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 K. Yamamoto, Gary A. Gudelsky
Neurotoxicology December 2016 DOI: 10.1016/j.neuro.2016.10.011 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical experimental study (rodent) Peer reviewed |
|---|---|
| Population | Rats |
| Interventions | MDMA MK-801 ceftriaxone kainic acid |
| Dose | MDMA 3×10 mg/kg, ip |
| Duration | At least 30 days following MDMA treatment |
| Measures | GAD67-immunoreactive cell counts, kainic acid-induced seizure susceptibility, extracellular glutamate concentration |
| Topics | MDMA Anxiety |
| Keywords | Excitotoxicity Gaba Glutamate |
| Key findings | Repeated MDMA (3×10 mg/kg) reduced GAD67-immunoreactive hippocampal neurons by 37-58% and increased kainic acid seizure susceptibility for at least 30 days. The NMDA antagonist MK-801 and the GLT-1 inducer ceftriaxone prevented both effects, and ceftriaxone reduced MDMA-induced extracellular glutamate increases, supporting a glutamatergic mechanism. |
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.
Comparable studies
Other preclinical and animal studies on MDMA for anxiety, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| 3,4-Methylenedioxymethamphetamine facilitates fear extinction learning Mice | 2015 | Preclinical experimental study | |
| Effects of acute social stress on the conditioned place preference induced by MDMA in adolescent and adult mice Adolescent (postnatal day 29-40) and adult (postnatal day 50-61) male mice | 2014 | Experimental study | |
| MDMA in Adolescent Male Rats Adolescent male rats (postnatal day 45) | 2006 | Controlled experiment | n = 12 |
| Psychedelics: A review of their effects on recalled aversive memories and fear/anxiety expression in rodents Rodents | 2024 | Review | |
| Differential behavioral outcomes of 3,4-methylenedioxymethamphetamine (MDMA-ecstasy) in anxiety-like responses in mice 2-month-old Balb/c male mice (25-35 g) | 2013 | Observational study | n = 70 |
Citations in the library
Cited by 4
- Psychedelics in Psychiatry: Neuroplastic, Immunomodulatory, and Neurotransmitter Mechanisms Pharmacological Reviews December 16, 2020
- Longitudinal Examination of Learning and Memory in Rats Following Adolescent Exposure to 3,4-Methylenedioxymethamphetamine or 5-Methoxy-N,N-Diisopropyltryptamine Journal of Behavioral and Brain Science 2017
- Treadmill Exercise Training Ameliorates Apoptotic Cells and DNA Oxidation in the Cerebral Cortex of Rats Exposed to Chronic Ketamine Abuse. Addiction Biology March 1, 2025
- Progression and Persistence of Neurotoxicity Induced by MDMA in Dopaminergic Regions of the Mouse Brain and Association with Noradrenergic, GABAergic, and Serotonergic Damage. Neurotoxicity Research November 2017
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