Repeated haloperidol treatment decreases σ₁ receptor binding but does not affect its mRNA levels in the guinea pig or rat brain

Abstract

The effects of chronic treatment with haloperidol on sigma (σ) receptors were investigated across brain regions and species. The regional distribution of [³H](+)-pentazocine binding to σ₁ receptor was similar between the guinea pig and rat brains. The highest level of binding was detected in the brain stem and lowest in the striatum and hippocampus. The regional distribution of [³H]1,3-di (2-tolyl) guanidine ([³H]DTG) binding in the presence of 100 nM (+)-pentazocine to σ₂ receptor was similar to that of the [³H](+)-pentazocine binding in the guinea pig brain, while in the rat brain high levels of [³H]DTG binding were detected in the cortex, frontal cortex and cerebellum. The intraperitoneal administration of 2 mg/kg of haloperidol to guinea pig and rats once a day for 21 days produced inhibition of [³H](+)-pentazocine binding but did not affect [³H]DTG binding to σ₂ receptors in any brain region examined. The effects of haloperidol on [³H](+)-penazocine binding in the rat were much weaker than those in the guinea pig. The regional distribution of the level of σ₁ receptor mRNA determined by the ribonuclease protection assay was similar to that of the [³H](+)-pentazocine binding activity, except in the cortex and cerebellum where the levels of σ₁ receptor mRNA were low in guinea pig and rat. Treatment with haloperidol did not affect the levels of σ₁ receptor mRNA in any brain region in either species. These findings suggested that the σ receptors differentially distributed in brain regions are down regulated by treatment with haloperidol across σ receptor subtypes and animal species without changing the transcriptional activity of the σ₁ receptor. The mechanisms by which σ receptors could be differently regulated in vivo by chronic treatment with haloperidol in different species may contribute to the therapeutic efficacy of haloperidol.

Introduction

Sigma (σ) receptors are defined as non-opiate and non-phencyclidine binding sites that mediate the psychomimetic actions of certain opioid derivatives Martin et al., 1976, Su, 1982, Tam and Cook, 1984. These receptors are widely distributed in the brain as well as in several peripheral tissues of endocrine and immune systems Su et al., 1988, Itzhak and Stein, 1990, Walker et al., 1990, Ferris et al., 1991. σ receptors can be divided into at least two subtypes, σ₁ and σ₂ receptors Hellewell and Bowen, 1990, Walker et al., 1990, Quirion et al., 1992. Based on this classification, (+)-pentazocine and (+)-N-allylnormetazocine ((+)-SKF10047) are classified as specific σ₁ receptor ligands, and 1, 3-di(2-tolyl)guanidine (DTG), a non-benzomorphan-type σ receptor ligand, has equal high affinities for σ₁ and σ₂ receptors. Thus, each receptor can be identified solely by ligand binding experiments using [³H](+)-pentazocine or [³H]DTG with (+)-pentazocine to mask labeling of σ₁ receptors. The functional significance of these receptors remains to be clarified. σ receptors have been suggested to be involved in the pathogenesis of psychiatric disorders. A wide variety of centrally acting drugs exhibit high to moderate affinities for σ receptors. Anti-psychotic drugs such as haloperidol and rimcazole are high affinity ligands for the σ receptors Walker et al., 1990, Ferris et al., 1991, Itzhak and Stein, 1991. σ ligands interact with the dopamine neurotransmitter system Walker et al., 1990, Zhang et al., 1993, Debonnel and de Montigny, 1996. Significant changes have been observed in σ binding activity in discrete brain areas of schizophrenic patients Weissman et al., 1991, Shibuya et al., 1992, Helmeste et al., 1996. More recently, a significant association was observed between polymorphisms in the σ₁ receptor gene and schizophrenia (Ishiguro et al., 1998).

Prolonged treatment with haloperidol induces severe extrapyramidal side effects in patients undergoing anti-psychotic therapy. Our previous studies showed that the chronic haloperidol treatment increases dopamine D₂ receptor binding activities as well as its mRNA levels in the rat striatum (Inoue et al., 1997). Itzhak and Alerhand (1989) and Itzhak and Stein (1991) reported that chronic haloperidol treatment induces the opposite effects on dopamine and σ receptors; that is, up-regulation of dopamine D₂ receptor and down-regulation of σ receptor. These findings suggested that σ receptors may play an important role in the psychomotor behavior and the extrapyramidal side effects of neuroleptics. Indeed, σ ligands produce dyskinesia in several animal models. Haloperidol, (+)-SKF10,047 and DTG produce marked dystonia in rats after microinjection into the red nucleus (Walker et al., 1988).

Due to the physiological and pharmacological relevance of σ receptors, it is important to understand the molecular nature of these receptors. Hanner et al. (1996) cloned a gene encoding the σ₁ receptor from guinea pig liver consisting of 223 amino acids that possesses a single putative transmembrane domain. Subsequently, the human Kekuda et al., 1996, Presad et al., 1998, mouse Seth et al., 1997, Pan et al., 1998 and rat σ₁ receptors (Seth et al., 1998) have been cloned.

We observed that haloperidol treatment induces down-regulation of σ₁ receptor binding activities but not σ₂ receptor binding activities, and this effect was greater in the guinea pig brain than in rat brain. To understand the molecular nature of these phenomena, we studied the levels of σ₁ receptor mRNA in various areas of the guinea pig and rat brain following treatment with haloperidol.