Calcium-dependent displacement of haloperidol-sensitive sigma receptor binding in rat hippocampal slices following tissue depolarization

To evaluate the possible existence of an endogenous ligand for the haloperidol-sensitive sigma receptor, we developed an in vitro competition assay to measure endogenous ligand release. Depolarization of in vitro hippocampal slices by either veratridine or potassium reduced [3H]ditolylguanidine binding in a calcium-dependent and transient manner. None of the drugs or iron substitutions directly affected [3H]ditolylguanidine binding to rat brain membranes. Veratridine-induced depolarization also reduced the binding of [3H](+)3-(3-hydroxyphenyl)-N-(1-propyl)piperidine, another sigma radioligand, in a calcium-dependent manner. Radioligand displacement was not associated with alteration in sigma receptor dissociation kinetics or receptor degradation in the hippocampal slice. In contrast, KC1 depolarization had no effect on [3H]ditolyguanidine binding to sigma receptors in liver slices. The results suggest that a calcium-dependent, depolarization-induced reduction in sigma receptor binding may have been caused by the release of an endogenous sigma ligand in rat hippocampal tissue.