MDMA produces a delayed and sustained increase in the extracellular concentration of glutamate in the rat hippocampus.

The neurochemical effects of MDMA (3,4-methylenedioxymethamphetamine) on monoaminergic and cholinergic systems in the rat brain have been well documented. However, little is known regarding the effects of MDMA on glutamatergic systems in the brain. In the present study the effects of multiple injections of MDMA on extracellular concentrations of glutamate in the striatum, prefrontal cortex, and dorsal hippocampus were examined. Two or four, but not one, injections of MDMA (10 mg/kg, i.p. at 2 h intervals) resulted in a 2-3 fold increase in the extracellular concentration of glutamate in the hippocampus; no increase was evident in the striatum or prefrontal cortex. Reverse dialysis of MDMA (100 μM) into the hippocampus also elicited an increase in extracellular glutamate. Treatment with the 5-HT reuptake inhibitor fluoxetine prevented the increase in extracellular glutamate in the hippocampus following the systemic administration of MDMA, as did treatment with the serotonin 5-HT2A/C receptor antagonist ketanserin. Moreover, reverse dialysis of the sodium channel blocker tetrodotoxin did not prevent the increase in extracellular glutamate in the hippocampus. These data support the view that stimulation of 5-HT2A/2C receptors on non-neuronal cells by 5-HT released by MDMA promotes glutamate efflux in the hippocampus.