科研之友
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摘要
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-HT1A, 5-HT1B, and 5-HT2A; dopamine (DA) D-2 autoreceptors, and alpha(1)- and alpha(2)-adrenergic receptors. In addition, the effects on 5-HT1A autoreceptors in the dorsal raphe nucleus (DRN) and D-2 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-HT1A agonism and was more potent than aripiprazole (ED50 - 230 and 700 mu g/kg, respectively). In the locus coeruleus, brexpiprazole reversed the inhibitory effect of the preferential 5-HT2A receptor agonist DOI (2,5-dimethoxy-4-iodoamphetamine) on norepinephrine neuronal firing (ED50 - 110 mu g/kg), demonstrating 5-HT2A antagonistic action. Brexpiprazole reversed the inhibitory effect of the DA agonist apomorphine on VTA DA neurons (ED50 - 61 mu g/kg), whereas it was ineffective when administered alone, indicating partial agonistic action on D-2 receptors. Compared with aripiprazole, which significantly inhibited the firing activity of VTA DA neurons, brexpiprazole displayed less efficacy at D-2 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 alpha(2)-adrenergic heteroceptor but not 5-HT1B autoreceptor antagonism. In the lateral geniculate nucleus, brexpiprazole displayed alpha(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.
- 出版日期2014-12
