A new mechanism of psychedelic action has been discovered in the brain.

A new mechanism of psychedelic action has been discovered in the brain.

A new mechanism of psychedelic action has been discovered in the brain.

A new article changed our understanding of how the drug turned the brain upside down by solving a long-standing molecular mystery in this field. The drug is thought to generate its effects by activating serotonin receptor type 2A (5-HT). These receptors are present on the surfaces of neurons throughout the brain. But if these compounds cause such strong hallucinations, why don't we always find our brain's natural serotonin supply?

The answer may have been found in neurons, where researchers at the University of California, Davis (UC Davis) found that the drug exerts its effect by activating an intracellular group of serotonin receptors. The team concluded that another molecule, possibly N, N-dimethyltryptamine (DMT), which occurs in short-lived but large-scale concentrations in the brain, is the natural stimulant of these intracellular receptors and not serotonin.

The results can explain why drug effects, such as neurological elasticity and even antidepressants, differ between different drugs. Can we ever use the psychedelic molecules in our brains to fight mood disorders?

Serotonin and anesthetics: a complex relationship

The research began with a series of laboratory experiments by Max Vargas, a UC Davis doctoral student. Professor David Olson, Vargas' supervisor, is interested in the function of neurological plastic in anesthetics. These molecules have been shown to repeatedly promote the growth of neural compounds called neural axons in the brain after being administered, which Olson and the team consider crucial to the drug's effects on mood disorders. Vargas wanted to investigate whether a stronger association with 5-HT2A extracellular receptors leads to more severe neurological elasticity. To the team's surprise, there was no such relationship.

Instead, the team found a positive correlation between the ability of compounds to cross cell membranes and their neuroplastic effects. This led the team to assume that intracellular receptor activation drives the growth of psychedelically stimulated neurons.

To test this hypothesis, the team reached into a deep chemical toolbox. They have changed the structures of two common drugs, DMT and psilocin, the active chemical components of the psychedelic fungus. They have also changed the structure of the chemical ketanserin, which is often used to prevent psychedelic activity because it can bind to and close 5-HT2A receptors. The three molecules can penetrate the cell membrane, but after modification, the new versions—N, N, N-dimethyltryptamine (TMT), psilocybin, and methylated ketanserin—could not.

These newly modified drugs could not promote the formation of neurons. Methyl ketanserin could not prevent the growth of neurons, although it was able to attach to surface-level 5HT2A receptors. What the molecules needed was a literal shock to the system.

Psychotropic science with high tension

A technique called high-voltage current electrics is applied to the cell membrane. This creates small holes in the membrane that allow molecules to penetrate the subsoil of the cell. In electrical cells, modified drugs suddenly managed to produce plasticity in the same way as congeners that did not change. Modified ketan also regained its ability to block once it was able to make its way into the cell.

The team that now works in kidney cells modified to over-express 5HT2A receptors showed that methyl ketanzyrene without electricity is perfectly capable of preventing serotonin from activating 5HT2A receptors, whereas it was only partially able to stop DMT because DMT was still able to attach to intracellular receptors. This indicates that serotonin is not the natural stimulant of a large proportion of 5HT2A receptors, although it is literally the molecule that defines it.

Researchers confirmed their results through a variety of other tests that initially work with a protein called serotonin vector (SERT), which transmits serotonin into neurons. SERT is usually not found in cortical neurons of mice, but its presence around serotonin in a molecule stimulates plasticity, an effect that disappeared when the drug citalopram, which blocks SERT, was added.

Research neurons for an antidepressant effect.

Afterward, the team developed experiments to investigate whether other effects of the drug, such as fast-acting antidepressants, also depend on intracellular 5HT2A activation. Mice were given a molecule called para-cloroamphetamine (PCA), a molecule that releases serotonin without activating the 5HT2A receptors themselves. A subset of these mice was genetically modified to express SERT, allowing serotonin produced by PCA to penetrate neurons. In unmodified animals that underwent behavioral tests approaching depression measurements, SERT did not lead to an improvement in their performance, but modified animals whose neurons were flooded with serotonin due to the presence of PCA and SERT showed an improvement in test performance.

Mice, of course, cannot complete mood questionnaires, so there is no way to test how the mood of these animals is affected. However, these measurements are the field standard for assessing depressive behavior. The researchers also found that modified mice showed a head trembling response once serotonin reached the interiors of their neurons, suggesting that this classic measure of "hallucination" activity might depend on the activation of intracellular receptors.

The study can change how we understand drug activity in the brain. In a perspective article, researchers at the University of Maryland named Dr. Ivan M. Hess and Professor Todd de Gould, who was not involved in the research, carried out the Vargas paper, "A major achievement in understanding the mechanism of drug action." Brian Roth, distinguished professor of protein and transitional proteomics treatments at the University of North Carolina School of Medicine, and Michael Hooker told technology networks that the paper was "a very important and potentially disturbing study."

Hess and Gold refer to the additional work that needs to be done to fully validate the results. Can these effects also be observed in humans? Which signal chain is involved? Does the drug, like mescalin, which has a completely different chemical structure, also activate intracellular 5HT2A receptors? All these questions remain unanswered. At present, the paper has done what Hess and Gold call "an important step forward for a rapidly growing and urgently needed area of study."


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