PSYCHEDELICS AND CLASSICAL ANTIDEPRESSANTS AS POSITIVE ALLOSTERIC MODULATORS OF TRKB

Accumulating evidence indicates that the plasticity-inducing and therapeutic effects of conventional antidepressant drugs are mediated by their interaction with TrkB receptor. It has additionally been reported that LSD and other psychedelic compounds also bind to TrkB with higher affinity.
In this study, we investigated whether psychedelics and classical antidepressants promote neurotrophic signaling via TrkB receptor interaction. Primary cortical cultures (DIV21) were treated with fluoxetine (10µM) or LSD (100nM) for one hour. Phosphorylation in TrkB Y816 tyrosine was checked as a marker of its activation by Western blot. LSD treatment showed a significant difference in phosphorylation of the receptor whereas fluoxetine did not.
Next, to check for induced structural changes in pyramidal neurons, primary hippocampal cultures (DIV21) were used. Cells were either treated with LSD (100nM) overnight or pretreated with the BDNF scavenger TrkB.FC for 10 minutes and then LSD (100nM) overnight. Spine formation after treatment was blindly quantified in dendrites areas of 15µm. This experiment showed a significant increase on spine count after LSD treatment, while the groups pretreated with TrkB.FC showed no significant difference with the negative control.
These results support that LSD interacts with TrkB as a positive allosteric modulator. The study provides further evidence that TrkB is a critical mediator of the effects of psychedelics and conventional antidepressants on neurotrophic signalling and neuroplasticity. These assays could enable testing of other potential antidepressants for their effects on plasticity.