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D-serine potentiates the induction of arc mRNA by MDMA in rat frontal cortex but not parietal cortex Arc (activity-regulated cytoskeleton associated gene) is a functional immediate early gene implicated in synaptic plasticity (Steward & Worley, 2001) . Expression of Arc in rat brain is induced by neuronal excitation and by stimulation of 5-HT2A, D 1 and glutamatergic NMDA receptors. MDMA (3,4-methylenedioxymethamphetamine) is an amphetamine analogue which induces the release of monoamines, principally 5-HT and dopamine, and acutely induces expression of Arc mRNA in rat brain in a regionally specific manner (Beveridge et al., 2004). D-Serine acts as a co-agonist at the NMDA receptor via the ‘glycine’ site to enhance ion flux following activation of the receptor by glutamate (Johnson & Ascher, 1987). In this study we have investigated the effect of co-administration of D-serine with MDMA on Arc mRNA expression in order to examine the role of glutamate in mediating neuronal effects of MDMA. Male Sprague-Dawley rats (225-250g) were administered (i.p.) either saline (1ml/kg), D-serine (100mg/kg), MDMA (15mg/kg) or both D-serine (100mg/kg) and MDMA (15mg/kg). The rats were killed 1 hour later and the brains isolated and immediately frozen in cooled isopentane. Arc mRNA expression was analysed by in situ hybridisation histochemistry using [35S]-dATP labelled oligonucleotide probe as described previously (Beveridge et al., 2004). Relative abundance of Arc mRNA in selected brain areas was determined by densitometric quantification of autoradiograms using NIH Image-J software. Statistical analysis of the results was made using 1-way or 2-way ANOVA as appropriate and Newman-Keuls post-hoc test with signficance set at P<0.05. In both cingulate and orbital regions of the frontal cortex, MDMA induced a significant increase in Arc mRNA expression of 152% and 99% respectivley (Table 1). D-Serine alone did not affect Arc expression in either brain region. However co-administration of D-serine with MDMA generated significantly greater expression of Arc in both cingulate (27%) and orbital (32%) cortex compared to the effect of MDMA alone. Two-way ANOVA indicated a significant interaction effect of MDMA and D-serine in both brain regions. In parietal cortex MDMA alone again induced a significant increase (174%) in Arc expression but this was not significantly altered by coadministration of D-serine. Table 1 : Effect of D-serine and/or MDMA on Arc mRNA expression in rat frontal cortex.
Data (nCi/g tissue) are expressed as mean +/- SEM (n=6). * P<0.05 v Saline ; # P<0.05 v MDMA This study demonstrates that although D-serine alone did not affect basal expression of Arc mRNA in rat cortex, co-administration with MDMA significantly potentiated expression relative to that induced by MDMA alone in frontal but not in parietal regions. Previous studies have demonstrated that the acute induction of Arc by MDMA is attenuated by prior administration of the NMDA receptor antagonist MK-801 (Beveridge & Elliott, unpublished observation). The current data provide further evidence that glutamate may be implicated in the neuronal mechanism by which MDMA induces Arc expression in frontal but not in parietal cortex.
Beveridge, TJR et al. (2004) Psychopharmacology 173 , 346-352. |
