MDMA increases glutamate release and reduces parvalbumin-positive GABAergic cells in the dorsal hippocampus of the rat: role of cyclooxygenase

Abstract

3,4-Methylenedioxymethamphetamine (MDMA; Ecstasy) is a popular drug of abuse with well-documented acute effects on serotonergic, dopaminergic, and cholinergic transmitter systems, as well as evidence of long-term disruption of serotoninergic systems in the rat brain. Recently, it was demonstrated that MDMA evokes a delayed and sustained increase in glutamate release in the hippocampus. The purpose of the present study was to determine the role of inflammatory mediators in the MDMA-induced increase in glutamate release, as well as the contribution of inflammatory pathways in the persistent neurochemical toxicity associated with repeated MDMA treatment. Treatment with the non-selective cyclooxygenase (COX) inhibitor ketoprofen and the COX-2 selective inhibitor nimesulide attenuated the increase in extracellular glutamate in the hippocampus evoked by repeated MDMA exposure (10 mg/kg, i.p., every 2 h); no attenuation was observed in rats treated with the COX-1 selective inhibitor piroxicam. Reverse dialysis of a major product of COX activity, prostaglandin E2, also resulted in a significant increase in extracellular glutamate in the hippocampus . Repeated exposure to MDMA diminished the number of parvalbumin-positive GABA interneurons in the dentate gyrus of the hippocampus, an effect that was attenuated by ketoprofen treatment. However, COX inhibition with ketoprofen did not prevent the long-term depletion of 5-HT in the hippocampus evoked by MDMA treatment. These data are supportive of the view that cyclooxygenase activity contributes to the mechanism underlying both the increased release of glutamate and decreased number of GABA interneurons in the rat hippocampus produced by repeated MDMA exposure.

Figure 1. Effect of the COX 1/2 inhibitor ketoprofen. COX-1 inhibitor piroxicam, and COX-2 inhibitor nimesulide on the MDMA-induced efflux of glutamate in the rat hippocampus

Rats received ketoprofen (5 mg/kg, s.c.), piroxicam (3 mg/kg, i.p.) (inset), nimesulide (7.5 mg/kg, i.p.) (inset) or vehicle 1 h prior to and 1 h and 3 h following the first injection of MDMA (10 mg/kg, i.p.) or vehicle. (n= 4-14 per group). Average basal glutamate for VEH-MDMA group was 2.54 ± 0.34 ng/20μL (uncorrected for recovery). Arrows indicate injections with MDMA or Veh. * Indicates values that differ significantly (p<0.05) from Veh-MDMA animals.

Figure 2. Extracellular glutamate concentrations in the hippocampus following reverse dialysis of PGE₂

PGE₂ (30μM) or vehicle was infused via the dialysis buffer into the hippocampus for a duration of 90 min after three 30 min baseline samples were taken. The concentration of PGE₂ was then increased to 100μM for an additional 90 min. (n=5-8 per group) *Indicates values that differ significantly (p<0.05) from those animals that received vehicle.

Figure 3. Effect of ketoprofen on the MDMA-induced reduction of parvalbumin-reactive GABAergic neurons in the rat hippocampus

Panel A is a representative photomicrograph depicting parvalbumin-immunoreactive cells in the dentate gyrus in control animals, as highlighted by the arrows, while panel B is representative of the dentate gyrus of animals given repeated doses of MDMA. Panel C depicts the quantitative assessment of PV-ir neurons in the dentate gyrus of vehicle- and MDMA-treated rats. Rats received ketoprofen (5 mg/kg, s.c.) or vehicle 1 h prior to and 1 h and 3 h following the first of 4 injections of MDMA (10 mg/kg, i.p.) or vehicle. (n = 4-8 per group) * indicates values that differ significantly (p<0.05) from those for animals that received VEH-VEH. # indicates values that differ significantly (p<0.05) from those for animals that received VEH-MDMA.