Skip to Main Content
 

Global Search Box

 
 
 
 

Files

File List


ucin1353342344.pdf (2.41 MB)

ETD Abstract Container

Abstract Header

Glutamate and MDMA Neurobehavioral Toxicity

Anneken, John H.
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1353342344

Abstract Details

2012, PhD, University of Cincinnati, Pharmacy: Pharmaceutical Sciences/Biopharmaceutics.
±-3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) is a ring-substituted amphetamine derivative, and a popular psychoactive drug of abuse. This drug evokes a well-documented acute increase in the release of serotonin, dopamine, and acetylcholine, as well as persistent reductions in markers of serotonin axon terminals across several brain regions. Little is known concerning the effect of MDMA exposure on the glutamatergic neurotransmitter system. Excitotoxicity resulting from excessive glutamate release has the potential to contribute to the long-term toxicity of MDMA, including neurochemical and behavioral deficits. The purpose of the present study was to assess the effect of repeated MDMA exposure on extracellular glutamate concentrations in the rat brain, the mechanism(s) underlying this potential response, and the potential behavioral consequences of altered glutamate release. It was found that two and four injections of MDMA (10 mg/kg, i.p.), but not one, significantly elevated the concentration of extracellular glutamate in the dorsal hippocampus. Furthermore, this increase was not observed in either the prefrontal cortex or the striatum. Direct infusion of MDMA to the hippocampus evoked a similar increase, suggesting a local, intrahippocampal site of action of the drug. Furthermore, serotonergic signaling through the 5HT2A/C receptor was implicated in the underlying mechanism of glutamate release by the attenuation of the MDMA effect with either the SSRI fluoxetine or the 5-HT2A/C inhibitor ketanserin. Local administration of the sodium-channel blocker TTX did not prevent the MDMA-induced increase in glutamate efflux, indicating a non-neuronal, e.g. glial, source of glutamate release. In agreement with this conclusion is the finding that pharmacological modulation of glutamate regulatory mechanisms, including upregulation of the GLT-1 glutamate transporter with ceftriaxone, mGluR2/3 stimulation via LY379268, and inhibition of the cystine-glutamate antiporter (Xc-) with 4-S-carboxyphenylglycine (CPG) each attenuated the observed glutamate efflux. The results strongly suggest the likely source of glutamate release is Xc-, which is expressed on glial cells. Results from additional studies into the mechanisms of this MDMA-evoked release of glutamate suggest that the glutamate response is dependent upon inflammatory activation mediated by cyclooxygenase-2, a pathway that can be activated by increased 5-HT2A receptor signaling in glial cells. Stimulated glutamate release was attenuated by the non-selective COX inhibitor ketoprofen (COX1/2) and nimesulide (COX-2), but not piroxicam (COX-1). Reverse dialysis of prostaglandin E2, a major product of COX activity, evoked an increase in hippocampal extracellular glutamate concentration, supporting the ability of COX activation to contribute to glutamate release. Further studies were conducted to determine the contribution of glutamate efflux to the long-term toxicity elicited by MDMA. Administration of ketoprofen to animals receiving a neurotoxic regimen of MDMA failed to attenuate the long-term depletion of 5-HT produced by MDMA in the hippocampus. Ketoprofen also failed to provide protection in water maze assessments of cognitive impairments following MDMA exposure. Together, the results of this study support the view that MDMA evokes a sustained, delayed increase in hippocampal glutamate from the cystine-glutamate antiporter following 5-HT2A activation of COX-2 signaling. Future studies will investigate the contribution of glutamate excitotoxicity to other neurochemical and behavioral deficits produced by MDMA.
Gary Gudelsky, PhD (Committee Chair)
J. F. Nash, PhD (Committee Member)
Jiukuan Hao, PhD (Committee Member)
Neil Richtand, MD (Committee Member)
Georg Weber, MD PhD (Committee Member)
184 p.
Pharmacology
MDMA; glutamate; cyclooxygenase; GABA; 5-HT2A;

Recommended Citations

Citations

  • Anneken, J. H. (2012). Glutamate and MDMA Neurobehavioral Toxicity [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1353342344

    APA Style (7th edition)

  • Anneken, John. Glutamate and MDMA Neurobehavioral Toxicity. 2012. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1353342344.

    MLA Style (8th edition)

  • Anneken, John. "Glutamate and MDMA Neurobehavioral Toxicity." Doctoral dissertation, University of Cincinnati, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1353342344

    Chicago Manual of Style (17th edition)

ucin1353342344
581
© 2012, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.