Repeated haloperidol treatment decreases sigma(1) receptor binding but does not affect its mRNA levels in the guinea pig or rat brain

The effects of chronic treatment with haloperidol on sigma (sigma) receptor s were investigated across brain regions and species. The regional distribu tion of [H-3](+)-pentazocine binding to sigma(1) receptor was similar betwe en 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 [H-3]1,3-di (2-tolyl) guanidine ([H-3]DTG) binding in the presence of 100 nM (+)-pentazocine to sigma(2) receptor was similar to that of the [H-3](+)-pentazocine binding in the guinea pig brain, while in the rat brain high levels of [H-3]DTG binding were detected in the cortex, fron tal cortex and cerebellum. The intraperitoneal administration of 2 mg/kg of haloperidol to guinea pig and rats once a day for 21 days produced inhibit ion of [H-3](S)-pentazocine binding but did not affect [H-3]DTG binding to sigma(2) receptors in any brain region examined. The effects of haloperidol on [H-3](+)-penazocine binding in the rat were much weaker than those in t he guinea pig. The regional distribution of the level of sigma(1) receptor mRNA determined by the ribonuclease protection assay was similar to that of the [H-3](S)-pentazocine binding activity, except in the cortex and cerebe llum where the levels of sigma(1) receptor mRNA were low in guinea pig and rat. Treatment with haloperidol did not affect the levels of sigma(1) recep tor mRNA in any brain region in either species. These findings suggested th at the a receptors differentially distributed in brain regions are down reg ulated by treatment with haloperidol across sigma receptor subtypes and ani mal species without changing the transcriptional activity of the sigma(1) r eceptor. The mechanisms by which a receptors could be differently regulated in vivo by chronic treatment with haloperidol in different species may con tribute to the therapeutic efficacy of haloperidol. (C) 2000 Elsevier Scien ce B.V. All rights reserved.