A part of atypical antipsychotics exert mood-stabilising effects via modulation of various monoamine receptors and intracellular signalling. Recent pharmacodynamic studies suggested that tripartite-synaptic transmission can be involved in pathophysiology of mood-disorders, schizophrenia, their associated cognitive impairments, and several adverse-reactions to atypical antipsychotics. Therefore, to explore mechanisms underlying antidepressive mood-stabilising and antipsychotic effects of lurasidone, we determined concentration-dependent effects of acute and subchronic lurasidone administrations on astroglial L-glutamate release, and expression of connexin43, ERK, AKT, adenosine monophosphate activated protein kinase (AMPK), 5-HT1A (5-HT1AR) and 5-HT7 (5-HT7R) receptors in cultured astrocytes using ultra-high-pressure liquid-chromatography with mass-spectrometry and capillary-immunoblotting systems. Therapeutically-relevant lurasidone concentration suppressed astroglial L-glutamate release through activated connexin43-containing hemichannel by decreasing connexin43 expression in plasma-membrane. Subchronic lurasidone administration downregulated 5-HT1AR and 5-HT7R in astroglial plasma-membrane concentration-dependently. Subchronic lurasidone administration attenuated ERK and AMPK signallings concentration-dependently without affecting AKT signalling. These results suggest that effects of subchronic lurasidone administration on astroglial L-glutamate release, 5-HT receptor, and intracellular signalling are similar to vortioxetine and different from mood-stabilising atypical antipsychotics, clozapine. Therefore, inhibitory effects of subchronic lurasidone administration on astroglial L-glutamate release through activated connexin43-containing hemichannel probably contribute to pathophysiology of antidepressive mood-stabilising effects of lurasidone. Furthermore, inhibitory effects of subchronic lurasidone administration on ERK and AMPK activities (without affecting AKT activity) induced by downregulation of 5-HT7R could result in clinical advantages of lurasidone, lower risk of weight gain.
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