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

Abstract

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.

Figure 1. Effect of MDMA on the extracellular concentration of glutamate in the rat hippocampus

Rats received MDMA (10 mg/kg, i.p.) or vehicle at 2 hr intervals for a total of 1, 2 or 4 injections. (n= 6–12 per group) * Indicates values that differ significantly (P<0.05) from vehicle-treated animals. The average baseline value for extracellular glutamate in the hippocampus was 2.81 ± 0.23 ng/20 µL (uncorrected for recovery).

Figure 2. Extracellular glutamate concentrations in the hippocampus, prefrontal cortex and striatum following MDMA administration

Rats received MDMA (10 mg/kg, i.p.) or vehicle at two hour intervals for a total of four injections (vehicle not shown). Microdialysis was performed in the hippocampus, the prefrontal cortex, or the striatum of separate groups of animals. (n= 4–7 per group) * Indicates values that differ significantly (P<0.05) from the corresponding vehicle-treated animals. The baseline values (mean± SEM) for extracellular glutamate were (in ng/20 µL): 4.52 ± 0.61 for the striatum; 3.37 ± 0.28 for the prefrontal cortex; 2.61 ± 0.56 for the dorsal hippocampus (uncorrected for recovery).

Figure 3. Extracellular glutamate concentrations in the hippocampus following reverse dialysis of MDMA

Extracellular glutamate was determined in the hippocampus of control animals and animals that received MDMA (100µM) via reverse dialysis into the hippocampus for 7 h beginning at time 0, as indicated by the solid horizontal line. (n=5–8 per group) *Indicates values that differ significantly (P<0.05) from those animals that received vehicle.

Figure 4. Effect of fluoxetine on the MDMA-induced increase in hippocampal glutamate efflux

Rats received fluoxetine (10 mg/kg, i.p.) or vehicle 30 min prior to the first of two injections of MDMA (10 mg/kg, ip, at 2 hr intervals) or vehicle. (n =4–9 per group) *Indicates values that differ significantly (P<0.05) from those for animals that received VEH+MDMA.

Figure 5. Effect of the 5-HT2A/C antagonist ketanserin on the MDMA-evoked increase in hippocampal glutamate efflux

Rats received ketanserin (3 mg/kg, i.p.) or vehicle 30 min prior to the first injection of MDMA (10 mg/kg, i.p.) or vehicle, then one h after the second injection of MDMA or vehicle. (n =5–13 per group) * indicates values that differ significantly (P<0.05) from those for animals that received VEH+MDMA

Figure 6. Effect of tetrodotoxin on the MDMA-evoked efflux of glutamate in the hippocampus

Tetrodotoxin (10 µM) or vehicle was administered via the dialysis buffer to the rat hippocampus 1 h prior to the first of three injections of MDMA (10 mg/kg, i.p.). (n=7–12 per group)