首页|Impact of 5-HT7 receptor inverse agonism of lurasidone on monoaminergic tripartite synaptic transmission and pathophysiology of lower risk of weight gain
Impact of 5-HT7 receptor inverse agonism of lurasidone on monoaminergic tripartite synaptic transmission and pathophysiology of lower risk of weight gain
扫码查看
点击上方二维码区域，可以放大扫码查看
原文链接
NSTL
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。
NSTL
