Abstract

Brexpiprazole, a compound sharing structural molecular characteristics with aripiprazole, is currently under investigation for the treatment of schizophrenia and depression. Using electrophysiologic techniques, the present study assessed the in vivo action of brexpiprazole on serotonin (5-HT) receptor subtypes 5-HT_1A, 5-HT_1B, and 5-HT_2A; dopamine (DA) D₂ autoreceptors, and α₁- and α₂-adrenergic receptors. In addition, the effects on 5-HT_1A autoreceptors in the dorsal raphe nucleus (DRN) and D₂ autoreceptors in the ventral tegmental area (VTA) were compared with those of aripiprazole, an agent in wide clinical use. In the DRN, brexpiprazole completely inhibited the firing of 5-HT neurons via 5-HT_1A agonism and was more potent than aripiprazole (ED₅₀ = 230 and 700 μg/kg, respectively). In the locus coeruleus, brexpiprazole reversed the inhibitory effect of the preferential 5-HT_2A receptor agonist DOI (2,5-dimethoxy-4-iodoamphetamine) on norepinephrine neuronal firing (ED₅₀ = 110 μg/kg), demonstrating 5-HT_2A antagonistic action. Brexpiprazole reversed the inhibitory effect of the DA agonist apomorphine on VTA DA neurons (ED₅₀ = 61 μg/kg), whereas it was ineffective when administered alone, indicating partial agonistic action on D₂ receptors. Compared with aripiprazole, which significantly inhibited the firing activity of VTA DA neurons, brexpiprazole displayed less efficacy at D₂ receptors. In the hippocampus, brexpiprazole acted as a full agonist at 5-HT_1A receptors on pyramidal neurons. Furthermore, it increased 5-HT release by terminal α₂-adrenergic heteroceptor but not 5-HT_1B autoreceptor antagonism. In the lateral geniculate nucleus, brexpiprazole displayed α_1B-adrenoceptor antagonistic action. Taken together, these results provide insight into the in vivo action of brexpiprazole on monoamine targets relevant in the treatment of depression and schizophrenia.