Brexpiprazole, a compound sharing structural molecular characteristics with aripiprazole, is currently under investigation for the treatment of schizophrenia and depression. Using electrophysiological techniques, the present study assessed the in vivo action of brexpiprazole on serotonin (5-HT)1A, 5-HT1B, 5-HT2A receptor subtypes, dopamine (DA) D2 autoreceptors, and α1- and α2-adrenergic receptors. In addition, the effects on 5-HT1A autoreceptors in the dorsal raphe nucleus (DRN) and D2 autoreceptors in the ventral tegmental area (VTA) were compared to those of aripiprazole, an agent in wide clinical use. In the DRN, brexpiprazole completely inhibited the firing of 5-HT neurons via 5-HT1A 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-HT2A receptor agonist DOI on norepinephrine neuronal firing (ED50=110 μg/kg), demonstrating 5-HT2A 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 to 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-HT1A receptors on pyramidal neurons. Furthermore, it increased 5-HT release by terminal α2-adrenergic heteroceptor but not 5-HT1B autoreceptor antagonism. In the lateral geniculate nucleus, brexpiprazole displayed α1B-adrenoceptor antagonistic action. Taken together, these results provide insight in the in vivo action of brexpiprazole on monoamine targets relevant in the treatment of depression and schizophrenia.
- The American Society for Pharmacology and Experimental Therapeutics