MDMA administration decreases serotonin but not N-acetylaspartate in the rat brain

Perrine, Shane A.; Ghoddoussi, Farhad; Michaels, Mark S.; Hyde, Elisabeth; Kuhn, Donald M.; Galloway, Matthew P.

doi:10.1016/j.neuro.2010.08.005

Cited by 25 publications

(30 citation statements)

References 75 publications

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“…To our knowledge, this is the first demonstration that MDMA reduces GAD67-IR in any brain region. These data are consistent with earlier reports that MDMA decreases the concentration of GABA in the hippocampus (Perrine et al, 2010) and reduces the number parvalbumin-IR GABAergic neurons in the hippocampus of rodents (Abad et al, 2014; Anneken et al, 2013; Collins et al, 2015a). …”

Section: Discussionsupporting

confidence: 93%

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

et al. 2016

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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 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.

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Section: Discussionsupporting

confidence: 93%

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

et al. 2016

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“…Acute MDMA administration in rodents was associated with elevated myo- inositol levels [52]. In humans, MRS studies among long-term and heavy methamphetamine/MDMA users suggest myo- inositol levels are elevated, while less frequent users exhibited unaltered neurochemistry.…”

Section: Resultsmentioning

confidence: 99%

“…Our examination revealed several working hypotheses. First, preclinical studies indicate that acute administration of tobacco smoke [108-110], alcohol [147, 153, 154], methamphetamine/MDMA [52, 210-212], and opioids [223, 227-229] activate the neuroimmune system. These findings have yet to be translated and confirmed in humans.…”

Section: Discussion and Future Directionsmentioning

confidence: 99%

“…In MS patients, higher myo- inositol levels were colocalized with brain lesions [39, 51]. Also, acute challenges with substances known to have proinflammatory effects (e.g., methylenedioxy-methamphetamine [MDMA]) increase myo- inositol levels in the brain [52]. However, myo- inositol has not been thoroughly validated as a neuroimmune marker and is not without caveats.…”

Section: Using Imaging To Measure Neuroimmune Biomarkersmentioning

confidence: 99%

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Imaging Biomarkers of the Neuroimmune System among Substance Use Disorders: A Systematic Review

et al. 2019

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There is tremendous interest in the role of the neuroimmune system and inflammatory processes in substance use disorders (SUDs). Imaging biomarkers of the neuroimmune system in vivo provide a vital translational bridge between preclinical and clinical research. Herein, we examine two imaging techniques that measure putative indices of the neuroimmune system and review their application among SUDs. Positron emission tomography (PET) imaging of 18 kDa translocator protein availability is a marker associated with microglia. Proton magnetic resonance spectroscopy quantification of myo-inositol levels is a putative glial marker found in astrocytes. Neuroinflammatory responses are initiated and maintained by microglia and astrocytes, and thus represent important imaging markers. The goal of this review is to summarize neuroimaging findings from the substance use literature that report data using these markers and discuss possible mechanisms of action. The extant literature indicates abused substances exert diverse and complex neuroimmune effects. Moreover, drug effects may change across addiction stages, i.e. the neuroimmune effects of acute drug administration may differ from chronic use. This burgeoning field has considerable potential to improve our understanding and treatment of SUDs. Future research is needed to determine how targeting the neuroimmune system may improve treatment outcomes.

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“…Acute MDMA induces 5-HT release from the dorsal raphe nucleus (Bradberry et al, 1990), known to be a major source of 5-HT for the forebrain (Azmitia and Segal, 1978; Jacobs and Azmitia, 1992; Koch and Galloway, 1997), although the subsequent effects of various repeated (experimenter-administered) dosing regimens have produced differential alterations of the 5-HT system. A commonly used neurotoxic dosing regimen (4 injections per day for 1–2 days) depletes monoamine neurotransmitter levels in adult rats, specifically 5-HT and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA), as well as 5-HT markers such as 5-HT transporters (SERT) and receptors, with varying degrees of recovery (Gurtman et al, 2002; McNamara et al, 1995; Perrine et al, 2010). These ‘neurotoxic’ effects are observed in a number of 5-HT projection fields although neuroanatomical specificity is seen with greater depletion in cortical and limbic areas and less in thalamic structures (Battaglia et al, 1991).…”

Section: Introductionmentioning

confidence: 99%

Behavioral and neurochemical effects of repeated MDMA administration during late adolescence in the rat

Cox

Shah

Cichon

et al. 2014

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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Adolescents and young adults disproportionately abuse 3,4-methylenedioxymethamphetamine (MDMA; ‘Ecstasy’); however, since most MDMA research has concentrated on adults, the effects of MDMA on the developing brain remain obscure. Therefore, we evaluated place conditioning to MDMA (or saline) during late adolescence and assessed anxiety-like behavior and monoamine levels during abstinence. Rats were conditioned to associate 5 or 10 mg/kg MDMA or saline with contextual cues over 4 twice-daily sessions. Five days after conditioning, anxiety-like behavior was examined with the open field test and brain tissue was collected to assess serotonin (5-hydroxytryptamine, 5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the dorsal raphe, amygdala, and hippocampus by high-pressure liquid chromatography (HPLC). In a separate group of rats, anxiety-like and avoidant behaviors were measured using the light–dark box test under similar experimental conditions. MDMA conditioning caused a place aversion at 10, but not at 5, mg/kg, as well as increased anxiety-like behavior in the open field and avoidant behavior in light–dark box test at the same dose. Additionally, 10 mg/kg MDMA decreased 5-HT in the dorsal raphe, increased 5-HT and 5-HIAA in the amygdala, and did not alter levels in the hippocampus. Overall, we show that repeated high (10 mg/kg), but not low (5 mg/kg), dose MDMA during late adolescence in rats increases anxiety-like and avoidant behaviors, accompanied by region-specific alterations in 5-HT levels during abstinence. These results suggest that MDMA causes a region-specific dysregulation of the serotonin system during adolescence that may contribute to maladaptive behavior.

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MDMA administration decreases serotonin but not N-acetylaspartate in the rat brain

Cited by 25 publications

References 75 publications

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

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

Imaging Biomarkers of the Neuroimmune System among Substance Use Disorders: A Systematic Review

Behavioral and neurochemical effects of repeated MDMA administration during late adolescence in the rat

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