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.

Amphetamine-related drugs neurotoxicity in humans and in experimental animals: Main mechanisms

“…Importantly, glutamatergic dysfunction has been linked to the manifestation of neurodegenerative disorders such as Alzheimer"s disease and PD. This, together with the ability of amphetamine-related drugs to stimulate the release of GLU (Anneken et al, 2013;Shoblock et al, 2003), suggests that this excitatory amino acid could play a role in the neurodegenerative processes induced by these drugs (Lipton et al, 1994;Quinton et al, 2006).…”

Cyclooxygenase-1 inhibition attenuates angiotensin II-salt hypertension and neurogenic pressor activity in the rat

“…After 4 days of COX inhibition or vehicle injection, ANG II (Sigma) or saline was infused at a constant rate of 150 ng·kg Ϫ1 ·min Ϫ1 sc for 14 days (from days 7-21) using a miniosmotic pump (2ML2, Alzet, Cupertino, CA). The dose of ketoprofen was chosen based on previous reports of using the drug in rats (1,29). Arterial pressure and HR were measured daily for the duration of the experiment.…”

MDMA-induced loss of parvalbumin interneurons within the dentate gyrus is mediated by 5HT2A and NMDA receptors

“…The increases in extracellular glutamate concentrations caused by systemic injections of MDMA appear to be mediated by 5HT efflux and prevented by the systemic injections of the non-specific 5HT2 receptor antagonist ketanserin (Anneken and Gudelsky, 2012, Anneken et al, 2013). It remains to be determined which 5HT2 receptor subtype within the hippocampus mediates the increases in extracellular glutamate concentrations.…”

“…Further evidence for neuronal cell loss caused by MDMA originates from recent reports of a loss of parvalbumin (PV) interneurons in the dentate gyrus of MDMA-exposed rodents (Anneken et al, 2013, Abad et al, 2014). These studies concluded that the loss of PV interneurons is associated with MDMA-induced increases in hippocampal glutamate; however, a direct causal role for glutamate receptor activation in mediating this effect remains to be established.…”