Psychedelics are trkb positive allosteric modulators
202306171317
Status:
Tags: Psychedelics neuroplasticity TrkB
Moliner2023 found that LSD binds directly to the TrkB receptor, promoting plasticity through a 5-HT2a-independent mechanism.
It was previously thought that psychedelics indirectly activated BDNF and TrkB through indirect, downstream effects resulting from 5-HT2a activation
LSD has 1000-fold higher affinity to TrkB than other antidepressants including SSRIs like fluoxetine, and RAADs like ketamine. LSD’s binding site to TrkB transmembrane domain overlaps partially with that of other antidepressants.
Psilocin displaces LSD bound to TrkB with high affinity, while fluoxetine and ketamine display substantially lower TrkB affinities. Conversely, hydroxynorketamine (a metabolite of ketamine), preferentially binds to TrkB but has low affinity for NMDA, and displaces LSD with high nanomolar concentrations from TkrB.
Lisuride (a non-hallucinogenic ergoline 5-ht2a agonist) displaces LSD from TrkB at higher nanomolar concentrations in a linear manner, but other LSD-related compounds like cabergoline and dihydroergotamine fail to displace LSD, as well as negative controls chlorpromazine and diazepam, ketanserin, M100907.
Importantly, it was found that psychedelics LSD, psilocin, and lisuride bind directly to native TrkB but not Y433F or TrkA.TM mutants.
LSD and psilocin bind in the extracellular-facing crevice of crisscrossed transmembrane domain dimers such taht both TMDs of a dimer are required for binding
LSD stabilizes TrkB TMD dimer in a conformation more favorable to activation by BDNF, similar to the mechanism for fluoxetine.
- Fluxoetine binds deeper in the TMD and requires membrane lipid stabilization
- LSD binds closer to membrane surface and establishes more stable interactins with dimer
- psilocin has a similar mechanism to LSD
LSD and psilocin induce a fast and long-lasting increase in dimerization of wild-type TrkB at nanomolar concentrations which is abolished in WT:Y433F heterodimers.
LSD increases phosphorylation of TrkB tyrosine 816 residues in cortical and hippocampal cultures
Lisuride increses TrkB dimerization at higher concentrations
Pretreatment with ketanserin or M100907 fail to prevent LSD and BDNF effects on TrkB dimerization
- Psychedelics induce TrkB dimerization in absence of 5-HT2a, ketanserin/M100907 do not interfere
TrkB.FC sequesters extracellular BDNF and prevents effects of LSD and BDNF on TrkB dimerization.
LSD potentiates effects of very low conc. BDNF on TrkB dimerization (by stabilizing TrkB dimerization)
- psychedelics do not directly activate TrkB but have effects on its dimerization that are dependent on release of endogenous BDNF → allosteric effect
TrkB is mainly localized in intracellular vesicles and transiently translocated to cell surface when exposed to BDNF. Psychedelics increase neuronal surface retention of TrkB independent from 5-ht2a activation & promote TrkB interaction with reaft-restricted Src fiamily kinase Fyn, increasing localization to raft-like synaptic membranes
Psychedelics promote BDNF downstream signaling by increasing TrkB interaction with phospholipase C gamma 1 ()
- TrkB interaction with is increased in PFC and hippocampus
LSD rapidly increases phosphorylation of ERK (pERK) independent of 5-HT2a and promotes phosphorylation of mTOR for at least 1 hours
BDNF mRNA is upregulated at 1 houra fter LSD treatment and BDNF protein levels are elevated at 24h without changes in Ntrk2 mRNA levels
Psychedelics induce rapid TrkB trafficking into dendritic spines
- LSD > psilocin
LSD nad psilocin increase spine density of mature neuronal cultures at 24h after treatment, but not of Y433F(+/-) mice. TrkB.FC but not M100907 prevents spinogenic effect of LSD → effect is dependent on BDNF release but not on 5-HT2a activation.
Psychedelics increase dendritic arbor complexity in neuronal cultues derived from WT but not Y433F(+/0) mice
- TrkB.FC but not M100907 prevents LSD effects on dendritogenesis.
- Discrepancy with previous research indicating that ketanserin can prevent the effects of LSD on dendritic arbor complexity in cultured neuron
Importantly, 5-ht2a activation does have downstream effects on TrkB signalling, and may mediate some of the neuroplasticity increases by psychedelics. But psychedelics also bind directly to TrkB and facilitate/promote activation by BDNF
LSD produced a sustained AD-like effect 7 days after administration in WT but not y433f(+-) mice
LSD-facilitated contextual extinction of conditioned fear response 72h after single admin, persistent for 4 weeks → blocked by y433f(+-) mutation