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3,4-methylenedioxymethamphetamine (MDMA, ecstasy)-induced egr-1 mRNA in rat brain: pharmacological manipulation
Y Shirayama1, K Hashimoto, M Iyo
1Division of Cortical Function Disorders, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Tokyo, Kodaira, Japan. yukihiko.shirayama@yale.edu
Abstract:
Using in situ hybridization and immunohistochemical techniques, we examined the expression pattern of egr-1 mRNA and Egr-1 protein in several brain regions following administration of 3, 4-methylenedioxymethamphetamine (MDMA). Furthermore, we also studied the role of N-methyl-D-aspartate (NMDA) receptor, dopamine D(1) receptor, 5-hydroxytryptamine (5-HT) transporter or 5-HT(2A) receptor in the induction of egr-1 mRNA by MDMA. Basal constitutive levels of egr-1 mRNA were detected in control rat brains. A single administration of MDMA (10 mg/kg) caused marked induction of egr-1 mRNA in the prefrontal cortex, striatum and hippocampal dentate gyrus. However, no changes in the egr-1 mRNA levels were detected in the CA1 region of hippocampus and occipital cortex after administration of MDMA (10 mg/kg). Furthermore, the expression of egr-1 mRNA in the prefrontal cortex, striatum and hippocampal dentate gyrus after administration of MDMA (10 mg/kg) was blocked significantly by pretreatment with NMDA receptor antagonist (5R, 10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,b]-cyclohepten-5, 10-imine ((+)-MK801; 1 mg/kg), dopamine D(1) receptor antagonist SCH 23390 (1 mg/kg) or 5-HT uptake inhibitor paroxetine (5 mg/kg), but not by 5-HT(2A) receptor antagonist SR46349B (5 mg/kg). However, high basal levels of Egr-1 immunoreactivity in the rat brain were not altered by administration of MDMA (10 mg/kg). These results suggest that MDMA alters the expression of egr-1 mRNA in several regions of rat brain, and that the expression of egr-1 mRNA by MDMA in the prefrontal cortex, striatum and hippocampal dentate gyrus appears to be mediated, at least in part, by NMDA receptor, dopamine D(1) receptor and 5-HT transporter.
Insights
3,4-methylenedioxymethamphetamine (MDMA) significantly increases egr-1 mRNA in specific rat brain regions. This induction is mediated by N-methyl-D-aspartate receptors, dopamine D(1) receptors, and serotonin transporters, but not 5-HT(2A) receptors.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- The immediate-early gene egr-1 (also known as Zif268) is rapidly induced by various stimuli in the brain.
- 3,4-methylenedioxymethamphetamine (MDMA) is a psychoactive drug with known effects on neurotransmitter systems.
- Understanding the molecular mechanisms underlying MDMA's effects is crucial for neuroscience research.
Purpose of the Study:
- To investigate the expression pattern of egr-1 mRNA and Egr-1 protein in rat brain regions after MDMA administration.
- To determine the roles of N-methyl-D-aspartate (NMDA) receptors, dopamine D(1) receptors, 5-hydroxytryptamine (5-HT) transporters, and 5-HT(2A) receptors in mediating MDMA-induced egr-1 mRNA expression.
Main Methods:
- In situ hybridization and immunohistochemical techniques were used to analyze egr-1 mRNA and Egr-1 protein expression.
- Rats were administered MDMA (10 mg/kg) and various receptor antagonists or inhibitors prior to tissue analysis.
- Specific brain regions examined included the prefrontal cortex, striatum, hippocampus (dentate gyrus and CA1), and occipital cortex.
Main Results:
- MDMA administration significantly induced egr-1 mRNA in the prefrontal cortex, striatum, and hippocampal dentate gyrus.
- No significant changes in egr-1 mRNA levels were observed in the CA1 region of the hippocampus or the occipital cortex.
- Pretreatment with NMDA receptor antagonist ((+)-MK801), dopamine D(1) receptor antagonist (SCH 23390), or 5-HT transporter inhibitor (paroxetine) blocked MDMA-induced egr-1 mRNA expression.
- 5-HT(2A) receptor antagonist (SR46349B) did not block the induction.
- MDMA did not alter the high basal levels of Egr-1 protein immunoreactivity.
Conclusions:
- MDMA alters egr-1 mRNA expression in specific rat brain regions.
- The induction of egr-1 mRNA by MDMA in the prefrontal cortex, striatum, and hippocampal dentate gyrus is mediated by NMDA receptors, dopamine D(1) receptors, and 5-HT transporters.
- Egr-1 protein levels were not affected by MDMA, suggesting post-transcriptional regulation or rapid protein turnover.