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

Background: Many psychoactive compounds have been developed to have more beneficial clinical efficacy than conventional drugs by adding agonistic action at 5-HT_1A receptors. The aim of the present study was to evaluate several psychotropic drugs that had been reported to behave as an agonist at 5-HT_1A receptor (aripiprazole, brexpiprazole, asenapine, lurasidone, and vortioxetine) in both rat and postmortem human brain membranes.

Methods: The [³⁵S]GTPγS binding assay for G_i/o proteins coupled with 5-HT_1A 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-HT_1A receptor agonism, involvement of other components, e.g., 5-HT_1B receptor agonism, was speculated by the biphasic inhibitory effects of the selective 5-HT_1A 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-HT_1A 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.

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