Separating the agony from ecstasy: R(-)-3,4-methylenedioxymethamphetamine has prosocial and therapeutic-like effects without signs of neurotoxicity in mice

Neuropharmacology. 2018 Jan;128:196-206. doi: 10.1016/j.neuropharm.2017.10.003. Epub 2017 Oct 6.

Abstract

S,R(+/-)-3,4-methylenedioxymethamphetamine (SR-MDMA) is an amphetamine derivative with prosocial and putative therapeutic effects. Ongoing clinical trials are investigating it as a treatment for post-traumatic stress disorder (PTSD) and other conditions. However, its potential for adverse effects such as hyperthermia and neurotoxicity may limit its clinical viability. We investigated the hypothesis that one of the two enantiomers of SR-MDMA, R-MDMA, would retain the prosocial and therapeutic effects but with fewer adverse effects. Using male Swiss Webster and C57BL/6 mice, the prosocial effects of R-MDMA were measured using a social interaction test, and the therapeutic-like effects were assessed using a Pavlovian fear conditioning and extinction paradigm relevant to PTSD. Locomotor activity and body temperature were tracked after administration, and neurotoxicity was evaluated post-mortem. R-MDMA significantly increased murine social interaction and facilitated extinction of conditioned freezing. Yet, unlike racemic MDMA, it did not increase locomotor activity, produce signs of neurotoxicity, or increase body temperature. A key pharmacological difference between R-MDMA and racemic MDMA is that R-MDMA has much lower potency as a dopamine releaser. Pretreatment with a selective dopamine D1 receptor antagonist prevented SR-MDMA-induced hyperthermia, suggesting that differential dopamine signaling may explain some of the observed differences between the treatments. Together, these results indicate that the prosocial and therapeutic effects of SR-MDMA may be separable from the stimulant, thermogenic, and potential neurotoxic effects. To what extent these findings translate to humans will require further investigation, but these data suggest that R-MDMA could be a more viable therapeutic option for the treatment of PTSD and other disorders for which SR-MDMA is currently being investigated.

Keywords: Enantiomers; MDMA; Neurotoxicity; PTSD; Prosocial.

MeSH terms

  • Animals
  • Body Temperature / drug effects
  • Brain / drug effects
  • Brain / metabolism
  • Conditioning, Classical / drug effects
  • Dopamine / metabolism
  • Dopamine Plasma Membrane Transport Proteins / metabolism
  • Extinction, Psychological / drug effects
  • Fear / drug effects
  • Glial Fibrillary Acidic Protein / metabolism
  • Hallucinogens / pharmacology*
  • Interpersonal Relations
  • Locomotion / drug effects
  • Male
  • Mice
  • Mice, Inbred C57BL
  • N-Methyl-3,4-methylenedioxyamphetamine / pharmacology*
  • Neurotoxicity Syndromes / prevention & control
  • Racemases and Epimerases / pharmacology*
  • Serotonin / metabolism
  • Stereoisomerism

Substances

  • Dopamine Plasma Membrane Transport Proteins
  • Glial Fibrillary Acidic Protein
  • Hallucinogens
  • Serotonin
  • Racemases and Epimerases
  • N-Methyl-3,4-methylenedioxyamphetamine
  • Dopamine