Are we finally beginning to better understand the processes of addiction, depression and the like!
"Psychedelics belong to a group of compounds called psychoplastogens, which can promote neuronal growth and restore atrophied connections in the brain. This ability makes the molecules promising as potential treatments for neuropsychiatric diseases such as chronic depression and addiction. In a new study, scientists have untangled the mechanism of how these compounds trigger the rewiring of the brain, providing a better understanding of why these compounds differ from other neurochemicals that share the same binding targets ...
Classic psychedelics such as psilocybin and LSD bind to the 5-hydroxytryptamine 2A (5-HT2A) receptor, an important G-protein-coupled receptor (GPCR) that’s involved in cellular signaling. But so does serotonin, the ubiquitous, mood-dictating neurotransmitter. The lingering mystery is why serotonin doesn’t stimulate the same neuroplasticity effects that psychedelic compounds do.
The new study has found the answer. “The location of the 5-HT2A receptor is critical for determining the kinds of signaling pathways that a ligand can induce,” ...
For a GPCR, the 5-HT2A receptor is weird. Most GPCR proteins reside on the cellular surface to relay signals between the cell and its environment. But in neurons, the majority of 5-HT2A receptors populate the inside of the cell. ... team discovered that psychoplastogens need to reach the receptors within neurons to spark intracellular signaling. Merely hitting the receptors on the outside won’t count.
“The fact that psychedelics may interact with intracellular receptors—that’s really interesting,” ... “a major advance.”
Serotonin—unlike N,N-dimethyltryptamine (DMT),which is found in ayahuasca brew, for example—is a polar molecule, so it can’t easily cross the lipid bilayer of the cell membrane to get inside. On the other hand, greasy compounds can access the intracellular space ...
However, if serotonin is able to enter the cell, it too can kick-start the same signaling events that would lead to neuronal growth. After [team] forced neurons to take up serotonin, the researchers observed them sprouting more branches and more protrusions as a result. The researchers also genetically engineered mice to express a serotonin transporter and saw antidepressant-like behavior, unlike control mice that did not produce the same protein.
The paper is a landmark study, because it opens up new questions about this particular plasticity mechanism, ... “What are the pathways activated by the serotonin 2A receptor located intracellularly? What are the pathways responsible for these medical effects?” ..."
"The mechanism underlying psychedelic action
Psychedelic compounds promote cortical structural and functional neuroplasticity through the activation of serotonin 2A receptors. However, the mechanisms by which receptor activation leads to changes in neuronal growth are still poorly defined. Vargas et al. found that activation of intracellular serotonin 2A receptors is responsible for the plasticity-promoting and antidepressant-like properties of psychedelic compounds, but serotonin may not be the natural ligand for those intracellular receptors ..."
From the absract:
"Decreased dendritic spine density in the cortex is a hallmark of several neuropsychiatric diseases, and the ability to promote cortical neuron growth has been hypothesized to underlie the rapid and sustained therapeutic effects of psychedelics. Activation of 5-hydroxytryptamine (serotonin) 2A receptors (5-HT2ARs) is essential for psychedelic-induced cortical plasticity, but it is currently unclear why some 5-HT2AR agonists promote neuroplasticity, whereas others do not. We used molecular and genetic tools to demonstrate that intracellular 5-HT2ARs mediate the plasticity-promoting properties of psychedelics; these results explain why serotonin does not engage similar plasticity mechanisms. This work emphasizes the role of location bias in 5-HT2AR signaling, identifies intracellular 5-HT2ARs as a therapeutic target, and raises the intriguing possibility that serotonin might not be the endogenous ligand for intracellular 5-HT2ARs in the cortex."
Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors (no public access)
5-HT2A receptors (colored) usually reside inside neurons, unlike most other signalling proteins that usually sit on the cell surface.
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