Effects of Atypical Antipsychotics, Clozapine, Quetiapine and Brexpiprazole on Astroglial Transmission Associated with Connexin43

2021

IJMS

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It has been established that enhancement of serotonergic transmission contributes to improvement of major depression; however, several post-mortem studies and experimental depression rodent models suggest that functional abnormalities of astrocytes play important roles in the pathomechanisms/pathophysiology of mood disorders. Direct effects of serotonin (5-HT) transporter inhibiting antidepressants on astroglial transmission systems has never been assessed in this context. Therefore, to explore the effects of antidepressants on transmission associated with astrocytes, the present study determined the effects of the selective 5-HT transporter inhibitor, escitalopram, and the 5-HT partial agonist reuptake inhibitor, vortioxetine, on astroglial L-glutamate release through activated hemichannels, and the expression of connexin43 (Cx43), type 1A (5-HT1AR) and type 7 (5-HT7R) 5-HT receptor subtypes, and extracellular signal-regulated kinase (ERK) in astrocytes using primary cultured rat cortical astrocytes in a 5-HT-free environment. Both escitalopram and 5-HT1AR antagonist (WAY100635) did not affect basal astroglial L-glutamate release or L-glutamate release through activated hemichannels. Subchronic (for seven days) administrations of vortioxetine and the 5-HT7R inverse agonist (SB269970) suppressed both basal L-glutamate release and L-glutamate release through activated hemichannels, whereas 5-HT1AR agonist (BP554) inhibited L-glutamate release through activated hemichannels, but did not affect basal L-glutamate release. In particular, WAY100635 did not affect the inhibitory effects of vortioxetine on L-glutamate release. Subchronic administration of vortioxetine, BP554 and SB269970 downregulated 5-HT1AR, 5-HT7R and phosphorylated ERK in the plasma membrane fraction, but escitalopram and WAY100635 did not affect them. Subchronic administration of SB269970 decreased Cx43 expression in the plasma membrane but did not affect the cytosol; however, subchronic administration of BP554 increased Cx43 expression in the cytosol but did not affect the plasma membrane. Subchronic vortioxetine administration increased Cx43 expression in the cytosol and decreased it in the plasma membrane. WAY100635 prevented an increased Cx43 expression in the cytosol induced by vortioxetine without affecting the reduced Cx43 expression in the plasma membrane. These results suggest that 5-HT1AR downregulation probably increases Cx43 synthesis, but 5-HT7R downregulation suppresses Cx43 trafficking to the plasma membrane. These results also suggest that the subchronic administration of therapeutic-relevant concentrations of vortioxetine inhibits both astroglial L-glutamate and Cx43 expression in the plasma membrane via 5-HT7R downregulation but enhances Cx43 synthesis in the cytosol via 5-HT1AR downregulation. This combination of the downregulation of 5-HT1AR, 5-HT7R and Cx43 in the astroglial plasma membrane induced by subchronic vortioxetine administration suggest that astrocytes is possibly involved in the pathophysiology of depression.

Section: Discussionmentioning

confidence: 99%

Distinct Effects of Escitalopram and Vortioxetine on Astroglial L-Glutamate Release Associated with Connexin43

Shiroyama

2021

IJMS

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“…However, if the assumption of sphericity had been violated (p < 0.05), the F value was analysed using Chi-Muller's corrected degrees of freedom. Lastly, when the F value was significant, data were analysed by Tukey's multiple-comparison test [33][34][35][36].…”

Section: Discussionmentioning

confidence: 99%

Effects of Financial Expenditure of Prefectures/Municipalities on Regional Suicide Mortality in Japan

Shiroyama

2021

IJERPH

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In Japan, suicide mortality has been improving from 2009; however, suicide remains one of the leading causes of death. Although previous studies identified solid relationships between governmental financial support for social welfare systems and suicide mortality, little attention is paid to how specific regional policies, designed according to regional cultural, economic, and social welfare situations, affect suicide mortality. Therefore, the present study analyses the relationships between the regional governmental expenditure of six major divisions and suicide mortality across the 47 prefectures in Japan from 2009 to 2018 using fixed-effect analysis of hierarchal linear regression with robust standard error. The expenditure in “public health”, “police”, “ambulance/fire services”, “welfare” and “education” is associated with reduction in suicide mortality, at least in some statistical indicators, whereas expenditure of “public works” indicated the influence of increasing suicide mortality or had no effect. Welfare expenditure was the most predominantly effective among the six major divisions of regional governmental expenditure. In the welfare subdivisions, expenditure of “child welfare” and “social welfare” was effective in a reduction in suicide mortality, but expenditure of “elderly welfare” surprisingly contributed to increasing suicide mortality. Child welfare expenditure negatively impacted suicide mortality in wide-ranging generations of both males and females; the positive effects of elderly welfare expenditure reached were limited as working-age populations increased, but unexpectedly did not affect the suicide mortality of elderly populations. The relatively increasing expenditure of elderly welfare with the relatively decreasing child welfare are unavoidable due to the Japanese social issues associated with a declining birth rate and ageing population. Furthermore, the budget of that regional government that can modify its expenditure structure by making its own policies is limited since most regional governmental expenditure is composed of essential expenditure for maintaining and operating regional social welfare systems. Although severe social situations in Japan are still unoptimised, the present results suggest that scientific-evidence-based redistributions of welfare expenditure in regional governments can at least partially improve Japanese society and welfare systems.

“…TAT-GAP19 also suppressed the stimulatory effects of both acute and subchronic administrations of 1000 nM ZTP on HK-ACSF-evoked astroglial L-glutamate release (F ZTP (1.1, 10.9) = 108.7 (p < 0.01), F TAT-GAP19 (1,10) = 20.4 (p < 0.01), F ZTP*TAT-GAP19 (1.1, 10.9) = 34.2 (p < 0.01)) (Figure 2B). The stimulatory effects of subchronic administration of clozapine and quetiapine were mediated by enhanced Cx43 trafficking to the plasma membrane via activation of protein kinase B (Akt) activity [38]. Therefore, according to previous findings, to explore the mechanisms of the stimulatory effects of acute and subchronic administration of a supratherapeutic concentration of ZTP (1000 nM) on astroglial L-glutamate release through astroglial hemichannels, astrocytes were exposed to an AKT inhibitor, 10-[4'-(N,N-diethylamino)butyl]-2-chlorophenoxazine hydrochloride (DEBC: 10 μM), for 6 hr [38].…”

Section: Interaction Between Supratherapeutic Concentrations Of Ztp and Astroglial Hemichannel Inhibitors On Astroglial L-glutamate Releamentioning

confidence: 99%

“…The stimulatory effects of subchronic administration of clozapine and quetiapine were mediated by enhanced Cx43 trafficking to the plasma membrane via activation of protein kinase B (Akt) activity [38]. Therefore, according to previous findings, to explore the mechanisms of the stimulatory effects of acute and subchronic administration of a supratherapeutic concentration of ZTP (1000 nM) on astroglial L-glutamate release through astroglial hemichannels, astrocytes were exposed to an AKT inhibitor, 10-[4'-(N,N-diethylamino)butyl]-2-chlorophenoxazine hydrochloride (DEBC: 10 μM), for 6 hr [38].…”

Section: Interaction Between Supratherapeutic Concentrations Of Ztp and Astroglial Hemichannel Inhibitors On Astroglial L-glutamate Releamentioning

confidence: 99%

“…In particular, recent studies demonstrated that the mood-stabilising antipsychotics clozapine and quetiapine rapidly enhanced Cx43 trafficking to the astroglial plasma membrane and activated Cx43-containing hemichannels, resulting in the increasing release of excitatory astroglial transmitters, such as L-glutamate [33,38,39]. Indeed, first-line antiseizure drugs, such as brivaracetam, carbamazepine, lacosamide and zonisamide, suppress the astroglial hemichannel's function [40,41].…”

Section: Introductionmentioning

confidence: 99%

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Effects of an Atypical Antipsychotic, Zotepine, on Astroglial L-Glutamate Release through Hemichannels: Exploring the Mechanism of Mood-Stabilising Antipsychotic Actions and Antipsychotic-Induced Convulsion

2021

Pharmaceuticals

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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.