Abstract
Sigma (σ) 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 a receptor, which is believed to play important roles in the pathogenesis of schizophrenia by as yet unknown mechanisms. Two subtypes of σ receptors (σ1 and σ2) have been identified, and the σ1 receptor was cloned. The chronic administration of haloperidol to guinea pigs produced a marked inhibition of the binding to σ1 receptor, but did not change σ2-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 σ1-receptor mRNA detected by the RNase protection assay. The treatment of rats with haloperidol inhibited σ1-receptor binding to a much lesser extent than that to guinea pigs. These finding suggest thathaloperidol 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 σ1-receptor without changing the transcriptional activity. The mechanisms through which σ receptors could be differently regulated in vivo by chronic treatment with haloperidol may contribute to the therapeutic efficacy of haloperidol.
