Abstract
Recently, accumulating preclinical findings suggest the possibility that functional abnormalities of tripartite synaptic transmission play important roles in the pathophysiology of schizophrenia and affective disorder. Therefore, to explore the novel mechanisms of mood-stabilizing effects associated with tripartite synaptic transmission, the present study determined the effects of mood-stabilizing antipsychotics, clozapine (CLZ), quetiapine (QTP) and brexpiprazole (BPZ), on the astroglial l-glutamate release and expression of connexin43 (Cx43) in the astroglial plasma membrane using cortical primary cultured astrocytes. Neither acute (for 120 min) nor subchronic (for 7 days) administrations of CLZ, QTP and BPZ affected basal astroglial l-glutamate release, whereas both acute and subchronic administration of CLZ, QTP and BPZ concentration-dependently enhanced astroglial l-glutamate release through activated hemichannels. Subchronic administration of therapeutic-relevant concentration of valproate (VPA), a histone deacetylase inhibiting mood-stabilizing antiepileptic drug, enhanced the stimulatory effects of therapeutic-relevant concentration of CLZ, QTP and BPZ on astroglial l-glutamate release through activated hemichannel. Subchronic administration of therapeutic-relevant concentration of CLZ, QTP and BPZ did not affect Cx43 protein expression in the plasma membrane during resting stage. After subchronic administration of VPA, acute and subchronic administration of therapeutic-relevant concentrations of CLZ increased Cx43 protein expression in the plasma membrane. Both acute administrations of therapeutic-relevant concentrations of QTP and BPZ did not affect, but subchronic administrations enhanced Cx43 protein expression in the astroglial plasma membrane. Furthermore, protein kinase B (Akt) inhibitor suppressed the stimulatory effects of CLZ and QTP, but did not affect Cx43 protein expression in the astroglial plasma membrane. These results suggest that three mood-stabilizing atypical antipsychotics, CLZ, QTP and BPZ enhance tripartite synaptic glutamatergic transmission due to enhancement of astroglial Cx43 containing hemichannel activities; however, the Cx43 activating mechanisms of these three mood-stabilizing antipsychotics were not identical. The enhanced astroglial glutamatergic transmission induced by CLZ, QTP and BPZ is, at least partially, involved in the actions of these three mood-stabilizing antipsychotics.
Highlights
Modulations of various monoamine receptors have provided the development of a number of atypical antipsychotics for the treatment of schizophrenia and affective disorders [1,2,3], whereas approximately two-thirds of patients with schizophrenia and affective disorders lack to achieve an adequate response to first-choice pharmacotherapy using conventional atypical antipsychotics, and as many as one-third of patients remain unwell even after several adequate trials of antipsychotics [1,2,3,4,5]
Recent neuropharmacological studies suggest that functional abnormalities of tripartite synaptic transmission possibly contribute to pathophysiology of schizophrenia, affective disorder, epilepsy and their associated cognitive impairments [7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22]
Connexon is formed by six connexins unit [2,3], and two connexons in two neighboring cells, neurons, astrocytes, oligodendrocytes and microglia form gap-junction with aqueous pore and charged surface walls, whereas single connexon contributes to chemical connection between intra- and extracellular spaces as a hemichannel [2,3,22]
Summary
Modulations of various monoamine receptors have provided the development of a number of atypical antipsychotics for the treatment of schizophrenia and affective disorders [1,2,3], whereas approximately two-thirds of patients with schizophrenia and affective disorders lack to achieve an adequate response to first-choice pharmacotherapy using conventional atypical antipsychotics, and as many as one-third of patients remain unwell even after several adequate trials of antipsychotics [1,2,3,4,5]. Recent neuropharmacological studies suggest that functional abnormalities of tripartite synaptic transmission possibly contribute to pathophysiology of schizophrenia, affective disorder, epilepsy and their associated cognitive impairments [7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22]. Under the several pathological conditions, such as depolarization, ischemia, specific cation mobilization and phosphorylation, generate persistent hemichannel opening, resulting in the sustained astroglial non-exocytotic release of excitatory L-glutamate, D-serine, adenosine triphosphate, kynurenine metabolites and eicosanoids, which toxically affect homeostasis systems [2,3,8,9,10,11,12,17,19,20,21,25]
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