Characterization of the peripheral‐type benzodiazepine receptors in cultured astrocytes: Evidence for multiplicity

Abstract

In mammalian brain peripheral benzodiazepine (PBZD) receptors are predominantly localized on astroglial cells. Previous studies utilizing whole membrane preparations from brain and peripheral organs of various species have indicated several distinctions between the drug-receptor interactions of the two prototypic PBZD receptor ligands, PK 11195 and Ro5-4864. The present study was undertaken to determine whether putative differences in the binding of PBZD receptor ligands in homogenates of primary astrocyte cultures can be interpreted as the labeling of PBZD receptor subtypes. Equilibrium competition and saturation binding experiments in homogenate preparations of primary astrocytes from cerebral cortex of new born rats revealed that [3H]PK 11195 labels twice the number of [3H]Ro5-4864 binding sites. Unlabeled Ro5-4864 competes for [3H]PK 11195 binding in a manner suggesting the existence of multiple PK 11195 binding sites. The competition binding experiments, using various benzodiazepines, indicate that one binding component of PK 11195 corresponds to Ro5-4864 binding sites, whereas the second is different. The latter binding site does not correspond to the central BZD receptor but displays the pharmacological properties of the PBZD receptor. Further differences between the binding of PK 11195 and Ro5-4864 in astrocytes were detected in the presence of ethanol which was more effective in inhibiting the binding of the latter. Subcellular distribution studies indicated, however, that the binding of both [3H]PK 11195 and [3H]Ro5-4864 is associated primarily with the mitochondrial fraction of astrocytes. Taken together, the present study indicates the existence of non-overlapping PBZD binding sites in astrocytes and thus suggests the existence of PBZD receptor subtypes.(ABSTRACT TRUNCATED AT 250 WORDS)

Peripheral benzodiazepine receptors are colocalized with activated microglia following transient global forebrain ischemia in the rat

“…In the brain, PBRs are mainly present in periventricular regions such as the choroid plexus, area postrema and ependyma (Richards and Mohler, 1984) while relatively low levels of binding sites are present in the brain parenchyma (Benavides et al, 1983). This anatomical distribution as well as binding studies in vitro (Syapin and Skolnick, 1979;McCarthy and Harden, 1981;Bender and Hertz, 1984;Sher and Machen, 1984;Olson et al, 1988;Black et al, 1990;Itzhak et al, 1993) strongly support the idea that PBRs are expressed on glial and other non-neuronal cells. Specifically, astrocytes (Syapin and Skolnick, 1979;Itzhak et al, 1993) and cells of monocytic lineage such as macrophages (Ruff et al, 1985;Zavala and Lenfant, 1987) are thought to express PBRs.…”

Neuroinflammation in Schizophrenia-Related Psychosis: A PET Study

“…As in activated microglia cells, the expression of the PBR is also increased in activated astrocytes (15)(16)(17). Increased 11 C-(R)-PK11195 can therefore represent activated microglia cells or astrocytes.…”

Benzodiazepine-induced protein tyrosine nitration in rat astrocytes

“…Because of the absence of the central benzodiazepine receptors on cultured astrocytes 11 and the induction of PTN by nanomolar concentrations of PBR ligands, such as PK 11195 or DBI but not by the central receptorbinding clonazepam (Fig. 1B), it seems possible that the PBR is involved in triggering the PTN response to diazepam in cultured astrocytes.…”

“…9 Unlike the central receptor, PBR expression in mammalian brain is largely confined to glial cells. 10,11 The function of PBR is incompletely understood, but there is good evidence that PBR plays a role in steroid biosynthesis by regulating cholesterol transport from the outer to the inner mitochondrial membrane, in the assembly of heme proteins as well as in cell proliferation and apoptosis. 9 A role of the PBR in the pathogenesis of HE has repeatedly been claimed (reviewed in Butterworth 12 and Norenberg et al 13 ).…”