Abstract
Microsomal epoxide hydrolase (mEH) and cytochrome Pโ450 (CYP) ensure the rapid detoxification of epoxides generated during the oxidative metabolism of xenobiotics. Although CYP has been demonstrated to modulate methamphetamine (METH)โinduced behavioral effects, little is known about the role of the mEH gene on these effects. We examined the role of mEH gene expression in METHโinduced conditioned place preference and behavioral sensitization by using mEH^โ/โ^ and wildโtype (WT) mice. Extracellular dopamine (DA) levels and DA uptake into synaptosomes were assessed by using an in vivo microdialysis and [^3^H]DA uptake assay. We applied doubleโlabel immunocytochemistry to characterize mEHโpositive cellular types. METHโinduced behavioral responses paralleled striatal cโFosโlike immunoreactivity. METH treatment resulted in increased extracellular DA levels in the nucleus accumbens but decreased synaptosomal DA uptake in the striatum. These behavioral and neurochemical changes were more pronounced in the mEH^โ/โ^ mice than in WT mice. In WT mice, mEHโlike immunoreactivity was expressed in astrocytes labeled by GFAP or S100B after METH treatment. The results suggest that epoxide intermediates mediate METH drug dependence and that astrocytic reactions of mEH protein are important in the endogenous modulation in response to METH drug dependence. ยฉ 2009 WileyโLiss, Inc.