Effect of adenosine receptors on 3, 4 methylene dioxy methamphetamine induced hyperthermic, neuroinflammatory and neurotoxic effects in mouse brain

Previous studies of ours and other groups in mice have shown that 3, 4 Methylenedioxymethamphetamine (MDMA, ecstasy) produces neurotoxic damage to dopaminergic neurons and neuroinflammation and caffeine, an adenosine A1/A2A antagonist enhances glial activation induced by MDMA, suggesting potential facilitation of neurodegenerative processes. In the present study we want to investigate effect of caffeine on MDMA induced dopaminergic neurotoxicity in adult mice, whereas selective A1 ( DPCPX ) and A2A ( SCH58261 ) antagonist will be evaluated in adult mice only. C57BL/6J male mice were treated with MDMA (4x20 mg/kg, i.p.) at 2 h interval alone or in combination with caffeine (10 mg/kg, i.p.), SCH 58261( 0.5 mg/kg, i.p.), DPCPX (0.5 mg/kg, i.p.) or saline 30 mins before first and third administration of MDMA. Caffeine, SCH 58261, DPCPX was given for two more days after MDMA treatment. Mice were sacrificed 48 h after last administration of MDMA. Immunohistochemistry of tyrosine hydroxylase (TH), CD11b and glial fibrillary acidic protein (GFAP) were performed to detect dopaminergic neuronal damage, microglia and astroglia activation respectively in substantia nigra pars compacta (SNc) and striatum (CPu). Repeated administration of MDMA induced significant decrease (15%) in TH positive neurons in SNc as compare to vehicle. Association of caffeine, SCH 58261, DPCPX with MDMA did not further decrease TH positive neurons as compare to MDMA alone. MDMA induced significant increase in CD11b immunoreactivity in SNc and CPu and GFAP immunoreactivity in CPu as compare to vehicle in adult mice. Treatment with SCH 58261 significantly potentiated MDMA induced increase in CD11b immunoreactivity in both SNc and CPu, whereas SCH58261 did not alter MDMA induced GFAP immunoreactivity in CPu. In contrast, treatment with DPCPX significantly potentiated both MDMA induced increase in CD11b and GFAP immunoreactivity in CPu but not in SNc. Results suggest that association of MDMA plus caffeine could produce increase of MDMA toxicity and both A1 and A2A receptors are involved in the potentiation of MDMA-mediated neuroinflammatory but not neurodegenerative effects suggesting a role of adenosine in MDMA harmful effects