The club drug MDMA (ecstasy) primarily causes serotonin release by reversing the serotonin transporter. This study in mice shows that blocking or removing the 5-HT2B receptor completely stops MDMA-induced hyperactivity and serotonin release in key brain regions (nucleus accumbens and ventral tegmental area). The 5-HT2B receptor acts presynaptically to regulate MDMA-stimulated serotonin release, a previously unknown role. These findings suggest that 5-HT2B receptor antagonists could be promising treatments for MDMA abuse.
Activation of the serotonin 2A (5-HT2A) receptor suppresses fear expression but does not affect retention of fear extinction. Using the psychedelic DOI in mice, the authors found that 5-HT2A receptor activation reduced anxiety-like avoidance behavior and diminished fear expression in multiple tasks, including passive avoidance and auditory fear conditioning. The effect depended on 5-HT2A receptors in the amygdala: local infusion of a 5-HT2A antagonist into the amygdala reversed the effect, while local DOI infusion into the amygdala was sufficient to suppress fear expression. These findings clarify a neural mechanism by which psychedelics may reduce fear, but provide no evidence that they enhance fear extinction memory.