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3,4-methylenedioxy-methamphetamine(MDMA)-induced Increases in Hippocampal Glutamate Concentrations and Its Impact on the Dentate Gyrus

Collins, Stuart A
http://orcid.org/0000-0003-0096-0119
http://rave.ohiolink.edu/etdc/view?acc_num=mco1438598527

Abstract Details

, Doctor of Philosophy (PhD), University of Toledo, Biomedical Sciences (Neurosciences and Neurological Disorders).
Recently it was demonstrated that MDMA causes a long-term decrease in parvalbumin (PV) expressing interneurons in the dentate gyrus which coincides with an increase in hippocampal glutamate. We hypothesized that the hippocampal glutamate increases mediated by MDMA leads to a loss of PV interneurons and reduces inhibition in the dentate gyrus. Accordingly, the decreases in PV interneurons seen 10 days following MDMA exposure were shown to be dependent upon activation of NMDA receptors during MDMA exposure. Additionally, our experiments demonstrated a role for 5HT2A receptors in mediating both the increases in glutamate within the dentate gyrus and PV interneuron decreases caused by MDMA. We also provided evidence suggesting that 5HT2A receptor activation mediates prostaglandin E2 (PGE2) increases and subsequent Prostaglandin E receptor 1 (EP1) receptor activation. EP1 receptor activation was shown to be necessary for MDMA-induced increases in glutamate concentrations and PV interneuron decreases in the dentate gyrus. Decreased parvalbumin immunoreactivity 10 days after MDMA exposure coincided with a decrease in paired-pulse inhibition and afterdischarge threshold. These changes in physiology were prevented by inhibition of EP1 and 5HT2A receptors during MDMA exposure. These findings suggest that MDMA-induced 5HT increases lead to 5HT2A receptor activation in the dentate gyrus, which elicits PGE2 increases and subsequent increases in glutamate concentrations. Furthermore, we demonstrate that this signaling is also necessary for MDMA-induced PV interneuron decreases and subsequent changes in dentate gyrus physiology suggestive of a lack of GABAergic inhibition.
Bryan Yamamoto (Advisor)
Joseph Margiotta (Committee Member)
Scott Molitor (Committee Member)
Nicolas Chiaia (Committee Member)
Richard Mooney (Committee Member)
127 p.
Neurosciences; Pharmacology; Physiology; Toxicology

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Citations

  • Collins, S. A. (2015). 3,4-methylenedioxy-methamphetamine(MDMA)-induced Increases in Hippocampal Glutamate Concentrations and Its Impact on the Dentate Gyrus [Doctoral dissertation, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=mco1438598527

    APA Style (7th edition)

  • Collins, Stuart. 3,4-methylenedioxy-methamphetamine(MDMA)-induced Increases in Hippocampal Glutamate Concentrations and Its Impact on the Dentate Gyrus. 2015. University of Toledo, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=mco1438598527.

    MLA Style (8th edition)

  • Collins, Stuart. "3,4-methylenedioxy-methamphetamine(MDMA)-induced Increases in Hippocampal Glutamate Concentrations and Its Impact on the Dentate Gyrus." Doctoral dissertation, University of Toledo, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=mco1438598527

    Chicago Manual of Style (17th edition)

mco1438598527
389
© 2015, all rights reserved.
This open access ETD is published by University of Toledo Health Science Campus and OhioLINK.