COCAINE AND FLUOXETINE INDUCE THE EXPRESSION OF THE HVH-5 GENE ENCODING A MAP KINASE PHOSPHATASE

A novel class of immediate early genes that encode enzymes of the MAP kinase phosphatase family has recently been described. These enzymes a re dual-specificity protein phosphatases and some show tissue-specific distribution, like the hVH-5 gene (homologue of vaccinia virus H1 pho sphatase gene clone 5), which is expressed predominantly in the adult brain. In this paper, we investigated whether the hVH-5 gene is induce d by psychostimulants in rat brain, as has been demonstrated for immed iate early genes encoding transcription factors. Using in situ hybridi zation, we found that i.p. injection of cocaine, amphetamine and caffe ine induced hVH-5 mRNA expression within 40 min in the nucleus accumbe ns (NAc), caudate putamen, frontal cortex and hippocampus, with a maxi mal effect in the NAc. The cocaine-induced hVH-5 gene induction involv es the serotonergic system, since it was abolished in the NAc by lesio ning serotonergic raphe projections with 5,7-dihydroxytryptamine. More over, the effect of cocaine was fully mimicked by the selective seroto nin uptake inhibitor fluoxetine. In contrast to what has been describe d for c-fos and egr-1 immediate early genes, we found that hVH-5 mRNA expression in the NAc and hippocampus was as significant after repeate d cocaine injections for 10 days as after a single injection. The cons iderable and prolonged induction of the MAP kinase phosphatase hVH-5 g ene by psychostimulant drugs in postmitotic brain cells, particularly in the NAc, could indicate that MAP kinase substrates are involved in the reinforcing properties of drugs of abuse. (C) 1998 Elsevier Scienc e B.V. All rights reserved.