PMID- 26670377
OWN - NLM
STAT- MEDLINE
DCOM- 20160822
LR  - 20181113
IS  - 1471-4159 (Electronic)
IS  - 0022-3042 (Print)
IS  - 0022-3042 (Linking)
VI  - 136
IP  - 5
DP  - 2016 Mar
TI  - 3,4-methylenedioxymethamphetamine increases excitability in the dentate gyrus: 
      role of 5HT2A receptor-induced PGE2 signaling.
PG  - 1074-84
LID - 10.1111/jnc.13493 [doi]
AB  - 3,4-methylenedioxymethamphetamine (MDMA) is a widely abused psychostimulant, 
      which causes release of serotonin in various forebrain regions. Recently, we 
      reported that MDMA increases 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 by MDMA. Administration of 
      MDMA into the dentate gyrus of rats increased PGE2 concentrations which was 
      prevented by coadministration of MDL100907, a 5HT2A receptor antagonist. 
      MDMA-induced increases in extracellular glutamate were inhibited by local 
      administration of SC-51089, an inhibitor of the EP1 prostaglandin receptor. 
      Systemic administration of SC-51089 during injections of MDMA prevented the 
      decreases in parvalbumin interneurons observed 10 days later. The loss of 
      parvalbumin immunoreactivity after MDMA exposure coincided with a decrease in 
      paired-pulse inhibition and afterdischarge threshold in the dentate gyrus. These 
      changes were prevented by inhibition of EP1 and 5HT2A receptors during MDMA. 
      Additional experiments revealed an increased susceptibility to kainic 
      acid-induced seizures in MDMA-treated rats, which could be prevented with SC51089 
      treatments during MDMA exposure. Overall, these findings suggest that 5HT2A 
      receptors mediate MDMA-induced PGE2 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 of 
      MDMA-treated rats. We 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 of prostaglandin 
      E2 (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.
CI  - (c) 2015 International Society for Neurochemistry.
FAU - Collins, Stuart A
AU  - Collins SA
AD  - Department of Neurosciences, The University of Toledo, Toledo, Ohio, USA.
FAU - Huff, Courtney
AU  - Huff C
AD  - James Winkle College of Pharmacy, University of Cincinnati, Cincinnati, Ohio, 
      USA.
FAU - Chiaia, Nicolas
AU  - Chiaia N
AD  - Department of Neurosciences, The University of Toledo, Toledo, Ohio, USA.
FAU - Gudelsky, Gary A
AU  - Gudelsky GA
AD  - James Winkle College of Pharmacy, University of Cincinnati, Cincinnati, Ohio, 
      USA.
FAU - Yamamoto, Bryan K
AU  - Yamamoto BK
AD  - Department of Neurosciences, The University of Toledo, Toledo, Ohio, USA.
AD  - Department of Pharmacology and Toxicology, Indiana University School of Medicine, 
      Indianapolis, Indiana, USA.
LA  - eng
GR  - DA007606/DA/NIDA NIH HHS/United States
GR  - R01 DA007606/DA/NIDA NIH HHS/United States
GR  - R01 DA035499/DA/NIDA NIH HHS/United States
GR  - DA007427/DA/NIDA NIH HHS/United States
GR  - R01 DA007427/DA/NIDA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20160119
PL  - England
TA  - J Neurochem
JT  - Journal of neurochemistry
JID - 2985190R
RN  - 0 (Central Nervous System Stimulants)
RN  - 0 (Hydrazines)
RN  - 0 (Oxazepines)
RN  - 0 (Receptor, Serotonin, 5-HT2A)
RN  - 0 (Serotonin 5-HT2 Receptor Antagonists)
RN  - 146033-02-5 (SC 51089)
RN  - 3KX376GY7L (Glutamic Acid)
RN  - K7Q1JQR04M (Dinoprostone)
RN  - KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine)
SB  - IM
MH  - Animals
MH  - Central Nervous System Stimulants/pharmacology
MH  - Dentate Gyrus/*drug effects/metabolism
MH  - Dinoprostone/metabolism
MH  - Glutamic Acid/metabolism
MH  - Hippocampus/drug effects/metabolism
MH  - Hydrazines/*pharmacology
MH  - Male
MH  - N-Methyl-3,4-methylenedioxyamphetamine/*pharmacology
MH  - Neurons/*drug effects
MH  - Oxazepines/*pharmacology
MH  - Rats, Sprague-Dawley
MH  - Receptor, Serotonin, 5-HT2A/*drug effects
MH  - Serotonin 5-HT2 Receptor Antagonists/*pharmacology
MH  - Signal Transduction/drug effects
PMC - PMC4755867
MID - NIHMS745893
OTO - NOTNLM
OT  - MDMA
OT  - PGE2
OT  - glutamate
OT  - hippocampus
OT  - parvalbumin
OT  - serotonin
COIS- Conflict of Interest: The authors declare no competing financial interests
EDAT- 2015/12/17 06:00
MHDA- 2016/08/23 06:00
PMCR- 2017/03/01
CRDT- 2015/12/17 06:00
PHST- 2015/07/17 00:00 [received]
PHST- 2015/12/04 00:00 [revised]
PHST- 2015/12/10 00:00 [accepted]
PHST- 2017/03/01 00:00 [pmc-release]
PHST- 2015/12/17 06:00 [entrez]
PHST- 2015/12/17 06:00 [pubmed]
PHST- 2016/08/23 06:00 [medline]
AID - 10.1111/jnc.13493 [doi]
PST - ppublish
SO  - J Neurochem. 2016 Mar;136(5):1074-84. doi: 10.1111/jnc.13493. Epub 2016 Jan 19.