PMID- 28741031
OWN - NLM
STAT- MEDLINE
DCOM- 20180530
LR  - 20240327
IS  - 1432-2072 (Electronic)
IS  - 0033-3158 (Print)
IS  - 0033-3158 (Linking)
VI  - 234
IP  - 19
DP  - 2017 Oct
TI  - Inhibition of serotonin transporters disrupts the enhancement of fear memory 
      extinction by 3,4-methylenedioxymethamphetamine (MDMA).
PG  - 2883-2895
LID - 10.1007/s00213-017-4684-8 [doi]
AB  - RATIONALE: 3,4-Methylenedioxymethamphetamine (MDMA) persistently improves 
      symptoms of post-traumatic stress disorder (PTSD) when combined with 
      psychotherapy. Studies in rodents suggest that these effects can be attributed to 
      enhancement of fear memory extinction. Therefore, MDMA may improve the effects of 
      exposure-based therapy for PTSD, particularly in treatment-resistant patients. 
      However, given MDMA's broad pharmacological profile, further investigation is 
      warranted before moving to a complex clinical population. OBJECTIVES: We aimed to 
      inform clinical research by providing a translational model of MDMA's effect, and 
      elucidating monoaminergic mechanisms through which MDMA enhances fear extinction. 
      METHODS: We explored the importance of monoamine transporters targeted by MDMA to 
      fear memory extinction, as measured by reductions in conditioned freezing and 
      fear-potentiated startle (FPS) in mice. Mice were treated with selective 
      inhibitors of individual monoamine transporters prior to combined MDMA treatment 
      and fear extinction training. RESULTS: MDMA enhanced the lasting extinction of 
      FPS. Acute and chronic treatment with a 5-HT transporter (5-HTT) inhibitor 
      blocked MDMA's effect on fear memory extinction. Acute inhibition of dopamine 
      (DA) and norepinephrine (NE) transporters had no effect. 5-HT release alone did 
      not enhance extinction. Blockade of MDMA's effect by 5-HTT inhibition also 
      downregulated 5-HT(2A)-mediated behavior, and 5-HT(2A) antagonism disrupted 
      MDMA's effect on extinction. CONCLUSIONS: We validate enhancement of fear memory 
      extinction by MDMA in a translational behavioral model, and reveal the importance 
      of 5-HTT and 5-HT(2A) receptors to this effect. These observations support future 
      clinical research of MDMA as an adjunct to exposure therapy, and provide 
      important pharmacological considerations for clinical use in a population 
      frequently treated with 5-HTT inhibitors.
FAU - Young, Matthew B
AU  - Young MB
AD  - Department of Psychiatry and Behavioral Sciences, Emory University School of 
      Medicine, 954 Gatewood Rd NE #2101, Atlanta, GA, 30329, USA.
FAU - Norrholm, Seth D
AU  - Norrholm SD
AD  - Department of Psychiatry and Behavioral Sciences, Emory University School of 
      Medicine, 954 Gatewood Rd NE #2101, Atlanta, GA, 30329, USA.
AD  - Atlanta VA Medical Center, Mental Health Service Line, Decatur, GA, USA.
FAU - Khoury, Lara M
AU  - Khoury LM
AD  - Emory University, Atlanta, GA, USA.
FAU - Jovanovic, Tanja
AU  - Jovanovic T
AD  - Department of Psychiatry and Behavioral Sciences, Emory University School of 
      Medicine, 954 Gatewood Rd NE #2101, Atlanta, GA, 30329, USA.
AD  - Atlanta VA Medical Center, Mental Health Service Line, Decatur, GA, USA.
FAU - Rauch, Sheila A M
AU  - Rauch SAM
AD  - Department of Psychiatry and Behavioral Sciences, Emory University School of 
      Medicine, 954 Gatewood Rd NE #2101, Atlanta, GA, 30329, USA.
AD  - Atlanta VA Medical Center, Mental Health Service Line, Decatur, GA, USA.
FAU - Reiff, Collin M
AU  - Reiff CM
AD  - Department of Psychiatry and Behavioral Sciences, Emory University School of 
      Medicine, 954 Gatewood Rd NE #2101, Atlanta, GA, 30329, USA.
FAU - Dunlop, Boadie W
AU  - Dunlop BW
AD  - Department of Psychiatry and Behavioral Sciences, Emory University School of 
      Medicine, 954 Gatewood Rd NE #2101, Atlanta, GA, 30329, USA.
FAU - Rothbaum, Barbara O
AU  - Rothbaum BO
AD  - Department of Psychiatry and Behavioral Sciences, Emory University School of 
      Medicine, 954 Gatewood Rd NE #2101, Atlanta, GA, 30329, USA.
FAU - Howell, Leonard L
AU  - Howell LL
AD  - Department of Psychiatry and Behavioral Sciences, Emory University School of 
      Medicine, 954 Gatewood Rd NE #2101, Atlanta, GA, 30329, USA. lhowell@emory.edu.
LA  - eng
GR  - P51 OD011132/OD/NIH HHS/United States
GR  - R01 MH094757/MH/NIMH NIH HHS/United States
GR  - K05 DA031246/DA/NIDA NIH HHS/United States
GR  - K21 GM000680/National Institute of General Medical Sciences/
GR  - K12 GM000680/GM/NIGMS NIH HHS/United States
PT  - Journal Article
DEP - 20170724
PL  - Germany
TA  - Psychopharmacology (Berl)
JT  - Psychopharmacology
JID - 7608025
RN  - 0 (Serotonin Plasma Membrane Transport Proteins)
RN  - 0 (Serotonin Uptake Inhibitors)
RN  - KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine)
SB  - IM
MH  - Animals
MH  - Dose-Response Relationship, Drug
MH  - Extinction, Psychological/*drug effects/physiology
MH  - Fear/*drug effects/physiology/psychology
MH  - Male
MH  - Memory/*drug effects/physiology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - N-Methyl-3,4-methylenedioxyamphetamine/therapeutic use/*toxicity
MH  - *Serotonin Plasma Membrane Transport Proteins/metabolism
MH  - Selective Serotonin Reuptake Inhibitors/*pharmacology/therapeutic use
MH  - Stress Disorders, Post-Traumatic/chemically induced/drug therapy/psychology
PMC - PMC5693755
MID - NIHMS895158
OTO - NOTNLM
OT  - Fear extinction
OT  - Fear-potentiated startle
OT  - MDMA
OT  - Monoamines
OT  - Serotonin
EDAT- 2017/07/26 06:00
MHDA- 2018/05/31 06:00
PMCR- 2018/10/01
CRDT- 2017/07/26 06:00
PHST- 2017/03/23 00:00 [received]
PHST- 2017/06/24 00:00 [accepted]
PHST- 2017/07/26 06:00 [pubmed]
PHST- 2018/05/31 06:00 [medline]
PHST- 2017/07/26 06:00 [entrez]
PHST- 2018/10/01 00:00 [pmc-release]
AID - 10.1007/s00213-017-4684-8 [pii]
AID - 10.1007/s00213-017-4684-8 [doi]
PST - ppublish
SO  - Psychopharmacology (Berl). 2017 Oct;234(19):2883-2895. doi: 
      10.1007/s00213-017-4684-8. Epub 2017 Jul 24.