3,4‐methylenedioxymethamphetamine increases excitability in the dentate gyrus: role of 5HT2A receptor‐inducedPGE2 signaling

Stuart A. Collins; Courtney L Huff; Nicolas Chiaia; Gary A. Gudelsky; Bryan K. Yamamoto

doi:10.1111/jnc.13493

3,4‐methylenedioxymethamphetamine increases excitability in the dentate gyrus: role of 5HT2A receptor‐inducedPGE2 signaling

Stuart A. Collins, Courtney L Huff, Nicolas Chiaia, Gary A. Gudelsky, Bryan K. Yamamoto

Journal of Neurochemistry March 1, 2016 DOI: 10.1111/jnc.13493 (opens in new tab)

Relevant Not relevant

Study at a glance

AI-extracted from the abstract

Characteristics	Preclinical experimental study Peer reviewed
Population	Rats
Interventions	MDMA MDL100907 kainic acid
Duration	10-day follow-up
Topics	MDMA
Key findings	The authors argue that MDMA activates 5HT2A receptors, increasing PGE2 and EP1 receptor signaling, which raises extracellular glutamate and causes loss of parvalbumin interneurons in the dentate gyrus. This loss was linked to reduced paired-pulse inhibition, lower afterdischarge threshold, and increased susceptibility to kainic acid-induced seizures, all prevented by EP1 or 5HT2A receptor inhibition during MDMA exposure.

Abstract

Abstract: 3,4‐methylenedioxymethamphetamine (MDMA) is a widely abused psychostimulant, which causes release of serotonin in various forebrain regions. Recently, we reported thatMDMAincreases extracellular glutamate concentrations in the dentate gyrus, via activation of 5HT2A receptors. We examined the role of prostaglandin signaling in mediating the effects of 5HT2A receptor activation on the increases in extracellular glutamate and the subsequent long‐term loss of parvalbumin interneurons in the dentate gyrus caused byMDMA. Administration ofMDMAinto the dentate gyrus of rats increasedPGE2 concentrations which was prevented by coadministration ofMDL100907, a 5HT2A receptor antagonist.MDMA‐induced increases in extracellular glutamate were inhibited by local administration ofSC‐51089, an inhibitor of theEP1 prostaglandin receptor. Systemic administration ofSC‐51089 during injections ofMDMAprevented the decreases in parvalbumin interneurons observed 10 days later. The loss of parvalbumin immunoreactivity afterMDMAexposure coincided with a decrease in paired‐pulse inhibition and afterdischarge threshold in the dentate gyrus. These changes were prevented by inhibition ofEP1 and 5HT2A receptors duringMDMA. Additional experiments revealed an increased susceptibility to kainic acid‐induced seizures inMDMA‐treated rats, which could be prevented withSC51089 treatments duringMDMAexposure. Overall, these findings suggest that 5HT2A receptors mediateMDMA‐inducedPGE2 signaling and subsequent increases in glutamate. This signaling mediates parvalbumin cell losses as well as physiologic changes in the dentate gyrus, suggesting that the lack of the inhibition provided by these neurons increases the excitability within the dentate gyrus ofMDMA‐treated rats. imageWe hypothesized that the widely abused psychostimulant MDMA causes a loss of parvalbumin (PV) cells and increases excitability in the dentate gyrus. MDMA increases serotonin (5HT) release and activates 5HT2A receptors. The increased activation of 5HT2A receptors promotes the production ofprostaglandinE2 (PGE2) and subsequent activation of EP1 receptors in the dentate gyrus. EP1 receptor activation leads to eventual excitotoxicity and loss of PV interneurons resulting in reduced inhibition and lowered seizure threshold resulting in increased seizure susceptibility.

Comparable studies

Other preclinical and animal studies on MDMA, most cited first.

Study	Year	Design
Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context)	1987	Experimental study
3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain	1987	Animal experiment
Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells	2006	In vitro laboratory study
Small Changes in Ambient Temperature Cause Large Changes in 3,4-Methylenedioxymethamphetamine (MDMA)-Induced Serotonin Neurotoxicity and Core Body Temperature in the Rat Rats	1998	Experimental study
Altered Serotonin Innervation Patterns in the Forebrain of Monkeys Treated with (±)3,4-Methylenedioxymethamphetamine Seven Years Previously: Factors Influencing Abnormal Recovery Squirrel monkeys treated with MDMA	1999	Observational cohort

Citations in the library

Cited by 5

Cites 13

and 8 more in the library