Abstract
Accumulating neuropsychopharmacological evidence has suggested that functional abnormalities of astroglial transmission and protein kinase B (Akt) contribute to the pathophysiology and/or pathomechanisms of several neuropsychiatric disorders, such as epilepsy, schizophrenia, affective disorders and antipsychotic-induced convulsions. Therefore, to explore the pathophysiology of mood-stabilising antipsychotics and the proconvulsive actions of atypical antipsychotics, the present study determined the effects of a mood-stabilising, atypical, antipsychotic agent, zotepine (ZTP), on astroglial L-glutamate release and the expression of connexin43 (Cx43) protein in cortical, primary, cultured astrocytes using ultra-high-pressure liquid chromatography and capillary immunoblotting systems. Both acute and subchronic administrations of therapeutically relevant concentrations of ZTP did not affect astroglial L-glutamate release or Cx43 expression in plasma membranes; however, chronic administration of a therapeutically relevant concentration of ZTP increased astroglial L-glutamate release and Cx43 expression in the plasma membrane. Subchronic administrations of a supratherapeutic concentration of ZTP enhanced astroglial L-glutamate release and Cx43 expression in the plasma membrane, whereas acute administration of a supratherapeutic concentration of ZTP enhanced astroglial L-glutamate release without affecting Cx43 expression. These stimulatory effects of ZTP on astroglial L-glutamate release through activated hemichannels and Cx43 trafficking to the astroglial plasma membrane were suppressed by the Akt inhibitor. These results suggest that ZTP enhances astroglial L-glutamate release in a concentration-dependent and time-dependent manner due to the enhanced function of astroglial hemichannels, probably via activation of Akt signalling. Therefore, the enhanced astroglial L-glutamatergic transmission induced by ZTP is, at least partially, involved in the mood-stabilising antipsychotic and proconvulsive actions of ZTP.
Highlights
Zotepine (ZTP), 2-[(8-chlorodibenzo[b,f]thiepin-10-yl)oxy]-N,N-dimethylethan-1-amine, is the first atypical antipsychotic drug to have been approved [1,2,3]
To determine the basal astroglial L-glutamate release and the L-glutamate release through activated astroglial hemichannels, cultured astrocytes were incubated in artificial cerebrospinal fluid (ACSF) and high K+ (100 mM) with Ca2+ -free ACSF (HK-ACSF) for 20 min (HK-ACSF-evoked stimulation) [40]
The stimulatory effects of acute administration of a supratherapeutic concentration of ZTP (1000 nM) on HK-ACSF-evoked L-glutamate release were not affected by DEBC, whereas DEBC suppressed the HK-ACSF-evoked L-glutamate release induced by. These results indicated that astroglial hemichannels could not contribute to basal astroglial L-glutamate release during the resting stage, whereas Cx43-containing astroglial hemichannels were activated by HK-ACSF-evoked stimulation, resulting in enhanced astroglial L-glutamate release
Summary
Zotepine (ZTP), 2-[(8-chlorodibenzo[b,f]thiepin-10-yl)oxy]-N,N-dimethylethan-1-amine, is the first atypical antipsychotic drug to have been approved [1,2,3]. ZTP was originally developed and launched in Japan in 1982; the term “atypical antipsychotics”. Based on its pharmacodynamic profile and clinical features, ZTP was later proposed to be classified as an “atypical antipsychotic” [2,3,4,5]. The receptor-binding profile of ZTP displays antagonism of the dopamine D2 and serotonin 5-HT2A receptors, similar to other atypical antipsychotics [4,5]. Several clinical studies have reported the effectiveness of ZTP in treating bipolar disorder [10,11,12,13].
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call