The selective 5-HT2A receptor agonist LPH-5 induces persistent and robust antidepressant-like effects in rodents
Anders A. Jensen, Cláudia R. Cecchi, Meghan Hibicke, Astrid H. Bach, Erik Kaadt, Emil Märcher-Rørsted, Charles D. Nichols, Betina Elfving, Jesper L. Kristensen
bioRxiv Preprint Server April 19, 2024 preprint DOI: 10.1101/2024.04.19.590212 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study |
|---|---|
| Population | Sprague Dawley rats, Flinders Sensitive Line rats, and Wistar Kyoto rats |
| Intervention | LPH-5 |
| Dose | 0.375 – 12.0 mg/kg, i.p.; 1.5 mg/kg, i.p.; 0.3 and 1.5 mg/kg, i.p. |
| Duration | Acute administration |
| Topics | Serotonin |
| Key points | Selective 5-HT2A receptor activation by LPH-5 induces antidepressant-like effects in multiple rat models, suggesting this receptor is key for the therapeutic benefits of classical psychedelics. |
Abstract
Psychedelic-assisted psychotherapy has over the last decade emerged as a promising treatment strategy for mental health disease, and the therapeutic potential in classical psychedelics such as psilocybin, LSD and 5-MeO-DMT is presently being pursued in a plethora of clinical trials. However, the resurgent interest in the drugs as therapeutics has also prompted a search for novel agents with more specific pharmacological activities than the rather promiscuous classical psychedelics. Here we present the results of an elaborate preclinical characterization of one such compound, LPH-5 [(S)-3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)piperidine]. LPH-5 was found to be a potent partial agonist at the 5-HT2A receptor (5-HT2AR) and to exhibit pronounced selectivity for this receptor over the related 5-HT2B and 5-HT2C receptors in a range of functional assays. LPH-5 (0.375 – 12.0 mg/kg, i.p.) dose-dependently induced head-twitch responses (HTR) in Sprague Dawley rats, with substantial 5-HT2AR engagement being observed at 0.5-1.0 mg/kg. Acute administration of LPH-5 (1.5 mg/kg, i.p.) induced robust antidepressant-like effects in Flinders Sensitive Line rats and adrenocorticotropic hormone-treated Sprague Dawley rats, and LPH-5 (0.3 and 1.5 mg/kg, i.p.) induced significant effects in a recently developed Wistar Kyoto rat model proposed to reflect the long-term antidepressant-like effects produced by psychedelics in humans. In conclusion, selective 5-HT2AR activation, as mediated here by LPH- 5, seems to hold antidepressant potential, suggesting that this activity component is key for the beneficial effects of classical psychedelics. Hence, we propose that LPH-5 and other 5-HT2AR- selective agonists could hold potential as therapeutics in psychiatric disease as a new generation of psychedelic-derived antidepressant.
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
Cites 35
- Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial Journal of Psychopharmacology November 30, 2016
- Psychedelics Promote Structural and Functional Neural Plasticity Cell Reports June 1, 2018
- Psilocybin with psychological support for treatment-resistant depression: six-month follow-up. Psychopharmacology November 8, 2017
- Global Street Food: la cocina de la calle Diseño interior 2009
- Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors Science February 16, 2023
and 30 more in the library