Neurobiology Of Psychedelics: 5-HT2A & TrkB (Banushi & Polito, 2023)

Описание: I. Introduction to Psychedelic Neurobiology
This video explores the cellular neurobiology of psychedelic drugs.
It is based on a comprehensive 2023 review by Banushi and Polito.
The content covers molecular mechanisms and therapeutic potential.
Understanding these pathways is key to future mental health treatments.

II. Classification & History
Psychedelics are categorized as tryptamines, ergolines, or phenethylamines.
Tryptamines like psilocybin share structure with serotonin.
Ergolines like LSD are derived from the ergot fungus.
Phenethylamines like mescaline are derived from the benzene ring.
Historical use dates back centuries for healing and spiritual rituals.
Modern research resumed recently after a hiatus starting in 1970.

III. Brain Models of Psychedelic Action
The CSTC model suggests disruption of thalamic gating to the cortex.
This disruption alters how internal and external information is processed.
The REBUS model proposes a relaxation of high-level prior beliefs.
This allows bottom-up sensory information to have more influence.
The CCC model focuses on the claustrum and cortical circuits.
Reduced cognitive control is a key feature of the psychedelic state.

IV. The 5-HT2A Receptor Pathway
Classic psychedelics primarily activate the serotonin 5-HT2A receptor.
These receptors are dense in layer 5 pyramidal neurons of the cortex.
Activation of 5-HT2A correlates with subjective hallucinogenic effects.
This pathway engages G-protein and beta-arrestin signaling.
High receptor density is found in the visual and prefrontal cortex.
5-HT2A activation increases entropy and signal diversity in the brain.

V. Neuroplasticity and the TrkB Receptor
Recent research highlights the role of the TrkB receptor in plasticity.
Psychedelics bind directly to TrkB with high affinity.
This binding promotes the production of BDNF.
BDNF supports neuronal survival, growth, and synaptic plasticity.
LSD binding to TrkB is 1,000 times stronger than other antidepressants.
TrkB activation may occur independently of 5-HT2A activation.

VI. Glutamate Signaling Mechanisms
Psychedelics increase extracellular glutamate in the prefrontal cortex.
This glutamate release stimulates AMPA receptors.
AMPA activation further promotes BDNF release and neuroplasticity.
This mechanism is shared with dissociative anesthetics like ketamine.
Glutamate pathways help rewire pathological neural circuitry.
This may explain sustained therapeutic effects after limited dosing.

VII. The Sigma-1 Receptor & DMT
DMT acts as an endogenous ligand for the Sigma-1 receptor (Sig-1R).
Sig-1R is located at the mitochondria-associated ER membrane.
Activation regulates calcium signaling and ATP production.
This pathway provides neuroprotection against cellular stress.
It may also reduce inflammation and support tissue regeneration.
High concentrations of DMT can inhibit ion channels via this receptor.

VIII. Anti-Inflammatory Properties
Psychedelics show promise as potent anti-inflammatory agents.
They inhibit cytokines and reduce inflammatory markers.
5-HT2A activation in immune cells modulates the immune response.
Sig-1R ligands also exhibit immunoregulatory properties.
This has implications for neurodegenerative and autoimmune disorders.

IX. Clinical Implications & Future Directions
Trials show benefits for depression, anxiety, PTSD, and addiction.
Neuroplasticity allows for rapid and sustained symptom relief.
Non-hallucinogenic analogs are being developed for therapeutic use.
These new compounds target plasticity without the psychedelic trip.
Future research aims to map specific circuit changes in humans.

X. Additional Resource Support
See NourishED RFI's NotebookLM Resource Support Page.
https://notebooklm.google.com/noteboo...

XI. Source
Banushi, B., & Polito, V. (2023). A comprehensive review of the current status of the cellular neurobiology of psychedelics. Biology, 12(11), 1380. https://doi.org/10.3390/biology12111380

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