The hallucinogen N,N-dimethyltryptamine (DMT) is an endogenous sigma-1 receptor regulator

Abstract

The sigma-1 receptor is widely distributed in the central nervous system and periphery. Originally mischaracterized as an opioid receptor, the sigma-1 receptor binds a vast number of synthetic compounds but does not bind opioid peptides; it is currently considered an orphan receptor. The sigma-1 receptor pharmacophore includes an alkylamine core, also found in the endogenous compound N,N-dimethyltryptamine (DMT). DMT acts as a hallucinogen, but its receptor target has been unclear. DMT bound to sigma-1 receptors and inhibited voltage-gated sodium ion (Na+) channels in both native cardiac myocytes and heterologous cells that express sigma-1 receptors. DMT induced hypermobility in wild-type mice but not in sigma-1 receptor knockout mice. These biochemical, physiological, and behavioral experiments indicate that DMT is an endogenous agonist for the sigma-1 receptor.

Fig. 1

Sigma-1 receptor ligand pharmacophore and binding affinities. (A) A basic sigma-1 receptor ligand pharmacophore variant of Glennon et al. (6) was derived by removal of the red bonds from the sigma-1 receptor ligands fenpropimorph, haloperidol, and cocaine. (B) Competitive binding curves of tryptamine,N-methyltryptamine, and DMT, against the radioactive sigma-1 receptor ligand [³H]-(+)-pentazocine. Curves are shown as percent specific binding (5 μM haloperidol). (C) Sigma-1 and sigma-2 receptor K_d values of trace amines and their N-methylated and N,N-dimethylated derivatives (scheme S2). Included are SEM values (n = 3 binding experiments) and R² values for a nonlinear regression curve fit. Solid arrows denote the direction of increasing affinity.

Fig. 2

Tryptamine, N-methyltryptamine, and DMT inhibition of photolabeling. Rat liver membranes (100 μg per lane) were suspended in the presence or absence of the protecting drugs. Samples were photolyzed with (A) 1 nM carrier-free [¹²⁵I]-IACoc or (B) 1 nM carrier-free [¹²⁵I]IAF. Ten micromolar (+)-pentazocine (P) protected sigma-1 receptor photolabeling, whereas 10 μM haloperidol (H) protected both sigma-1 and sigma-2 receptors. Percent band intensities are shown as compared to controls performed in the absence of protecting ligand (−).

Fig. 3

Sodium channel inhibition by DMT. (A) In the presence or absence of 10 μM haloperidol, wild type (WT) orsigma-1receptorknock-out (KO) mouse liver homogenates (200 μg/lane) were photolabeled with 1 nM [¹²⁵I]IAF. (B) Examples of I_Na evoked by steps from −80 to −10 mV in HEK293 or COS-7 cells expressing hNav1.5 channel in the absence (control, black), presence (DMT, red), and after wash out (recovery, blue) of 100 μM DMT. Average inhibition by DMT was determined by measuring peak I_Na. Bars represent mean ± SEM (n = 3 cells). I_Na inhibition in HEK293 cells differed significantly from that in COS-7 cells (*P < 0.03). (C) Examples of I_Na evoked as described in (B) in neonatal cardiac myocytes from WT and KO mice in the absence (control, black), presence (DMT, red), and after wash out (recovery, blue) of 100 μM DMT. Current inhibition in WT was significantly different from that in KO (*P < 0.002, n = 7 neonatal cardiac myocytes).

Fig. 4

DMT-induced hypermobility abrogated in the sigma-1 KO mouse. (A) Distances traveled by WT and KO mice were measured in an open-field assay in 5-min increments. Pargyline was injected 2 hours before DMT or vehicle (Veh) ip injection. Bars represent mean ± SEM (n = 8 to 14 mice). WT mice showed a significant (***P < 0.0001) increase in mobility in response to DMT as compared to KO mice. (B) Total distance traveled over 30 min after DMT, vehicle (Veh), or methamphetamine (Meth, n = 6 mice) injection in WT and KO mice. (C) Methamphetamine serves as a positive control for hypermobility in KO mice.