[Functional characterization of a sigma receptor and its gene expression by haloperidol]

Sigma (sigma) receptors are expressed in the brain as well as endocrine and immune systems. Several antipsychotic drugs such as haloperidol and pentazocine can bind to the sigma receptor, which is believed to play important roles in the pathogenesis of schizophrenia by as yet unknown mechanisms. Two subtypes of sigma receptors (sigma 1 and sigma 2) have been identified, and the sigma 1 receptor was cloned. The chronic administration of haloperidol to guinea pigs produced a marked inhibition of the binding to sigma 1 receptor, but did not change sigma 2-receptor binding. Scatchard analysis demonstrated that the inhibition was due to a reduction in the number of binding sites without changes in the affinity. The treatment with haloperidol also did not affect sigma 1-receptor mRNA detected by the RNase protection assay. The treatment of rats with haloperidol inhibited sigma 1-receptor binding to a much lesser extent than that to guinea pigs. These finding suggest that haloperidol or its metabolite, reduced haloperidol, which is produced in greater quantity in humans and guinea pigs than in rats and mice, might influence protein translation or modification of sigma 1-receptor without changing the transcriptional activity. The mechanisms through which sigma receptors could be differently regulated in vivo by chronic treatment with haloperidol may contribute to the therapeutic efficacy of haloperidol.