When the Endogenous Hallucinogenic Trace Amine N,N-Dimethyltryptamine Meets the Sigma-1 Receptor Tsung-Ping Su, Teruo Hayashi

and D. Bruce Vaupel (10 March 2009) Science Signaling 2 (61), pe12. [DOI: 10.1126/scisignal.261pe12]

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26). norepinephrine. which reacted normally to the locomotor stimulating effect of methamphetamine. or the ability to suppress the magnitude of startle induced by an incoming acoustic signal that had been previously experienced (20). the locomotor-stimulating action of DMT resembles that of SKF10047 (24. Although DMT at 1 μM is as potent in eliciting cAMP accumulation as the prototypic trace amine tryptamine or LSD (19). and 5-hydroxytryptamine (5-HT). These results definitively link the action of DMT to the Sig-1R.N-Dimethyltryptamine Meets the Sigma-1 Receptor Tsung-Ping Su. however. it is unclear whether TAARs mediate the psychedelic effect of trace amines. tyramine. National Institute on Drug Abuse. e-mail. 333 Cassell Drive.1 D. *Corresponding author. high concentrations of DMT (100 μM.nih. 2010 www. However. specifically the 5-HT2A subtype. Downloaded from stke. about 7 times as high as its affinity for Sig-1R) could nonetheless inhibit voltage-gated sodium channels (24). including DMT. National Institute on Drug Abuse. Although this affinity is not impressive when compared to other Sig-1R ligands. a genetic study has demonstrated associations between polymor phisms in the TAAR4 subtype with susceptibility to schizophrenia (21). leading both groups to propose that DMT was an endogenous hallucinogen (4–6). Telephone. DMT is the main ingredient in the hallucinogenic beverage called “ayahuasca. as well as some of their metabolites or derivatives. Furthermore. Some amino acid metabolites are biogenic amines that. Saavedra and Axelrod then demonstrated the formation of DMT in rat and human brain (6). because TAAR antagonists have not been tested in humans in this regard.gov. did not become hyperactive in response to DMT (24). a phenomenon also observed with the prototypic Sig-1R agonist N-allylnormetazocine. Thus. do not involve the 5-HT system or other monoaminergic systems (16). 2Neuroimaging Research Branch. Furthermore. Department of Health and Human Services. and tryptamine. MD 21224.*1 Teruo Hayashi. an opiate analog better known as SKF-10047 (26). DMT is generally believed to exert its psychedelic effects through the 5-HT receptor. 1 Cellular humans (4. 5). Sig-1R knockout mice.sciencemag. TSU@intra.SCIENCESIGNALING. MD 21224. (19). 32).PERSPECTIVE NEUROSCIENCE When the Endogenous Hallucinogenic Trace Amine N. Here. it is possible that the psychedelic action of DMT might be mediated in part through sigma-1 receptors. TAs are purported to be involved in several human diseases (1). NIH Suite 3304. we focus on f indings related to N. 3). such as jerking.org on July 29. Several studies have since confirmed the psychedelic properties of DMT in humans (7–14).5 to 35 mg/kg administered intraperitoneally). DMT binds to the Sig1R with a moderate affinity at about 14 μM (24).org 10 March 2009 Vol 2 Issue 61 pe12 1 . These trace amines (TAs) include βphenylethylamine. including hallucination. which was identified by using the semisynthetic hallucinogen lysergic acid diethylamide (LSD) (15). USA. Intramural Research Program. we present a hypothetical signaling scheme that might be triggered by the binding of DMT to sigma-1 receptors. They are therefore a relevant animal model for schizophrenia because the PPI is typically impaired in schizophrenic patients (20). 333 Cassell Drive. which activate adenylyl cyclase and cause cyclic adenosine monophosphate (cAMP) accumulation (18. unlike the major neurotransmitter amines. However. synephrine. a hallmark action of Sig-1R ligands and Sig-1Rs (25). octopamine. and tremor. 333 Cassell Drive. the Sig-1R was recognized to be a nonopiate receptor (29–31) that might mediate the psychotomimetic effect not only of SKF10047 but also of the dissociative anesthetic phencyclidine (PCP) (28. a universal antagonist for all opiate receptor subtypes (28). Micromolar concentrations of DMT enhances phosphatidylinositol production in a manner that is not blocked by the 5-HT2A receptor antagonist ketanserin (17). Thus. 19). it was speculated that TAARs mediated part of the pharmacological or psychedelic effect of trace amines. conflicting reports later emerged that demonstrated a lack of association between the TAAR4 or TAAR6 gene and schizophrenia (22. Volume 2 Issue 61 pe12 N. Cellular Pathobiology Section. 23). With the discovery of the G protein–coupled TAassociated receptors (TAARs). including DMT. Baltimore. NIDA. DMT has been recently shown to bind sigma-1 receptors. fax. National Institutes of Health. Baltimore. Bruce Vaupel2 Published 10 March 2009. In addition. Here. A report now demonstrates that DMT targets a receptor called the sigma-1 receptor (Sig-1R) (24). Using purif ied DMT. USA. the same laboratory later found that the psychotomimetic effect of SKF-10047 was not reversed by naloxone. However. are typically present at low concentrations and accumulate in high amounts only if the amine-digestive enzyme monoamine oxidase is inhibited. The Sig-1R was originally thought to be the opiate receptor subtype that mediated the psychotomimetic or drug-induced psychotic-like effect of SKF-10047 in animals (27). certain behaviors seen in rats treated with DMT (0. such as (+)pentazocine (which has an affinity in nanomolar range).” which has been brewed (by boiling the bark of Banisteriopsis caapi together with the leaves of Psychotria viridis) and used by indigenous people around the South American Amazon basin (2. Cellular Neurobiology Research Branch. a tryptamine metabolite with psychedelic effects. it remains to be fully established whether TAARs mediate the psychotomimetic action of DMT.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. Thus. USA. 443-740-2804. 443-740-2142. TAAR1 knockout mice display a def icit in “prepulse inhibition” (PPI). gene association studies attempting to link TAARs and psychiatric disturbances have generated conflicting results as to whether TAARs are involved in schizophrenic symptomatologies. which are ligand-regulated molecular chaperones whose function includes inhibiting various voltage-sensitive ion channels. Department of Health and Human Services. retropulsion. Intramural Research Program. Baltimore. which suggests that part of the action of DMT is not mediated through 5-HT receptors. MD 21224. Szara and colleagues f irst reported the psychoactive effect of the compound in Pathobiology Section. such as dopamine.N-dimethyltryptamine (DMT). as well as LSD. IRP.nida. National Institutes of Health.

Sig-1R ligands might shift the site of action of Sig-1R chaperones from the center of the cell to its periphery. high concentrations of Sig-1R ligands may allow Sig-1Rs to directly interact with and inhibit channel proteins (24. why the channel-inhibiting concentration of DMT is almost 10 times as high as its affinity concentration (24). Sig-1Rs at the MAM enhance Ca2+ signaling from the ER into mitochondria (34.4. the acid-sensing ion channel (41). do sigma-1 receptors mediate the psychedelic effect of DMT? First.org 10 March 2009 Vol 2 Issue 61 pe12 2 . 1). High concentrations of Sig-1R ligands tonically inhibit the small conductance K+ (SK) channel. amnesia. We therefore speculate that Sig1Rs may partially mediate the psy- chotomimetic effects of DMT. Sig-1Rs and related molecules or organelles are illustrated in the postsynaptic region for the sake of simplicity. However. Sig-1Rs localize at the interface between the endoplasmic reticulum (ER) and mitochondrion.4 channel (38). 1. stroke. including (+)pentazocine and PRE-084. and P/Q-type Ca2+ channels (40). 35). 2010 BiP ER Ca2+ TCA Sig-1R BiP ATP production Mitochondria Low concentration of DMT High concentration of DMT Fig.5 channel (24. 38).SCIENCESIGNALING. such as visual hallucinations in humans (7–14). Secondly. the voltagegated N-. binding immunoglobulin protein (BiP). are not reported to cause psychotomimetic-like effects in animals (43). activates the tricarboxylic acid (TCA) cycle. they can translocate from the MAM to the plasma membrane (also termed the plasmalemma) or the subplasma membrane area when stimulated by higher concentrations (e. This may explain why higher concentrations of Sig1R ligands result in the inhibition of various ion channels at the plasma membrane and. PCP and SKF-10047 cause animals to behave as if they are hallucinating (they move their heads and eyes as if they are tracking objects in the air) (28). the KV1. at concentrations close to their Ki values. By stabilizing IP3 receptors. binding immunoglobulin protein (BiP) (34). and the volume-regulated Cl– channel (42) are also inhibited by high concentrations of Sig-1R ligands. particularly when ligands are present at concentrations close to their affinities (34).PERSPECTIVE PCP is thought to induce its mind-altering effect through the N-methyl. Sig-1R ligands. allowing them to act as molecular chaperones to inositol 1. at approximately 10-fold Ki) of Sig-1R ligands or when Sig-1Rs are overexpressed in cells (36–38) (Fig.D -aspartate (NMDA) receptor. (B) Higher concentrations of DMT cause the translocation of Sig-1Rs from the MAM to the plasma membrane. which is known as the mitochondria-associated ER membrane (MAM). Sig-1R agonists at affinity concentrations (i. Sig-1Rs have been implicated in diseases such as addiction. close to their Ki values) cause Sig-1Rs to disassociate from another ER chaperone. in particular. depression. 25). Thus.e. leading to the inhibition of ion channels.N-dimethyltryptamine through sigma-1 receptors.. although they may also be present presynaptically or in glia. moderate concentrations of selective Sig-1R ligands. This enhances Ca2+ signaling from the ER into mitochondria (34.g. allowing Sig-1Rs to chaperone inositol 1.org on July 29. we need to specify that Sig-1Rs have not been firmA DMT B Ion channel Inhibited ion channel Sig-1R Low DMT MAM sER High DMT IP3R Downloaded from stke. 35). which in turn leads to the potentiation of NMDA receptors (39). Although Sig-1Rs reside primarily at the ER. So. Hypothetical scheme illustrating the signaling of N. and cancer (33).4. pain. and increases adenosine triphosphate (ATP) production (35). By triggering the translocation of Sig1Rs from the MAM to the plasma membrane or subplasma membrane. The NaV1.5-trisphosphate (IP3) receptors. Could the psychotomimetic effect caused by PCP and SKF-10047 in animals (28) be explained by PCP or SKF-10047 blocking NMDA receptors and not by their binding to Sig-1Rs? www.. 1). In the present scheme. including DMT. L-. (A) Sigma-1 receptors (Sig-1Rs) at the mitochondrion-associated endoplasmic reticulum (ER) membrane (MAM) function as ligand-activated molecular chaperones. the possibility that Sig-1Rs are involved in psychotomimesis cannot be totally excluded at present. In addition to their postulated psychotomimetic action.5-trisphosphate receptors (IP3Rs) at the MAM (34). cause the dissociation of Sig-1Rs from another ER chaperone.sciencemag. ly established as being involved in causing psychotomimesis. thereby activating the tricarboxylic acid (TCA) cycle and increasing the production of adenosine triphosphate (ATP) (35) (Fig. and systematic behavioral studies are needed to differentiate between the SKF-10047– and PCP-induced effects mediated by the Sig-1R versus the NMDA receptor.

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