Role of the 5-HT₂A receptor in the locomotor hyperactivity produced by phenylalkylamine hallucinogens in mice.
Adam L. Halberstadt, Susan B Powell, Mark A. Geyer
Neuropharmacology July 2013 DOI: 10.1016/j.neuropharm.2013.01.014 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Animal behavioral pharmacology study Peer reviewed |
|---|---|
| Population | C57BL/6J mice and 5-HT2A knockout mice |
| Interventions | Mescaline 2 5-dimethoxy-4-ethylamphetamine (DOET) 5-dimethoxy-4-propylamphetamine (DOPR) 4 5-trimethoxyamphetamine (TMA-2) (4-bromo-3 6-dimethoxybenzocyclobuten-1-yl)methylamine (TCB-2) 5-dimethoxy-4-tert-butylamphetamine (DOTB) M100907 |
| Dose | 0.1-10 mg/kg i.p. (DOTB dose range) |
| Measures | Behavioral Pattern Monitor (BPM) |
| Topics | Serotonin |
| Key points | Low doses of the hallucinogens mescaline, DOET, DOPR, TMA-2, and TCB-2 increased locomotor activity in mice, whereas the non-hallucinogenic DOTB did not. The 5-HT2A antagonist M100907 blocked mescaline- and TCB-2-induced hyperactivity, and these compounds did not increase activity in 5-HT2A knockout mice, indicating the effect depends on 5-HT2A receptor activation. |
Abstract
The 5-HT₂A receptor mediates the effects of serotonergic hallucinogens and may play a role in the pathophysiology of certain psychiatric disorders, including schizophrenia. Given these findings, there is a need for animal models to assess the behavioral effects of 5-HT₂A receptor activation. Our previous studies demonstrated that the phenylalkylamine hallucinogen and 5-HT₂A/₂C agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) produces dose-dependent effects on locomotor activity in C57BL/6J mice, increasing activity at low to moderate doses and reducing activity at high doses. DOI did not increase locomotor activity in 5-HT₂A knockout mice, indicating the effect is a consequence of 5-HT₂A receptor activation. Here, we tested a series of phenylalkylamine hallucinogens in C57BL/6J mice using the Behavioral Pattern Monitor (BPM) to determine whether these compounds increase locomotor activity by activating the 5-HT₂A receptor. Low doses of mescaline, 2,5-dimethoxy-4-ethylamphetamine (DOET), 2,5-dimethoxy-4-propylamphetamine (DOPR), 2,4,5-trimethoxyamphetamine (TMA-2), and the conformationally restricted phenethylamine (4-bromo-3,6-dimethoxybenzocyclobuten-1-yl)methylamine (TCB-2) increased locomotor activity. By contrast, the non-hallucinogenic phenylalkylamine 2,5-dimethoxy-4-tert-butylamphetamine (DOTB) did not alter locomotor activity at any dose tested (0.1-10 mg/kg i.p.). The selective 5-HT₂A antagonist M100907 blocked the locomotor hyperactivity induced by mescaline and TCB-2. Similarly, mescaline and TCB-2 did not increase locomotor activity in 5-HT₂A knockout mice. These results confirm that phenylalkylamine hallucinogens increase locomotor activity in mice and demonstrate that this effect is mediated by 5-HT₂A receptor activation. Thus, locomotor hyperactivity in mice can be used to assess phenylalkylamines for 5-HT₂A agonist activity and hallucinogen-like behavioral effects. These studies provide additional support for the link between 5-HT₂A activation and hallucinogenesis.
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 28
- Effect of Hallucinogens on Unconditioned Behavior Current Topics in Behavioral Neurosciences 2016
- Pharmacology and Toxicology of N-Benzylphenethylamine ("NBOMe") Hallucinogens. Current Topics in Behavioral Neurosciences 2017
- Mescaline: The forgotten psychedelic Neuropharmacology October 14, 2022
- Sex-specific effects of psychedelic drug exposure on central amygdala reactivity and behavioral responding. Translational Psychiatry April 8, 2023
- The Bright Side of Psychedelics: Latest Advances and Challenges in Neuropharmacology International Journal of Molecular Sciences January 10, 2023
and 23 more in the library
Cites 25
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- Using Psilocybin to Investigate the Relationship between Attention, Working Memory, and the Serotonin 1A and 2A Receptors Journal of Cognitive Neuroscience October 1, 2005
- Differential contributions of serotonin receptors to the behavioral effects of indoleamine hallucinogens in mice Journal of Psychopharmacology December 8, 2010
and 20 more in the library