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

Fukuyama, Kouji; Okada, Motohiro

doi:10.3390/ph14111116

Cited by 9 publications

(17 citation statements)

References 76 publications

(156 reference statements)

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“…Our proposed hypothesis regarding the mechanisms of Brex on astroglial transmission demonstrated by the present and previous studies [ 12 , 18 , 34 , 41 , 43 ] is summarised in Figure 10 . demonstrations by in vitro experiments using cultured astrocytes have indicated the possibility that the inhibitory effects of Brex on 5-HT7R play important roles in the clinical actions of Brex via the modulation of astroglial signalling.…”

Section: Discussionmentioning

confidence: 55%

“…The major procedures of preparation of the cultured astrocytes and the study design are described in the following Section 4.2 . according to our previous studies [ 12 , 18 , 34 , 37 , 38 , 39 , 40 , 41 , 42 , 43 ].…”

Section: Resultsmentioning

confidence: 99%

“…In contrast, a selective 5-HT transporter inhibitor enhanced Akt phosphorylation via the activation of 5-HT1AR [ 55 ]. Furthermore, subchronic applications of haloperidol and mood-stabilising atypical antipsychotics, such as clozapine, olanzapine, quetiapine, risperidone, and zotepine, activate Akt signalling [ 12 , 41 , 52 , 53 , 54 ]. In contrast to Akt signalling, acute applications of haloperidol, clozapine, and risperidone acutely activate Erk signalling in hippocampal neurons [ 50 , 51 ], whereas these effects were not observed in D2R-deficit mice [ 49 ].…”

Section: Discussionmentioning

confidence: 99%

“…The clinical features of Brex for the treatment of mood disorders involve dominant antidepressant-like action compared to other antipsychotics [ 4 , 5 , 6 , 7 ]. Mood-stabilising antipsychotics (clozapine, quetiapine, and zotepine) enhance astroglial L-glutamate release through activated connexin43-containing hemichannels [ 12 , 28 , 41 ], whereas 5-HT transporter-inhibiting antidepressants and lurasidone suppress astroglial L-glutamate release via the suppression of astroglial connexin43-containing hemichannel activities [ 13 , 15 , 18 , 43 , 44 ]. Therefore, the enhancement and suppression of connexin43 function probably contribute to mood-stabilising and antidepressive actions, respectively [ 15 , 18 , 34 , 44 ].…”

Section: Discussionmentioning

confidence: 99%

“…The present study demonstrated that the effects of Brex on tripartite synaptic transmission are probably y generated by complicated mechanisms compared to those of clozapine, quetiapine, zotepine, and lurasidone [ 12 , 28 , 41 ]. The therapeutic relevant concentration of Brex weakly enhanced astroglial L-glutamate release through connexin43-containing hemichannel, similar to clozapine, quetiapine, and zotepine [ 12 , 28 , 41 ]; however, the effect of Brex on trafficking and transcription processes of connexin43 was rather similar to lurasidone and vortioxetine, which suppress connexin43 function via their 5-HT7R inverse agonistic action [ 18 , 34 ]. These results suggest that the 5-HT7R inverse agonist-like action of Brex cannot be ignored as a mechanism of antidepressive-dominant mood-stabilising effects of Brex.…”

Section: Discussionmentioning

confidence: 99%

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Brexpiprazole Reduces 5-HT7 Receptor Function on Astroglial Transmission Systems

Fukuyama

Motomura

Okada

2022

IJMS

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Several atypical antipsychotics exert mood-stabilising effects via the modulation of various monoamine receptors and intracellular signallings. Recent pharmacodynamic studies suggested that tripartite synaptic transmission can contribute to the pathophysiology of schizophrenia and mood disorders, their associated cognitive impairment, and several adverse reactions to atypical antipsychotics. Therefore, to explore the mechanisms underlying the antidepressive mood-stabilising and antipsychotic effects of brexpiprazole (Brex), we determined the effects of subchronic administration of therapeutically relevant concentrations/doses of Brex on the protein expression of 5-HT receptors, connexin43, cAMP levels, and intracellular signalling in cultured astrocytes and rat hypothalamus using ultra-high-pressure liquid chromatography with mass spectrometry and capillary immunoblotting systems. Subchronic administration of a therapeutically relevant concentration of Brex (300 nM) downregulated both 5-HT1A (5-HT1AR) and 5-HT7 (5-HT7R) receptors, in addition to phosphorylated Erk (pErk), without affecting phosphorylated Akt in the astroglial plasma membrane. Subchronic administration of 300 nM Brex decreased and increased phosphorylated AMPK and connexin43, respectively, in the astroglial cytosol fraction. A therapeutically relevant concentration of Brex acutely decreased the astroglial cAMP level, whereas, under the inhibition of 5-HT1AR, Brex did not affect astroglial cAMP levels. However, the 5-HT7R-agonist-induced increased astroglial cAMP level was inhibited by Brex. In contrast to the in vitro study, systemic subchronic administration of effective doses of Brex (3 and 10 mg/kg/day for 14 days) increased the cAMP level but did not affect phosphorylated AMPK in the rat hypothalamus. These results suggest several complicated pharmacological features of Brex. Partial 5-HT1AR agonistic action predominates in the low range of therapeutically relevant concentrations of Brex, whereas in the high range, 5-HT7R inverse agonist-like action is overlapped on the 5-HT1A agonistic action. These unique suppressive effects of Brex on 5-HT7R play important roles in the clinical features of Brex regarding its antidepressive mood-stabilising actions.

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