3,4-Methylenedioxymethamphetamine facilitates fear extinction learning

MDMA (ecstasy) enhances the extinction of fear memories in mice through a mechanism dependent on brain-derived neurotrophic factor (BDNF). When administered before extinction training, MDMA persistently improved long-term extinction of conditioned fear. The drug increased Fos expression in the amygdala and medial prefrontal cortex, while BDNF expression rose specifically in the amygdala after extinction training. Direct infusion of MDMA into the basolateral amygdala recapitulated the extinction enhancement, and blocking BDNF signaling abolished it. These findings suggest MDMA may be a useful adjunct to exposure-based therapies for PTSD and other anxiety disorders involving altered fear learning.

Study at a glance

Abstract

Abstract Acutely administered 3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’) has been proposed to have long-term positive effects on post-traumatic stress disorder (PTSD) symptoms when combined with psychotherapy. No preclinical data support a mechanistic basis for these claims. Given the persistent nature of psychotherapeutic gains facilitated by MDMA, we hypothesized that MDMA improves fear extinction learning, a key process in exposure-based therapies for PTSD. In these experiments, mice were first exposed to cued fear conditioning and treated with drug vehicle or MDMA before extinction training 2 days later. MDMA was administered systemically and also directly targeted to brain structures known to contribute to extinction. In addition to behavioral measures of extinction, changes in mRNA levels of brain-derived neurotrophic factor ( Bdnf ) and Fos were measured after MDMA treatment and extinction. MDMA (7.8 mg kg −1 ) persistently and robustly enhanced long-term extinction when administered before extinction training. MDMA increased the expression of Fos in the amygdala and medial prefrontal cortex (mPFC), whereas increases in Bdnf expression were observed only in the amygdala after extinction training. Extinction enhancements were recapitulated when MDMA (1 μg) was infused directly into the basolateral complex of the amygdala (BLA), and enhancement was abolished when BDNF signaling was inhibited before extinction. These findings suggest that MDMA enhances fear memory extinction through a BDNF-dependent mechanism, and that MDMA may be a useful adjunct to exposure-based therapies for PTSD and other anxiety disorders characterized by altered fear learning.