Altered gene expression in frontal cortex and midbrain of 3,4-methylenedioxymethamphetamine (MDMA) treated mice: Differential regulation of GABA transporter subtypes
✍ Scribed by Weiping Peng; Rabi Simantov
- Book ID
- 102382296
- Publisher
- John Wiley and Sons
- Year
- 2003
- Tongue
- English
- Weight
- 173 KB
- Volume
- 72
- Category
- Article
- ISSN
- 0360-4012
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✦ Synopsis
Abstract
Changes in gene expression were examined in the brain of mice treated with a drug of abuse, 3,4‐methylenedioxymethamphetamine (MDMA, also called Ecstasy). Frontal cortex and midbrain mRNA, analyzed by differential display polymerase chain reaction (DD‐PCR) method, showed an altered expression of several cDNAs, 11 of which were isolated, cloned and sequenced. The sequence of one MDMA‐induced mRNA corresponds (99.3%) to the mouse γ‐amino butyric acid (GABA) transporter 1 (mGAT1). The established involvement of GABA neurotransmission in the activity of several abused drugs prompted us to focus herein on MDMA effect on the GABA transporter gene family. Semi‐quantitative PCR analysis with primers selective to the reported mGAT1 sequence confirmed that MDMA treatment increased mGAT1 expression. Time‐course study of the expression of the three GABA transporter subtypes showed that MDMA induced a differential temporal activation of mGAT1 and mGAT4, but had no effect on mGAT2. Quantitative real‐time PCR further proved the increased expression of mGAT1 and mGAT4 upon MDMA treatment. Western immunoblotting with anti‐GAT1 antibodies showed that MDMA also increased GAT1 protein levels, suggesting that neurotransmission of GABA was altered. MDMA effect was also verified in serotonin transporter knockout (−/−) mice that are insensitive behaviorally to MDMA; the drug did not increase GAT1 protein level in these mutants. In mice, tiagabine and NO‐711, inhibitors of GABA transporters, restrained MDMA‐induced acute toxicity and death. These results should facilitate novel approaches to prevent deleterious effects, including fatality, induced by MDMA and similar abused psychostimulants. © 2003 Wiley‐Liss, Inc.