%0 Journal Article %A M A Connor %A C Chavkin %T Ionic zinc may function as an endogenous ligand for the haloperidol-sensitive sigma 2 receptor in rat brain. %D 1992 %J Molecular Pharmacology %P 471-479 %V 42 %N 3 %X In the search for an endogenous sigma transmitter, whose existence was previously suggested by release studies, we tested the effects of releasable substances known to be present in the hippocampus, and we determined that ionic zinc may function as an endogenous ligand for the haloperidol-sensitive sigma 2 site. Zn2+ displaced 1,3-di(2-[5-3H]tolyl)guanidine ([3H]DTG) from two binding sites in rat brain membranes, with an IC50 for the high affinity site of 110 +/- 3 microM and for the low affinity site of 20 +/- 4 mM. The sigma 1-selective ligand (+)-[3H]pentazocine was only weakly displaced from rat brain membranes by Zn2+ (IC50 = 1.4 +/- 0.05 mM). These results indicate that the Zn(2+)-sensitive sigma binding site corresponds to the sigma 2 site. The interaction between Zn2+ and the sigma 2 site may have physiological significance, because ionic zinc is present in synaptic vesicles in the brain and may function to regulate binding at the sigma 2 site. To test this hypothesis, we measured the effects of metallothionein peptide 1, a specific zinc chelator, on the actions of the putative endogenous sigma ligand(s) released in the hippocampus by focal electrical stimulation. Release of the endogenous sigma ligand(s) was measured by competition with specific radioligand binding in live hippocampal slices. High frequency, focal, electrical stimulation of the zinc-containing mossy fibers in the hilar region of the hippocampus caused a decrease in the specific binding of [3H]DTG, (+)-[3H]3-(3-hydroxyphenyl)-N-(1-propyl)piperidine, or (+)-[3H]pentazocine to sigma sites. The decrease in [3H]DTG binding was largely blocked by metallothionein peptide 1, whereas the decrease in (+)-[3H]pentazocine binding was unaffected. These results suggest that Zn2+ may act as an endogenous ligand at sigma 2 sites in the rat hippocampus. %U https://molpharm.aspetjournals.org/content/molpharm/42/3/471.full.pdf