MDMA-induced loss of parvalbumin interneurons within the dentate gyrus is mediated by 5HT2A and NMDA receptors.
MDMA is a widely abused psychostimulant which causes a rapid and robust release of the monoaminergic neurotransmitters dopamine and serotonin. Recently, it was shown that MDMA increases extracellular glutamate concentrations in the dorsal hippocampus, which is dependent on serotonin release and 5HT2A/2C receptor activation. The increased extracellular glutamate concentration coincides with a loss of parvalbumin-immunoreactive (PV-IR) interneurons of the dentate gyrus region. Given the known susceptibility of PV interneurons to excitotoxicity, we examined whether MDMA-induced increases in extracellular glutamate in the dentate gyrus are necessary for the loss of PV cells in rats. Extracellular glutamate concentrations increased in the dentate gyrus during systemic and local administration of MDMA. Administration of the NMDA receptor antagonist, MK-801, during systemic injections of MDMA, prevented the loss of PV-IR interneurons seen 10 days after MDMA exposure. Local administration of MDL100907, a selective 5HT2A receptor antagonist, prevented the increases in glutamate caused by reverse dialysis of MDMA directly into the dentate gyrus and prevented the reduction of PV-IR. These findings provide evidence that MDMA causes decreases in PV within the dentate gyrus through a 5HT2A receptor-mediated increase in glutamate and subsequent NMDA receptor activation.
Department of Neurosciences, The University of Toledo, Toledo, OH 43614, 3000 Arlington Avenue #1007, United States.
Stuart A
SA
Collins
James Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH 45267, 3225 Eden Avenue #136, United States.
Gary A
GA
Gudelsky
Department of Neurosciences, The University of Toledo, Toledo, OH 43614, 3000 Arlington Avenue #1007, United States. Electronic address: bryan.yamamoto@utoledo.edu.
Bryan K
BK
Yamamoto
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000633:toxicity*; D018891:Dentate Gyrus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism; D007395:Interneurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D017551:Microdialysis; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000633:toxicity*; D010320:Parvalbumins / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A / Q000187:drug effects* / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists* / Q000378:metabolism; D058826:Serotonin 5-HT2 Receptor Agonists / Q000633:toxicity*; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000494:pharmacology; D013997:Time Factors; D015854:Up-Regulation
D000697:Central Nervous System Stimulants; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D010320:Parvalbumins; D044402:Receptor, Serotonin, 5-HT2A; D016194:Receptors, N-Methyl-D-Aspartate; D058826:Serotonin 5-HT2 Receptor Agonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D018698:Glutamic Acid; D018817:N-Methyl-3,4-methylenedioxyamphetamine
GABA; Glutamate; Hippocampus; MDMA; Parvalbumin; Serotonin