Decreased Benzodiazepine Receptor Density in Rat Cerebellum Following Neurotoxic Doses of Phenytoin

Abstract

The effect of acute and chronic administration of phenytoin on [3H]flunitrazepam binding was examined in the rat cerebellum. There was no significant effect of phenytoin on [3H]flunitrazepam binding in the rat cerebellum 1 and 6 h after a single i.p. injection of 200 mg/kg of phenytoin. However, after 14 days and 28 days of chronic phenytoin administration, significant decreases in [3H]flunitrazepam receptor density were observed, with no changes in apparent affinity constants in the rat cerebellum. This effect of phenytoin was dose-dependent, as lower doses of phenytoin (100 mg/kg/day) for 14 or 28 days produced no alterations in [3H]flunitrazepam binding the the rat cerebellum. Light-microscopic examination of the rat cerebellum treated with 200 mg/kg/day of phenytoin for 14 days showed degeneration of the Purkinje cells, with edematous Bergmann astrocytes. These data provide evidence for the neuronal localization of benzodiazepine receptors on cerebellar Purkinje cells.

Benzodiazepine Receptor Binding in Cerebellar Cortex: Observations in Olivopontocerebellar Atrophy

“…In agreement with these autoradiographic findings in rats, neurochemical studies of cerebella of mutant mice lacking Purkinje cells (Nervous) show a 20-67% reduction in benzodiazepine receptor density in cerebellum (Lippa et al, 1978;Speth and Yamamura, 1979;Skolnick et al, 1979;Braestrup et al, 1979;Chang et al, 1980). Similarly, chronic administration of high doses of phenytoin, which destroys Purkinje cells, is associated with an approximately 50% reduction in rat cerebellar benzodiazepine receptor density (Mimaki et al, 1980). These data provide evidence for the neuronal localization of benzodiazepine receptors on rodent cerebellar Purkinje cells.…”

“…Moreover, decreased benzodiazepine receptor density has been observed in cerebella of mutant strains of mice deficient in Purkinje cells (Lippa et al, 1978;Speth and Yamamura, 1979;Skolnick et al, 1979;Braestrup et al, 1979;Chang et al, 1980). and in cerebella of rats deficient in Purkinje cells consequent to treatment with high doses of phenytoin (Mimaki et al, 1980). Although the possible significance of the cerebellar benzodiazepine receptor with respect to both normal and pathophysiological brain function is not known, it is of interest that oral diazepam produces oculomotor deficits in hu-mans similar to the changes observed in patients with olivopontocerebellar atrophies (Rothenberg and Selkoe, 1981).…”

Multireceptor analysis in human neocortex reveals complex alterations of receptor ligand binding in focal epilepsies

“…Acute valproate, although not diazepam or phenobarbital, administration results in increased cortical BZ binding‐site densities (Mimaki et al., 1984). Acute phenytoin administration does not alter cerebellar BZ densities, although chronic treatment results in a decrease (Mimaki et al., 1980). Chronic lamotrigine administration results in decreased densities of cortical but not hippocampal 5‐HT 1A receptor densities (Vinod & Subhash, 2002).…”