A comparison of effects of methamphetamine and MDMA on astroglial and microglial activation, considered to be indirect markers of tissue damage and repair, was performed in rats. Rats either received saline, 4 injections of 10 mg/kg methamphetamine given every 2 h, or 2 injections of 20 mg/kg MDMA given 7 h apart, and across 4 consecutive days. Methamphetamine-treated rats were killed 3 d post-drug, and MDMA-treated rats were killed 3 or 7 d post-drug. The researchers examined striatal, hippocampal and parietal tissues. As expected, lethality increased with increasing ambient temperature (from 22 to 28 deg. C), and lethality was also higher in rats weighing more than 250 mg. Methamphetamine decreased body weight by 10.3% 24 h post-drug, but weight returned to normal 72 h later, when sacrificed. Weight only significantly declined (by 9.3%) on the third day of the MDMA regimen, and weight loss peaked 24 h after the final dose. Weight loss remained significant 72 h post-treatment, but not 7 days later. As expected, methamphetamine reduced striatal dopamine transporter, assessed via a binding assay with the dopamine uptake inhibitor GBR 12935 in the presence versus absence of the dopaminergic drug bupropion. MDMA reduced striatal dopamine transporter sites 3 days post-drug, but not 7 days post-drug. (Referring to another study, the researchers state that methamphetamine reduces dopamine transporter sites for at least 7 days post-drug). Methamphetamine only reduced serotonin transporter in striatal tissue, as assessed via binding with radiolabelled paroxetine (a serotonin uptake inhibitor) in the presence versus absence of clomipramine (tricyclic antidepressant with some serotonin uptake inhibiting activity). By contrast, MDMA reduced serotonin transporter sites hippocampus and parietal cortex, as well as in striatum, 3 and 7 days post-drug. Numbers of striatal and hippocampal serotonin transporter sites increased at 7 d after MDMA, with number of serotonin transporter sites still reduced, but greater at 3 d post-drug. Numbers of serotonin uptake sites in parietal tissue remained reduced both at 3 and 7 days post-MDMA. Microglial activation was assessed via binding assay with PK 11195, a peripheral benzodiazepine receptor (PBR) ligand, as PBR density is considered a marker of microglial activation. Methamphetamine increased striatal PBR density. (Findings from another study indicate that PBR density is no longer increased 7 days after methamphetamine). MDMA did not increase PBR density in the striatum or parietal cortex, and there was only a trend for increased PBR in hippocampus at 3 days post-drug, but not 7 days post-drug. Another immunoassay of microglial activity using the specific antigen OX-6 was performed on tissues from MDMA-treated animals only; this study failed to detect microglial activation in cortex or striatum at 3 and 7 days post-drug. However, microglial activation (detected by greater OX-6 reactivity) was seen in dentate gyrus 3 days post-drug, with evidence of activated microglia no longer seen 7 days post-drug. Astroglial activation was assessed with an assay for heat shock protein 27 (HSP27). Tissues from methamphetamine-treated animals had increased cortical, striatal and hippocampal levels of HSP27, while tissues from MDMA-treated animals did not show any increase in HSP27 in any brain region examined in this study, at 3 or 7 days post-drug. An immunoassay for glial fibrilliary acidic protein (GFAP) also failed to find an increase in cortical or striatal GFAP in tissue from MDMA-treated animals at 3 or 7 days post-drug, but a slight increase was seen in hippocampal (CA1) GFAP 7 days post-drug only. Study demonstrate that methamphetamine activates astroglia and microglia, both involved in the repair of damaged tissue, while MDMA fails to activate either form of glial cell. Absence of microglial activation despite reduction in neurotransmitter transporter sites may be interpreted as indicative of transmitter downregulation and internalization of transporters. Hence, findings do not necessarily confirm serotonin neurotoxicity after MDMA, though the authors note that findings from other studies still support the case for serotonin neurotoxicity. Overall, study findings show that unlike methamphetamine, MDMA does not provoke a potentially harmful inflammatory response, but that MDMA may also fail to stimulate potentially beneficial actions arising from astroglial and microglial activation. This is one of only a few reports directly comparing effects of methamphetamine with MDMA. The implications for human ecstasy users are unclear, since it is not clear what consequences would follow directly from the absence of glial activation.