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 are dual-specificity protein phosphatases and some show tissue-specific distribution, like the hVH-5 gene (homologue of vaccinia virus H1 phosphatase gene clone 5), which is expressed predominantly in the adult brain. In this paper, we investigated whether the hVH-5 gene is induced by psychostimulants in rat brain, as has been demonstrated for immediate early genes encoding transcription factors. Using in situ hybridization, we found that i.p. injection of cocaine, amphetamine and caffeine induced hVH-5 mRNA expression within 40 min in the nucleus accumbens (NAc), caudate putamen, frontal cortex and hippocampus, with a maximal effect in the NAc. The cocaine-induced hVH-5 gene induction involves the serotonergic system, since it was abolished in the NAc by lesioning serotonergic raphé projections with 5,7-dihydroxytryptamine. Moreover, the effect of cocaine was fully mimicked by the selective serotonin uptake inhibitor fluoxetine. In contrast to what has been described 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 repeated cocaine injections for 10 days as after a single injection. The considerable and prolonged induction of the MAP kinase phosphatase hVH-5 gene 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.