Antagonism of Adenosine A 1 or A 2A Receptors Amplifies the Effects of MDMA on Glial Activation in the Mouse Brain: Relevance to Caffeine–MDMA Interactions

Background: Previous studies by our group have demonstrated that caffeine, an antagonist of adenosine A 1 and A 2A receptors, amplifies the glial activation induced by 3,4-methylendioxymethamphetamine (MDMA, “ecstasy”) in mice. To elucidate the mechanisms underlying this effect, the present study evaluated whether selective antagonists for the A 1 or the A 2A adenosine receptor had any influence on MDMA-induced glial activation.

Methods: MDMA (4×20 mg/kg) was administered to mice, alone or in combination with either the A 1 antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, 0.5 mg/kg) or the A 2A antagonist 5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c) pyrimidine (SCH 58261, 0.5 mg/kg). Immunoreactivity for complement type 3 receptor (CD11b) and glial fibrillary acidic protein (GFAP) was then studied in the striatum and substantia nigra pars compacta (SNc) to evaluate microglial and astroglial activation.

Results: DPCPX amplified the elevation of both CD11b and GFAP immunoreactivity triggered by MDMA in the striatum, but did not affect MDMA-induced glial activation in the SNc. This effect was similar to that previously observed in mice treated with caffeine and MDMA in combination. Conversely, SCH 58261 potentiated MDMA-elicited elevation of CD11b immunoreactivity in both the striatum and SNc, but did not modify the effects of MDMA on GFAP in either region.

Conclusions: These results demonstrate that both A 1 and A 2A receptors regulate MDMA-stimulated glial activation, and suggest that caffeine elicits the same effect chiefly by acting on A 1 receptors.