MOP Reduction During Long-Term Methamphetamine Withdrawal was Restored by Chronic Post-Treatment with Fluoxetine

H.      Yamamoto; Y.      Takamatsu; K.      Imai; E.      Kamegaya; Y.      Hagino; M.      Watanabe; T.      Yamamoto; I.      Sora; H.      Koga; K.      Ikeda

doi:10.2174/157015911795017056

Abstract

Previously, we found fluoxetine reduces methamphetamine preference in mice. However, effects of fluoxetine on developed methamphetamine preference and on methamphetamine induced gene expression changes have been largely unknown. The present study investigates effects of post-treatment with fluoxetine on methamphetamine dependence and on gene expressions after long-term withdrawal in mice. First, we examined whether chronic post-treatment with fluoxetine attenuated methamphetamine-conditioned place preference. Next, we examined the changes in gene expression levels after long-term withdrawal (with saline or fluoxetine treatment) following chronic methamphetamine treatment. Using mRNA from the pooled frontal cortices of 10 mice per group, gene expression analyses were performed using a customdeveloped cDNA array and a real-time quantitative reverse transcription-PCR. Chronic post-treatments with fluoxetine abolished the conditioned place preference developed by methamphetamine administrations. Even after long-term withdrawal from repeated methamphetamine administration, μ-opioid receptor (MOP) gene expression was significantly reduced in the frontal cortex. The reduced MOP gene expression in the frontal cortex was restored by chronic administration with fluoxetine. These changes were confirmed by Western blot analyses. These findings suggest that the chronic posttreatments with fluoxetine might be effective for restoring the reduction of MOP levels in the frontal cortex following long-term abstinence from methamphetamine.

Keywords: Methamphetamine, conditioned place preference, gene expression, withdrawal, fluoxetine, mu-opioid receptor, frontal cortex, mice, Serotonergic System, Chronic Post- Treatment