When the endogenous hallucinogenic trace amine N, N-dimethyltryptamine meets the sigma-1 receptor

This theory building study (2009) presents a hypothetical signaling scheme involving the sigma-1 receptor to explain the psychedelic effects of DMT.

Abstract

“N,N-dimethyltryptamine (DMT) is a hallucinogen found endogenously in human brain that is commonly recognized to target the 5-hydroxytryptamine 2A receptor or the trace amine–associated receptor to exert its psychedelic effect. DMT has been recently shown to bind sigma-1 receptors, which are ligand-regulated molecular chaperones whose function includes inhibiting various voltage-sensitive ion channels. Thus, it is possible that the psychedelic action of DMT might be mediated in part through sigma-1 receptors. Here, we present a hypothetical signaling scheme that might be triggered by the binding of DMT to sigma-1 receptors.”

Authors: Tsung-Ping Su, Teruo Hayashi & D. Bruce Vaupel

Summary

DMT is a hallucinogen that targets the 5-hydroxytryptamine 2A receptor and the trace amine – associated receptor. It has also been shown to bind to sigma-1 receptors, which inhibit voltage-sensitive ion channels.

Some amino acid metabolites are biogenic amines, which are present in the brain at low concentrations and accumulate in high amounts only if the amine-digestive enzyme monoamine oxidase is inhibited. These metabolites are purported to be involved in several human diseases.

DMT is generally believed to exert its psychedelic effects through the 5-HT receptor, but certain behaviors seen in rats treated with DMT do not involve the 5-HT system or other monoaminergic systems. It is unclear whether G protein – coupled TA-associated receptors (TAARs) mediate the psychotomimetic effect of trace amines, including DMT, because TAAR antagonists have not been tested in humans in this regard. Furthermore, gene association studies have generated conflicting results as to whether TAARs are involved in schizophrenic symptomatologies, including hallucination.

DMT targets a receptor called the sigma-1 receptor (Sig-1R), and binds to it with a moderate affinity at about 14 m. High concentrations of DMT can inhibit voltage-gated sodium channels, a hallmark action of Sig-1R ligands and Sig-1Rs.

The Sig-1R was originally thought to be the opiate receptor subtype that mediated the psychotomimetic effect of SKF-10047 in animals, but it was later recognized to be a nonopiate receptor that might mediate the psychotomimetic effect of PCP.

Sig-1Rs localize at the mitochondria-associated ER membrane (MAM) and act as molecular chaperones to inositol 1,4,5-trisphosphate (IP3) receptors, thereby activating the tricarboxylic acid (TCA) cycle and increasing the production of adenosine triphosphate (ATP). Sig-1Rs reside primarily at the ER, but can translocate to the plasma membrane or subplasma membrane area when stimulated by high concentrations of Sig-1R ligands or when Sig-1Rs are overexpressed in cells. This may explain why high concentrations of DMT inhibit several ion channels at the plasma membrane.

The possibility that sigma-1 receptors are involved in psychotomimesis cannot be totally excluded at present. However, it might be difficult to distinguish the psychedelic effect mediated by NMDA receptor blockade from that mediated by Sig-1Rs in animal studies.

DMT has been used to compare the psychedelic effects of ketamine with those of DMT. DMT effects seem to be more related to the paranoid-type psychoses with particular positive formal thought disorders.

DMT might signal through sigma-1 receptors by dissociating Sig-1Rs from the Sig-1R-BiP complex, unleashing the chaperone activity of the free form of Sig-1Rs at the MAM, and then translocating Sig-1Rs to the plasma membrane to inhibit voltage-gated ion channels.

The discovery of DMT as an endogenous hallucinogen and the characterization of Sig-1Rs as ligand-regulated chaperone receptors represent potential breakthroughs in drug abuse research. However, many questions remain, including the physiological importance of the DMT signaling through Sig-1Rs.

Fig. 1.

Sigma-1 receptors at the mitochondrial-associated endoplasmic reticulum membrane function as ligand-activated molecular chaperones, which enhance Ca2+ signaling from the ER into mitochondria, activate the tricarboxylic acid (TCA) cycle, and increase adenosine triphosphate (ATP) production.

Study details

Compounds studied
DMT

Topics studied
Neuroscience

Study characteristics
Theory Building

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