Interaction of psychoactive tryptamines with biogenic amine transporters and serotonin receptor subtypes.
Bruce E. Blough, Antonio Landavazo, Ann M Decker, John S. Partilla, Michael H. Baumann, Richard B Rothman
Psychopharmacology October 1, 2014 DOI: 10.1007/s00213-014-3557-7 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro experimental study Peer reviewed |
|---|---|
| Population | Rat brain synaptosomes; HEK293, Gα16-CHO, and CHOk1 cells transfected with human receptors |
| Topics | Serotonin |
| Keywords | Hallucinogens Psychedelics Psychoactive substances Hallucinogenic compounds Synthetic tryptamines Serotonin receptors 5-HT₂A Receptor Brain receptors Receptor interactions Serotonin transporters Serotonin reuptake Sert Serotonin transporter activity Neuropharmacology Psychopharmacology Drug mechanisms |
| Citations | 99 |
| Key findings | All psychoactive tryptamines are 5-HT₂A agonists, but serotonin transporter (SERT) activity may contribute significantly to the pharmacology of certain compounds, and two tertiary amines were found to be selective substrates at SERT, dispelling the notion that 5-HT-releasing activity is limited only to primary or secondary amines. |
Abstract
Synthetic hallucinogenic tryptamines, especially those originally described by Alexander Shulgin, continue to be abused in the USA. The range of subjective experiences produced by different tryptamines suggests that multiple neurochemical mechanisms are involved in their actions, in addition to the established role of agonist activity at serotonin 2A (5-HT₂A) receptors. This study evaluated the interaction of a series of synthetic tryptamines with biogenic amine neurotransmitter transporters and with serotonin (5-HT) receptor subtypes implicated in psychedelic effects. Neurotransmitter transporter activity was determined in rat brain synaptosomes. Receptor activity was determined using calcium mobilization and DiscoveRx PathHunter assays in HEK293, Gα16-CHO, and CHOk1 cells transfected with human receptors. Twenty-one tryptamines were analyzed in transporter uptake and release assays, and 5-HT₂A, serotonin 1A (5-HT₁A), and 5-HT₂A β-arrestin functional assays. Eight of the compounds were found to have 5-HT-releasing activity. Thirteen compounds were found to be 5-HT uptake inhibitors or were inactive. All tryptamines were 5-HT₂A agonists with a range of potencies and efficacies, but only a few compounds were 5-HT1A agonists. Most tryptamines recruited β-arrestin through 5-HT₂A activation. All psychoactive tryptamines are 5-HT₂A agonists, but 5-HT transporter (SERT) activity may contribute significantly to the pharmacology of certain compounds. The in vitro transporter data confirm structure-activity trends for releasers and uptake inhibitors whereby releasers tend to be structurally smaller compounds. Interestingly, two tertiary amines were found to be selective substrates at SERT, which dispels the notion that 5-HT-releasing activity is limited only to primary or secondary amines.
Comparable studies
Other preclinical and animal studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
Citations in the library
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- Receptor interaction profiles of novel psychoactive tryptamines compared with classic hallucinogens. European Neuropsychopharmacology May 20, 2016
- Designer drugs: mechanism of action and adverse effects Archives of Toxicology April 1, 2020
- Psychedelics in Psychiatry: Neuroplastic, Immunomodulatory, and Neurotransmitter Mechanisms Pharmacological Reviews December 16, 2020
- Novel psychoactive substances (designer drugs): overview and pharmacology of modulators of monoamine signalling Swiss Medical Weekly January 11, 2015
- N, N-Dimethyltryptamine (DMT), an Endogenous Hallucinogen: Past, Present, and Future Research to Determine Its Role and Function Frontiers in Neuroscience August 6, 2018
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Cites 35
- Psilocybin occasioned mystical-type experiences: immediate and persisting dose-related effects. Psychopharmacology December 1, 2011
- Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin Synapse 2000
- Mystical experiences occasioned by the hallucinogen psilocybin lead to increases in the personality domain of openness Journal of Psychopharmacology September 28, 2011
- Mystical-type experiences occasioned by psilocybin mediate the attribution of personal meaning and spiritual significance 14 months later Journal of Psychopharmacology May 30, 2008
- Salvinorin A: a potent naturally occurring nonnitrogenous kappa opioid selective agonist. Proceedings of the National Academy of Sciences September 3, 2002
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