Inhibition of serotonin transporters disrupts the enhancement of fear memory extinction by 3,4-methylenedioxymethamphetamine (MDMA)

• Type of Material: Article
• Authors: Matthew B. Young, Emory University; Seth Norrholm, Emory University; Lara M. Khoury, Emory University; Tanja Jovanovic, Emory University; Sheila Rauch, Emory University; Collin M. Reiff, Emory University; Boadie Dunlop, Emory University; Barbara Rothbaum, Emory University; Leonard Howell, Emory University
• Language: English
• Date: 2017-10-01
• Publisher: SRL Archive
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017, Springer-Verlag GmbH Germany.
• Final Published Version (URL): http://dx.doi.org/10.1007/s00213-017-4684-8
• Title of Journal or Parent Work: Психофармакология и биологическая нарко / Psychopharmacology and Biological Narcology
• ISSN: 1606-8181
• Volume: 234
• Issue: 19
• Start Page: 2883
• End Page: 2895
• Grant/Funding Information: L.L.H. was supported by NIH/NIDA K05 DA031246. B.O.R. has funding from Wounded Warrior Project, Department of Defense Clinical Trial Grant No.W81XWH-10-1-1045, “Enhancing Exposure Therapy for PTSD: Virtual Reality and Imaginal Exposure with a Cognitive Enhancer”, National Institute of Mental Health Grant No. 1R01MH094757-01, “Prospective Determination of Psychobiological Risk Factors for Posttraumatic Stress,” Brain and Behavior Research Foundation (NARSAD) Distinguished Investigator Grant, “Optimal Dose of early intervention to prevent PTSD”, and McCormick Foundation “Brave Heart: MLB's Welcome Back Veterans SouthEast Initiative.”; B.W.D. has received research support from Assurex, Axsome, Bristol-Myers Squibb, GlaxoSmithKline, Janssen, NIMH, Otsuka, Pfizer, and Takeda. He has served as a consultant to Pfizer and Medavante.; Dr. Rothbaum receives royalties from Oxford University Press, Guilford, APPI, and Emory University and received one advisory board payment from Genentech.; M.B.Y. was supported by a NIH/NIGMS IRACDA grant K21 GM000680 awarded to Emory University.
• Keywords: EXPOSURE THERAPY; ECSTASY; MDMA; DOPAMINE RELEASE; 5-HT2A RECEPTORS; Life Sciences & Biomedicine; RECEPTOR FUNCTION; Science & Technology; Fear-potentiated startle; Fear extinction; C57BL/6J MICE; Pharmacology & Pharmacy; Monoamines; RHESUS-MONKEYS; Neurosciences; HEALTHY HUMANS; Psychiatry; POSTTRAUMATIC-STRESS-DISORDER; Neurosciences & Neurology; Serotonin; POTENTIATED STARTLE
• Research Categories: Psychology, Clinical; Biology, Neuroscience; Health Sciences, Pharmacology

Abstract

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-HT2A-mediated behavior, and 5-HT2Aantagonism 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-HT2Areceptors 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.