Tolerance and Cross-Tolerance among Psychedelic and Nonpsychedelic 5-HT2A Receptor Agonists in Mice.
Mario de la Fuente Revenga, Alaina M Jaster, John McGinn, Gabriella M Silva, Somdatta Saha, Javier González-Maeso
ACS Chemical Neuroscience July 28, 2022 DOI: 10.1021/acschemneuro.2c00170 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Animal behavioral and molecular study Peer reviewed |
|---|---|
| Population | Mice, including β-arrestin-2 knockout mice |
| Interventions | DOI LSD lisuride M100907 |
| Duration | 4 days of repeated administration; tolerance assessed 24 h after a single administration |
| Measures | head twitch response (HTR) |
| Topics | LSD Serotonin |
| Keywords | Animals Mice, knockout Humans Amphetamines Receptor, serotonin, 5-ht2a Behavior, animal Beta-arrestins Tolerance Serotonin 2a receptor 5-ht2ar Head-twitch response Psychedelics Lisuride Classical hallucinogens |
| Key points | Tolerance to the DOI-induced head twitch response developed after repeated or single DOI administration and showed cross-tolerance with LSD, but not with the nonpsychedelic agonist lisuride. The authors conclude that this tolerance requires 5-HT2A receptor activation and occurs through a mechanism independent of β-arrestin-2. |
Abstract
Classical psychedelics represent a subgroup of serotonergic psychoactive substances characterized by their distinct subjective effects on the human psyche. Another unique attribute of this drug class is that such effects become less apparent after repeated exposure within a short time span. The classification of psychedelics as a subgroup within the serotonergic drug family and the tolerance to their effects are replicated by the murine head twitch response (HTR) behavioral paradigm. Here, we aimed to assess tolerance and cross-tolerance to HTR elicited by psychedelic and nonpsychedelic serotonin 2A receptor (5-HT2AR) agonists in mice. We show that repeated (4 days) administration of the psychedelic 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) induced a progressive decrease in HTR behavior. Tolerance to DOI-induced HTR was also observed 24 h after a single administration of this psychedelic. Pretreatment with the 5-HT2AR antagonist M100907 reduced not only the acute manifestation of DOI-induced HTR, but also the development of tolerance to HTR. Additionally, cross-tolerance became apparent between the psychedelics DOI and lysergic acid diethylamide (LSD), whereas repeated administration of the nonpsychedelic 5-HT2AR agonist lisuride did not affect the ability of these two psychedelics to induce HTR. At the molecular level, DOI administration led to down-regulation of 5-HT2AR density in mouse frontal cortex membrane preparations. However, development of tolerance to the effect of DOI on HTR remained unchanged in β-arrestin-2 knockout mice. Together, these data suggest that tolerance to HTR induced by psychedelics involves activation of the 5-HT2AR, is not observable upon repeated administration of nonpsychedelic 5-HT2AR agonists, and occurs via a signaling mechanism independent of β-arrestin-2.
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
Cited by 47
- Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential. Nature Communications December 15, 2023
- A non-hallucinogenic LSD analog with therapeutic potential for mood disorders. Cell Reports March 28, 2023
- 5-HT2A receptors: Pharmacology and functional selectivity. Pharmacological Reviews April 23, 2025
- Serotonin 2A Receptor (5-HT2AR) Agonists: Psychedelics and Non-Hallucinogenic Analogues as Emerging Antidepressants Chemical Reviews November 30, 2023
- Mechanisms and molecular targets surrounding the potential therapeutic effects of psychedelics. Molecular Psychiatry September 1, 2023
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Cites 30
- Trial of Psilocybin versus Escitalopram for Depression New England Journal of Medicine April 14, 2021
- Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder JAMA Psychiatry November 4, 2020
- Psychedelics Promote Structural and Functional Neural Plasticity Cell Reports June 1, 2018
- Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action Neuroreport December 1, 1998
- Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Neuron July 5, 2021
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