2. Academic Validation
  3. Agonistic properties of a series of psychotropic drugs at 5-HT1A receptors in rat and human brain membranes determined by [35S]GTPγS binding assay

Agonistic properties of a series of psychotropic drugs at 5-HT1A receptors in rat and human brain membranes determined by [35S]GTPγS binding assay

  • Pharmacol Rep. 2023 Jan 13. doi: 10.1007/s43440-023-00448-6.
Yuji Odagaki 1 2,  Masaki Mikami 3,  Masakazu Kinoshita 4,  J Javier Meana 5 6,  Luis F Callado 5 6,  Jesús A García-Sevilla 7,  Dasiel Oscar Borroto-Escuela 8,  Kjell Fuxe 8
Affiliations

Affiliations

  • 1 Department of Psychiatry, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-machi, Iruma-gun, 350-0495, Saitama, Japan. [email protected].
  • 2 Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, 156-8506, Tokyo, Japan. [email protected].
  • 3 Medical Student, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-machi, Iruma-gun, 350-0495, Saitama, Japan.
  • 4 Department of Psychiatry, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-machi, Iruma-gun, 350-0495, Saitama, Japan.
  • 5 Department of Pharmacology, University of the Basque Country, UPV/EHU, 48940, Leioa, Bizkaia, Spain.
  • 6 Biocruces Bizkaia Health Research Institute, and Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM, Madrid, Spain.
  • 7 Laboratory of Neuropharmacology, IUNICS/IdISPa, University of the Balearic Islands (UIB), Palma de Mallorca, Spain.
  • 8 Department of Neuroscience, Biomedicum, Karolinska Institute, 171 77, Stockholm, Sweden.
PMID: 36637685 DOI: 10.1007/s43440-023-00448-6
Abstract

Background: Many psychoactive compounds have been developed to have more beneficial clinical efficacy than conventional drugs by adding agonistic action at 5-HT1A receptors. The aim of the present study was to evaluate several psychotropic drugs that had been reported to behave as an agonist at 5-HT1A receptor (aripiprazole, brexpiprazole, asenapine, lurasidone, and vortioxetine) in both rat and postmortem human brain membranes.

Methods: The [35S]GTPγS binding assay for Gi/o proteins coupled with 5-HT1A receptors was performed in rat brain membranes and postmortem human brain membranes.

Results: The specific binding was stimulated by brexpiprazole in rat hippocampus, human hippocampus, and human prefrontal cortex. Aripiprazole also behaved as an agonist in the same brain regions. Interestingly, its potency was much higher in rat hippocampal membranes than in human brain membranes, indicating the possibility of species differences. Although vortioxetine was an efficacious stimulator at high concentrations, its potency was undeterminable because of a lack of saturability. In addition to 5-HT1A receptor agonism, involvement of other components, e.g., 5-HT1B receptor agonism, was speculated by the biphasic inhibitory effects of the selective 5-HT1A receptor neutral antagonist. Negligible stimulatory effects were obtained as to lurasidone and asenapine.

Conclusions: Our previous studies have raised the concept of a psychoactive drug group with a common pharmacological mechanism of action, i.e., 5-HT1A receptor agonism, consisting of perospirone, aripiprazole, ziprasidone, clozapine, quetiapine, nemonapride, and trazodone. The present study demonstrates the data indicating that brexpiprazole and probably vortioxetine are included in this drug group. Lurasidone and asenapine are excluded from this group.

Keywords

Brexpiprazole; G-protein; Psychotropic drug; Serotonin 5-HT1A receptor; Vortioxetine.

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