses of PHT (10 mg/kg) produced a decrease in the discharge rate in individual Purkinje cells with a time course which was delayed and prolonged compared with the changes in serum levels of PHT. A single intraperitoneal dose of PHt (100 mg/kg) produced a statistically significant (p < 0.02) decrease in Purkinje cell discharge rate. Similar results (p < 0.01) were obtained after pretreatment with PHT (50 mg/kg daily for 14 days, including the day of the experiment). Both injection schedules produced nontoxic serum PHT levels during the recording period. Pretreatment with PHT doses of 10 mg/kg for 14 days (including the experimental day) produced a smaller decrease in Purkinje cell discharge rate (p < 0.05). When pretreatment ceased the day before the electrophysiological experiment, no significant changes in Purkinje cell activity were observed, and serum PHT levels were not detectable at the end of the experiment. None of the pretreatment schedules produced overt signs of cerebellar dysfunction or motor impairment. These findings indicate that PHT may increase the output from the cerebellum by suppressing Purkinje cell activity. Since this effect occurs without producing cerebellar symptoms, it may account for some of the therapeutic action of PHT at nontoxic levels in man.