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.

Cerebellar Impairment Following Acute Nontoxic Administration of Phenytoin in Rat

“…The sig- nificantly higher increase of cerebellar level is consistent with PHT brain binding and a drug sequestration in the CNS by limitedexit kinetics (Ramsay et al, 1979;. The increase in P-cell firing rate induced by PHT is in agreement with the findings by Halpern and Julien (1972), Julien (1974), Julien andLaxer (1974), andShimizu et al (1977), but it is contrary to the observations of Puro and Woodward (1973) and Latham and Paul (1980). Beyond the possible effects of different doses, treatment schedules, and animal species, one can observe that all the experiments, including our own, indicating a PHT-induced increase in P-cell firing rate were performed in awake paralyzed animals.…”

“…Beyond the possible effects of different doses, treatment schedules, and animal species, one can observe that all the experiments, including our own, indicating a PHT-induced increase in P-cell firing rate were performed in awake paralyzed animals. On the contrary, Puro and Woodward (1973) and Latham and Paul (1980) worked with alothane and urethane anesthesia, respectively. The effect of these two anesthetic agents on cerebellar activity has not yet been reported, but both drugs induce an impairment in mitochondria1 function (Cohen, 1973;Grist and Baum, 1974;Ginsberg et al, 1977).…”

“…Taking account of these contradictions, Latham and Paul (1980) pointed out the importance of relating drug plasma levels to P-cell spontaneous activity. They observed from their analyses of interspike interval histograms that PHT acted by depressing the P-cell discharge rate, and that the time course of depression of the P-cell did not parallel the changes in serum levels of PHT.…”

“…As long-term use produces PHT accumulation in the brain (Houghton et al, 1975), care should be taken to distinguish between the effect of an acute single dose and that of long-term treatment with PHT. Moreover, an analysis of interspike interval histograms (Latham and Paul, 1980) can only furnish information of a quantitative nature.…”

Dose‐Response Analysis of Phenytoin on Electrically Induced Seizures and Spontaneous Activity of Cerebellar Purkinje Cells in the Frog

“…The augmentation of Purkinje cell activity by antiepileptic drugs was first proposed as a mechanism of action by Julien and Halpern (1971), who found that anticonvulsant doses of phenytoin increased the firing rate of Purkinje cells in unanesthetized, curarized cats. Although some investigators have confirmed these results in cats (Shimizu et al, 1977;Fernandez-Guardiola et al, 1979), others have failed to demonstrate phenytoin-induced augmentation of Purkinje cell activity in cats (Latham and Paul, 1976) and rats (Pieri and Haefely, 1976;Puro and Woodward, 1973;Latham and Paul, 1980). These conflicting results may have arisen from differences in experimental animals, anesthetic protocols, microelectrode recording techniques, and/or phenytoin doses and routes of administration.…”