Differential Modulation by Cations of Sigma and Phencyclidine Binding Sites in Rat Brain

Abstract

The present investigation attempted to differentiate haloperidol-sensitive sigma sites (σ_H) from phencyclidine (PCP) binding sites in rat brain membranes. We studied the effects of several cations at physiologically relevant concentrations on the binding of radioligands selective for σ_H sites ([³H]haloperidol, [³H](+)3-PPP**), and [³H](+)SKF10,047), or for PCP sites ([³H]PCP and [³H]TCP). The PCP sites displayed a markedly greater sensitivity to cations than σ_H sites. This property was reflected by a greater extent of inhibition of the binding of PCP-selective relative to σ_H-selective ligands at a given cation concentration, as well as by lower IC₅₀'s and by steeper slopes of the cation dose-response curves. Divalent cations were approximately 100 times more potent than monovalent cations. All cations were inhibitory, except Sr²⁺ and Ba²⁺ which, at micromolar concentrations, enhanced PCP binding but not σs_H binding. Thus, PCP-selective sites appeared to be distinct from σ_H sites with regards to several aspects of cation modulation. This is consistent with the view that PCP and σ_H sites are distinct molecular entities. Further, the marked cation sensitivity of the PCP site is consistent with the current hypothesis according to which the PCP site is linked to the N-methyl-D-aspartate (NMDA) receptor-cation channel complex.