Role of microsomal epoxide hydrolase in methamphetamine-induced drug dependence in mice.
Microsomal epoxide hydrolase (mEH) and cytochrome P-450 (CYP) ensure the rapid detoxification of epoxides generated during the oxidative metabolism of xenobiotics. Although CYP has been demonstrated to modulate methamphetamine (METH)-induced behavioral effects, little is known about the role of the mEH gene on these effects. We examined the role of mEH gene expression in METH-induced conditioned place preference and behavioral sensitization by using mEH(-/-) and wild-type (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 double-label immunocytochemistry to characterize mEH-positive cellular types. METH-induced behavioral responses paralleled striatal c-Fos-like 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(-/-) mice than in WT mice. In WT mice, mEH-like 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.
Shin
Eun-Joo
EJ
Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon, South Korea.
Bing
Guoying
G
Chae
Jong Seok
JS
Kim
Tae Woo
TW
Bach
Jae-Hyung
JH
Park
Dae Hun
DH
Yamada
Kiyofumi
K
Nabeshima
Toshitaka
T
Kim
Hyoung-Chun
HC
D019969:Amphetamine-Related Disorders / Q000201:enzymology* / Q000235:genetics; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D015153:Blotting, Western; D003216:Conditioning, Operant / Q000187:drug effects*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004851:Epoxide Hydrolases / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D008694:Methamphetamine / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013037:Spatial Behavior / Q000187:drug effects
D008694:Methamphetamine; D004851:Epoxide Hydrolases; D004298:Dopamine