Repeated haloperidol treatment decreases σ 1 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 σ 1 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 σ 2 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 σ 2 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 σ 1 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 σ 1 receptor mRNA were low in guinea pig and rat. Treatment with haloperidol did not affect the levels of σ 1 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 σ 1 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.