MDMA decreases glutamic acid decarboxylase (GAD) 67-immunoreactive neurons in the hippocampus and increases seizure susceptibility: Role for glutamate

Courtney L. Huff, Rachel L. Morano, James P. Herman, Bryan Yamamoto, Gary A. Gudelsky

Research output: Contribution to journalArticle

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Abstract

3,4-Methylenedioxy-methamphetamine (MDMA) is a unique psychostimulant that continues to be a popular drug of abuse. It has been well documented that MDMA reduces markers of 5-HT axon terminals in rodents, as well as humans. A loss of parvalbumin-immunoreactive (IR) interneurons in the hippocampus following MDMA treatment has only been documented recently. In the present study, we tested the hypothesis that MDMA reduces glutamic acid decarboxylase (GAD) 67-IR, another biochemical marker of GABA neurons, in the hippocampus and that this reduction in GAD67-IR neurons and an accompanying increase in seizure susceptibility involve glutamate receptor activation. Repeated exposure to MDMA (3 × 10 mg/kg, ip) resulted in a reduction of 37–58% of GAD67-IR cells in the dentate gyrus (DG), CA1, and CA3 regions, as well as an increased susceptibility to kainic acid-induced seizures, both of which persisted for at least 30 days following MDMA treatment. Administration of the NMDA antagonist MK-801 or the glutamate transporter type 1 (GLT-1) inducer ceftriaxone prevented both the MDMA-induced loss of GAD67-IR neurons and the increased vulnerability to kainic acid-induced seizures. The MDMA-induced increase in the extracellular concentration of glutamate in the hippocampus was significantly diminished in rats treated with ceftriaxone, thereby implicating a glutamatergic mechanism in the neuroprotective effects of ceftriaxone. In summary, the present findings support a role for increased extracellular glutamate and NMDA receptor activation in the MDMA-induced loss of hippocampal GAD67-IR neurons and the subsequent increased susceptibility to evoked seizures.

Original languageEnglish (US)
Pages (from-to)282-290
Number of pages9
JournalNeuroToxicology
Volume57
DOIs
StatePublished - Dec 1 2016

Fingerprint

Glutamate Decarboxylase
Methamphetamine
Neurons
Glutamic Acid
Hippocampus
Seizures
Ceftriaxone
Kainic Acid
Glutamate Receptors
Chemical activation
Amino Acid Transport System X-AG
GABAergic Neurons
Parvalbumins
Dizocilpine Maleate
Dentate Gyrus
Presynaptic Terminals
Street Drugs
Neuroprotective Agents
Interneurons
N-Methylaspartate

Keywords

  • Excitotoxicity
  • GABA
  • Glutamate
  • MDMA

ASJC Scopus subject areas

  • Neuroscience(all)
  • Toxicology

Cite this

MDMA decreases glutamic acid decarboxylase (GAD) 67-immunoreactive neurons in the hippocampus and increases seizure susceptibility : Role for glutamate. / Huff, Courtney L.; Morano, Rachel L.; Herman, James P.; Yamamoto, Bryan; Gudelsky, Gary A.

In: NeuroToxicology, Vol. 57, 01.12.2016, p. 282-290.

Research output: Contribution to journalArticle

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