Repeated haloperidol treatment decreases σ1 receptor binding but does not affect its mRNA levels in the guinea pig or rat brain
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.
Section snippets
Materials
(+)-Pentazocine succinate, DTG, rimcazole and (+)-SKF10047 were synthesized by Otsuka Pharmaceutical (Tokushima, Japan). Drugs were obtained from the following sources: haloperidol (Sigma, St. Louis, MO, USA), [3H](+)-pentazocine (1161.8 GBq/mmol), [3H]DTG (1295.0 GBq/mmol) and [α-32P]UTP (∼111 TBq/mmol) (DuPont-NEN, Wilmington, DE, USA), T7 polymerase (Promega, Madison, WI, USA) and restriction enzymes (New England Biolabs, Beverly, MA, USA). All other reagents were of analytical grade and
Regional distribution of σ1 and σ2 binding sites in the guinea pig and rat brain
Fig. 2, Fig. 3 show the regional distributions of σ1 and σ2 binding sites labeled by [3H](+)-pentazocine and [3H]DTG in the presence of 0.1 μM (+)-pentazocine, respectively, in the guinea pig (Fig. 2) and rat brain (Fig. 3). In both species, σ1 binding sites were abundant in the brain stem such as the pons and medulla and in the mesencephalon, but low in the striatum and hippocampus. The distribution of σ2 binding sites in the guinea pig brain was similar to that of σ1 binding sites, and they
Discussion
We discriminated between σ1 and σ2 binding sites by binding assay using [3H](+)-pentazocine and [3H]DTG. As reported previously De Costa et al., 1989, DeHaven-Hudkins et al., 1992, Akunne et al., 1997, in our preliminary experiments [3H](+)-pentazocine binding was completely inhibited by 100 nM (+)-pentazocine, whereas [3H]DTG binding was only partially inhibited. DTG shows similar high affinities for both σ1 and σ2 binding sites. Thus, σ2 binding sites were labeled with [3H]DTG in the presence
Acknowledgements
We thank Otsuka Pharmaceutical (Tokushima, Japan) for generously donating σ ligands. We also thank the Research Center for Molecular Medicine, Hiroshima University School of Medicine for the use of their facilities. This work was supported by grants-in-aid for Scientific Research (B) from the Ministry of Education, Science, Sports and Culture of Japan (11694281).
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