A single dose of the psychedelic psilocybin reduces conditioned behavior and withdrawal caused by the opioid oxycodone in male mice but not in females. This sex-specific effect is mediated by the 5-HT2A receptor in frontal cortex pyramidal neurons that project to the nucleus accumbens. Psilocybin also alters epigenomic regulation after repeated oxycodone exposure and induces sex-specific structural plasticity in the nucleus accumbens independently of the 5-HT2A receptor. Female frontal cortex and nucleus accumbens show fewer changes at gene enhancer regions in response to psilocybin, repeated oxycodone, or their combination compared to males, with the frontal cortex displaying more pronounced sex differences at the epigenomic level.
The drug MDMA, also known as ecstasy, is being studied as a possible aid in psychotherapy for hard-to-treat mental health conditions, but how it works in the brain is not fully understood. In experiments with mice, the S(+) form of MDMA, but not the R(-) form, activated a specific serotonin receptor (5-HT2AR) and caused changes in brain cell connections in the frontal cortex of males. The R(-) form had little effect except for a head-twitch response in females. Blocking the serotonin transporter with fluoxetine prevented these effects, showing that MDMA works indirectly by increasing serotonin levels. These results reveal that MDMA's effects on brain plasticity depend on both the drug's chemical form and the sex of the animal.