title: MDMA decreases glutamic acid decarboxylase (GAD) 67-immunoreactive neurons in the hippocampus and increases seizure susceptibility: Role for glutamate.
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 (3×10mg/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 30days 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.
authors: Division of Pharmaceutical Sciences, University of Cincinnati-James Winkle College of Pharmacy, Cincinnati, OH 45267, United States.
authors: Courtney L
authors: CL
authors: Huff
authors: Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati-College of Medicine, Cincinnati, OH, 45219, United States.
authors: Rachel L
authors: RL
authors: Morano
authors: Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati-College of Medicine, Cincinnati, OH, 45219, United States.
authors: James P
authors: JP
authors: Herman
authors: Department of Pharmacology and Toxicology, Indiana University-School of Medicine, Indianapolis, IN 46202, United States.
authors: Bryan K
authors: BK
authors: Yamamoto
authors: Division of Pharmaceutical Sciences, University of Cincinnati-James Winkle College of Pharmacy, Cincinnati, OH 45267, United States. Electronic address: Gary.Gudelsky@uc.edu.
authors: Gary A
authors: GA
authors: Gudelsky
mesh_terms: D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000627:therapeutic use; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D005786:Gene Expression Regulation / Q000187:drug effects*; D005968:Glutamate Decarboxylase / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism; D006213:Hallucinogens / Q000494:pharmacology*; D006624:Hippocampus / Q000166:cytology*; D007608:Kainic Acid / Q000633:toxicity; D008297:Male; D017551:Microdialysis; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D018690:Excitatory Amino Acid Agonists; D006213:Hallucinogens; D018698:Glutamic Acid; D016291:Dizocilpine Maleate; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D007608:Kainic Acid
keywords: Excitotoxicity; GABA; Glutamate; MDMA