When the Endogenous Hallucinogenic Trace Amine
            <i>N,N</i>
            -Dimethyltryptamine Meets the Sigma-1 Receptor

Su, Tsung‐Ping; Hayashi, Teruo; Vaupel, D. Bruce

doi:10.1126/scisignal.261pe12

Cited by 100 publications

(106 citation statements)

References 42 publications

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“…The activity of σ 1 receptors could be reciprocally inhibited by an association with binding immunoglobulin protein (BiP) through the formation of a σ 1 receptor -BiP complex, and σ 1 -receptor agonists could exert a chaperone activity with respect to σ 1 receptors by breaking the tether of the σ 1 receptor -BiP complex (18). Recently, the endogenous hallucinogenic amine N,N-dimethyltryptamine (DMT) was shown to be an endogenous σ-receptor ligand, and DMT as well as σ 1 -receptor agonists were shown to induce the dissociation of σ 1 receptors from the σ 1 receptor -BiP complex (22). Taken together, these results suggest that κ-opioid receptor agonists and non-competitive NMDA-receptor antagonists may regulate endogenous σ 1 -receptor systems by regulating DMT, which induces a hallucinogenic effect.…”

Section: Hallucination and σ 1 Receptorsmentioning

confidence: 99%

Discriminative Stimulus Effects of Hallucinogenic Drugs: a Possible Relation to Reinforcing and Aversive Effects

et al. 2012

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Abstract. The subjective effects of drugs are related to the kinds of feelings they produce, such as euphoria or dysphoria. One of the methods that can be used to study these effects is the drug discrimination procedure. Many researchers are trying to elucidate the mechanisms that underlie the discriminative stimulus effects of abused drugs (e.g., alcohol, psychostimulants, and opioids). Over the past two decades, the patterns of drug abuse have changed, so that club/recreational drugs such as phencyclidine (PCP), 3,4-methylenedioxymethamphetamine (MDMA), lysergic acid diethylamide (LSD), and ketamine, which induce perceptual distortions, like hallucinations, are now more commonly abused, especially in younger generations. However, the mechanisms of the discriminative stimulus effects of hallucinogenic drugs are not yet fully clear. This review will briefly focus on the recent findings regarding hallucinogenic/psychotomimetic drug-induced discriminative stimulus effects in animals. In summary, recent research has demonstrated that there are at least two plausible mechanisms that can explain the cue of the discriminative stimulus effects of hallucinogenic drugs; one is mediated mainly by 5-HT 2 receptors, and the other is mediated through sigma-1 (σ 1 )-receptor chaperone regulated by endogenous hallucinogenic ligand.

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Section: Hallucination and σ 1 Receptorsmentioning

confidence: 99%

Discriminative Stimulus Effects of Hallucinogenic Drugs: a Possible Relation to Reinforcing and Aversive Effects

et al. 2012

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“…Recently, biochemical, physiologic, and behavioral experiments demonstrated that DMT is an endogenous agonist at s-1 receptors (s-1Rs) (12); the hypothetical signaling scheme triggered by this binding has also been reported (13). These facts, together with our intention to provide insight into this issue, led us to develop in vivo DMT (compared with tryptamine) studies in animal models.…”

mentioning

confidence: 95%

In Vivo Long-Term Kinetics of Radiolabeled N,N-Dimethyltryptamine and Tryptamine

Vitale¹,

Pomilio²,

Cañellas³

et al. 2011

J Nucl Med

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N,N-dimethyltryptamine (DMT), a strong psychodysleptic drug, has been found in higher plants, shamanic hallucinogenic beverages, and the urine of schizophrenic patients. The aim of this work was to gain better knowledge on the relationship between this drug and hallucinogenic processes by studying DMT behavior in comparison with tryptamine. Methods: 131 I-labeled DMT and tryptamine were injected into rabbits. g-Camera and biodistribution studies were performed. Brain uptake, plasma clearance, and renal excretion were assessed for each indolealkylamine. Results: DMT and tryptamine showed different behavior when brain uptake, residence time, and excretion were compared. Labeled DMT entered the brain 10 s after injection, crossed the blood-brain barrier, and bound to receptors; then it was partially renally excreted. It was detected in urine within 24 h after injection and remained in the brain, even after urine excretion ceased; up to 0.1% of the injected dose was detected at 7 d after injection in the olfactory bulb. In contrast, tryptamine was rapidly taken up in the brain and fully excreted 10 min after injection. Conclusion: To our knowledge, this is the first demonstration that exogenous DMT remains in the brain for at least 7 d after injection. Although labeled DMT and tryptamine behave as agonists for at least 5-hydroxytryptamine 2A receptor, 5-hydroxytryptamine 2C receptor, trace amine-associated receptor, and s-1 putative receptor targets, binding to the latter can explain the different behavior of labeled DMT and tryptamine in the brain. The persistence in the brain can be further explained on the basis that DMT and other N,N-dialkyltryptamines are transporter substrates for both the plasma membrane serotonin transporter and the vesicle monoamine transporter 2. Furthermore, storage in vesicles prevents DMT degradation by monoamine oxidase. At high concentrations, DMT is taken up by the serotonin transporter and further stored in vesicles by the vesicle monoamine transporter 2, to be released under appropriate stimuli. Moreover, the 131 I-labeling proved to be a useful tool to perform long-term in vivo studies. Incont inuation of our research on labeled compounds, such as phenethylamines, tryptamines, and harmines and native Amazonian N,N-dimethyltryptamine (DMT)-containing beverages such as ayahuasca (1-3) (also called ayahoasca and hoasca tea), we now report the in vivo behavior of DMT and tryptamine.DMT (Fig. 1) is a psychodysleptic compound that has been found in a variety of higher plants (4,5) and organisms (6), brain and other tissues of mammals and humans (6,7), and the urine of schizophrenic patients (2,8-10).As a hallucinogen, DMT was reported as a direct postsynaptic agonist at 5-hydroxytryptamine 2A (5-HT 2A ) receptors and a partial agonist at 5-hydroxytryptamine 2C (5-HT 2C ) receptors (11). Recently, biochemical, physiologic, and behavioral experiments demonstrated that DMT is an endogenous agonist at s-1 receptors (s-1Rs) (12); the hypothetical signaling scheme triggered by this binding ha...

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“…-1 Receptor ligands, including neurosteroids, regulate this receptor-chaperone activity in an agonist/antagonist fashion Hayashi et al, 2009). In addition, -1 receptors were recently found to bind the psychedelic drug N,N-dimethyltryptamine and eventually produce a blockade of sodium channels, possibly through translocation of -1 receptors from the ER to the plasma membrane region (Fontanilla et al, 2009;Johannessen et al, 2009;Su et al, 2009).…”

mentioning

confidence: 99%

Regulation of σ-1 Receptors and Endoplasmic Reticulum Chaperones in the Brain of Methamphetamine Self-Administering Rats

Hayashi¹,

Justinová²,

Cormaci³

et al. 2009

J Pharmacol Exp Ther

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-1 Receptors are endoplasmic reticulum (ER) chaperones that are implicated in the neuroplasticity associated with psychostimulant abuse. We immunocytochemically examined the distribution of -1 receptors in the brain of drug-naive rats and then examined the dynamics of -1 receptors and other ER chaperones in specific brain subregions of rats that self-administered methamphetamine, received methamphetamine passively, or received only saline injections. -1 Receptors were found to be expressed in moderate to high levels in the olfactory bulb, striatum, nucleus accumbens shell, olfactory tubercle, amygdala, hippocampus, red nucleus, ventral tegmental area, substantia nigra, and locus ceruleus. Methamphetamine, whether self-administered or passively received, significantly elevated ER chaperones including the -1 receptor, BiP, and calreticulin in the ventral tegmental area and substantia nigra. In the olfactory bulb, however, only the -1 receptor chaperone was increased, and this increase occurred only in rats that actively self-administered methamphetamine. Consistent with an increase in -1 receptors, extracellular signal-regulated kinase was found to be activated and protein kinase A attenuated in the olfactory bulb of methamphetamine self-administering rats. -1 Receptors in the olfactory bulb were found to be colocalized with dopamine D1 receptors. These results indicate that methamphetamine induces ER stress in the ventral tegmental area and substantia nigra in rats whether the drug is received actively or passively. However, the changes seen only in rats that actively self-administered methamphetamine suggest that D1 and -1 receptors in the olfactory bulb might play an important role in the motivational conditioning/learning aspects of methamphetamine self-administration in the rat.

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When the Endogenous Hallucinogenic Trace Amine N,N -Dimethyltryptamine Meets the Sigma-1 Receptor

Cited by 100 publications

References 42 publications

Discriminative Stimulus Effects of Hallucinogenic Drugs: a Possible Relation to Reinforcing and Aversive Effects

Discriminative Stimulus Effects of Hallucinogenic Drugs: a Possible Relation to Reinforcing and Aversive Effects

In Vivo Long-Term Kinetics of Radiolabeled N,N-Dimethyltryptamine and Tryptamine

Regulation of σ-1 Receptors and Endoplasmic Reticulum Chaperones in the Brain of Methamphetamine Self-Administering Rats

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