The Hallucinogen N,N -Dimethyltryptamine (DMT) Is an Endogenous Sigma-1 Receptor Regulator

Chuang

Proc. Natl. Acad. Sci. U.S.A.

et al. 2015

115

The sigma-1 receptor (Sig-1R) chaperone at the endoplasmic reticulum (ER) plays important roles in cellular regulation. Here we found a new function of Sig-1R, in that it translocates from the ER to the nuclear envelope (NE) to recruit chromatin-remodeling molecules and regulate the gene transcription thereof. Sig-1Rs mainly reside at the ER-mitochondrion interface. However, on stimulation by agonists such as cocaine, Sig-1Rs translocate from ER to the NE, where Sig-1Rs bind NE protein emerin and recruit chromatin-remodeling molecules, including lamin A/C, barrier-to-autointegration factor (BAF), and histone deacetylase (HDAC), to form a complex with the gene repressor specific protein 3 (Sp3). Knockdown of Sig-1Rs attenuates the complex formation. Cocaine was found to suppress the gene expression of monoamine oxidase B (MAOB) in the brain of wild-type but not Sig-1R knockout mouse. A single dose of cocaine (20 mg/kg) in rats suppresses the level of MAOB at nuclear accumbens without affecting the level of dopamine transporter. Daily injections of cocaine in rats caused behavioral sensitization. Withdrawal from cocaine in cocaine-sensitized rats induced an apparent time-dependent rebound of the MAOB protein level to about 200% over control on day 14 after withdrawal. Treatment of cocaine-withdrawn rats with the MAOB inhibitor deprenyl completely alleviated the behavioral sensitization to cocaine. Our results demonstrate a role of Sig-1R in transcriptional regulation and suggest cocaine may work through this newly discovered genomic action to achieve its addictive action. Results also suggest the MAOB inhibitor deprenyl as a therapeutic agent to block certain actions of cocaine during withdrawal.T he endoplasmic reticulum (ER) plays important roles in cellular functions, including synthesis of proteins and regulation of Ca 2+ signaling between the ER and plasma membrane (1) and between the ER and mitochondria (2-4). However, because the ER interacts with other organelles in the cell, other functions related to the ER remain to be uncovered.The sigma-1 receptor (Sig-1R) (5-8) is an ER chaperone molecule that resides at the ER-mitochondrion interface referred to as the mitochondria-associated ER membrane (MAM), where the Sig-1R ensures proper ER-mitochondrion Ca 2+ signaling for cellular survival (3, 9), as well as sustains the activity of an ER stress sensor IRE1 at the MAM (10). The Sig-1R can translocate from the MAM to plasma membrane of the cell to regulate ion channels and receptors on the plasma membrane (8,(11)(12)(13)(14). Cocaine is a Sig-1R agonist (3) that causes the dissociation of Sig-1R from its cognate binding partner BiP (3,8), and consequently the translocation of Sig-1Rs to the plasma membrane, where Sig-1Rs interact with voltage-gated potassium channel subfamily A member 2 (Kv1.2) to shape the neuronal and behavioral responses to cocaine (15).Cocaine also causes the translocation of Sig-1Rs from the ER to the nucleus (16), where Sig-1Rs are shown to be present at the nuclear envelope (NE) (17). H...

mentioning

confidence: 99%

Sigma-1 receptor mediates cocaine-induced transcriptional regulation by recruiting chromatin-remodeling factors at the nuclear envelope

Chuang

Proc. Natl. Acad. Sci. U.S.A.

et al. 2015

115

“…Por ejemplo, la mezcalina es reconocida como el principio activo del peyote (Lophophora williamsii) y su mecanismo de acción se atribuye a la * Es interesante notar la afinidad de los receptores opioides sigma con la dimetiltriptamina (DMT). 25 actividad de este alcaloide como agonista de los receptores postsinápticos de serotonina 2A en el cerebro, una propiedad que comparte con otros alucinógenos como la psilocibina, la DMT y el LSD. Ésta es una descripción bastante precisa, pero difícilmente puede considerarse completa.…”

Section: El Posible "Mecanismo De Acción" Un Reto Relevante Para El unclassified

Salvia divinorum: enigma psicofarmacológico y resquicio mente-cuerpo

Dı́az

2014

Salud Ment

SUMMARYIn the present paper, the multidisciplinary research on Salvia divinorum and its chemical principles is analyzed regarding whether the ethnobotany, phytochemistry, psychopharmacology, and neuropharmacology of this sacred psychoactive plant and main principle clarify its experienced effects and divinatory uses. The scientific endeavor traverses from the recorded traditional ceremonies and beliefs, continues with the botanical identification, the isolation of active molecules, the characterization of mental and neural effects, the possible therapeutic applications, and impinges upon the mind-body problem. The departure point of this search is ethnopharmacology, and therefore the traditional beliefs, ritual uses, and mental effects of this Mazatec sacred mint recorded during a 1973-1983 field research project are described. A water potion of crushed leaves produced short-lasting light-headedness, dysphoria, tactile and proprioceptive sensations, a sense of depersonalization, amplified sound perception, and increased visual and auditory imagery, but no actual hallucinations. Similar effects were described using questionnaires and are attributable to the diteprene salvinorin A, but cannot be explained solely by its specific and potent brain kappa-opioid receptor agonist activity. Some requirements for a feasible classification and mechanism of action of consciousness-altering products are proposed and include the activation of neural networks comprising several neurochemical systems. Top-down analyses should be undertaken in order to characterize such neural networks and eventually allowing to explore the differential ethnic effects. As is the case for other consciousness-altering preparations, a careful and encompassing research on this plant and principle can be consequential to academic undertakings ranging from the mind-body problem and a better understanding of shamanic ecstasy, to the potential generation of analgesic, antidepressant, and drug-abuse attenuating products.Key words: Consciousness-altering drugs, ethnopharmacology, kappa opioid receptor agonist, Mazatec shamanism, mechanism of action, mind-body problem, Salvia divinorum, salvinorin. RESUMENEn el presente trabajo se considera la investigación multidisciplinaria sobre Salvia divinorum y sus principios químicos activos con el objeto de valorar si la etnobotánica, la fitoquímica, la psicofarmacología y la neurofarmacología de esta planta psicoactiva y su principal producto químico, la salvinorina A, clarifican sus efectos mentales y sus usos adivinatorios. Esta labor científica ha trascurrido desde el registro inicial de ceremonias y creencias, ha continuado con la identificación botánica, el aislamiento de los principios químicos, la caracterización de los efectos mentales y cerebrales, las posibles aplicaciones terapéuticas y ha llegado a incurrir en el problema mente-cuerpo. Dado que el punto de partida de esta investigación es la transdisciplina de la etnofarmacología, se retoman aquí las creencias tradicionales, los usos rituales y los efe...

“…The protein has two transmembrane regions and two steroid-binding domains. The latter forms a pocket that serves as a binding site for cholesterol, steroids and sphingolipids (Palmer et al 2007;Fontanilla et al 2009). A wide range of synthetic or natural compounds ('sigma ligands'), including opiates, antipsychotics, psychostimulants, alkaloids and antidepressants, also bind to sigma-1 receptors (Palmer et al 2008;Maurice and Su 2009).…”

Section: Introductionmentioning

confidence: 99%

“…A wide range of synthetic or natural compounds ('sigma ligands'), including opiates, antipsychotics, psychostimulants, alkaloids and antidepressants, also bind to sigma-1 receptors (Palmer et al 2008;Maurice and Su 2009). In vivo, endogenous dimethyltryptamine (DMT) interacts with sigma-1 receptors in the brain but the physiological significance of this is not clear (Fontanilla et al 2009;Mavlyutov et al 2012).…”

Section: Introductionmentioning

confidence: 99%

Sigma-1 receptors modulate neonatal Nav1.5 ion channels in breast cancer cell lines

et al. 2016

co-immunoprecipitation experiments. Furthermore, application of sigma-1 drugs to the cells reduced the surface expression of nNa v 1.5 protein, which could explain how sigma-1 receptor activation could alter the metastatic behaviour of breast cancer cells. Overall, these results are consistent with the idea of a sigma-1 protein behaving like either a "chaperone" or a regulatory subunit associated with nNa v 1.5.