Reduction in benzodiazepine receptors associated with Purkinje cell degeneration in ‘nervous’ mutant mice

Benzodiazepine Receptor Binding in Cerebellar Cortex: Observations in Olivopontocerebellar Atrophy

“…In their study, benzodiazepine receptors were found mostly in the molecular cell layer, and in particular were highly associated with Purkinje cell dendrites. 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).…”

“…Other mechanisms by which Purkinje cell loss in our OPCA patients may have resulted in elevated benzodiazepine receptor binding include: (a) The possibility that enhanced benzodiazepine binding may have occurred on proliferating glial cells; this, however, seems unlikely since the clonazepam-displaceable [3H]flunitrazepam binding procedure used in our study is considered to be specific for neuronal elements (Gallager et al, 1981); (b) the possibility that gross tissue shrinkage, which typically occurs in cerebella of patients with OPCA (cf. Konigsmark and Weiner 1970), might have artifactually elevated the benzodiazepine receptor concentration; however, in this respect, DNA concentration (per milligram tissue wet weight) in cerebellar cortex of our ataxia patients was normal as compared with nonneurological control patients (Kish and Hornykiewicz, unpublished observations), and, furthermore, gross tissue shrinkage also occurs in cerebellum of the Nervous mutant mouse with Purkinje cell degeneration and severely reduced number of benzodiazepine receptors (Skolnick et al, 1979).…”

“…In this regard, autoradiographic experiments using [3H]benzodiazepines have suggested the presence of benzodiazepine receptors on both human (Young and Kuhar, 1979) and rodeni (Palacios and Kuhar, 1982) Purkinje cell dendrites and somata. 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).…”

GABA‐Benzodiazepine‐Barbiturate Receptor Interactions

“…As with GABA receptors, lesions of the neostriatum lead to a decrease in benzodiazepine binding in that area (Sperk and Schlogl, 1979;Chang et al, 1980); however, whereas these lesions result in an increase in GABA binding sites in the substantia nigra Waddington and Cross, 1980), benzodiazepine binding is decreased in affinity (Biggio et al, 1979), although the sensitivity to enhancement by GABA (discussed below) was increased (Shibuya et a]., 1980). Lesions of the cerebellum (Chang et al, 1980;Biggio et al, 1980;Speth et al, 1981) and mutants depleted in certain types of cerebellar cells (Lippa et al, 1978;Skolnick et al, 1979;Speth et al, 1981) demonstrate that the majority of detectable GABA receptor sites are localized to granule cells without apparent correspondence of benzodiazepine binding sites, which are proportionally more dense on Purkinje cells. Whether benzodiazepine receptors are found in any cells or membrane locations iacking GABA receptors remains in question.…”

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

“…Recent studies on the localization of benzodiazepine receptors have suggested that these receptors are localized in Brodmann layers 111, IV-A, and IV-C in the cerebral cortex (Young and Kuhar, 1979) and in the Purkinje cell layer in the cerebellum (Lippa et al, 1978;Skolnick et al, 1979;.…”