Brexpiprazole Reduces 5-HT7 Receptor Function on Astroglial Transmission Systems

Abstract

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.

Dose-Dependent Biphasic Action of Quetiapine on AMPK Signalling via 5-HT7 Receptor: Exploring Pathophysiology of Clinical and Adverse Effects of Quetiapine

“…An Akt inhibitor, 10-[4-(N,N-diethylamino)butyl]-2-chlorophenoxazine hydrochloride (DEBC: 10 μM), Erk inhibitor, 5-(2-Phenyl-pyrazolo[1,5-a]pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridazin-3-ylamine (FR180204: 20 μM) [ 18 , 31 , 39 , 40 , 52 ] and AMPK inhibitor, dorsomorphin (10 μM) [ 54 ], also did not affect basal astroglial D-serine release ( Figure 1 B), whereas ripple-burst evoked D-serine release was inhibited by 10 μM DEBC and 20 μM FR180204, but was not affected by 10 μM dorsomorphin ( Figure 1 C).…”

“…Indeed, a 5-HT7R and 5-HT transporter-inhibiting antidepressant, vortioxetine [ 36 , 37 ], suppresses astroglial L-glutamate release via inhibition of connexin43 (Cx43) trafficking to the plasma membrane [ 31 ]. Similar to vortioxetine, mood-stabilising antipsychotics, such as brexpiprazole and lurasidone, which are effective for bipolar depression but not for mania, also suppress astroglial L-glutamate release due to the same mechanism [ 18 , 28 , 38 , 39 , 40 , 41 ]. It has been demonstrated that 5-HT7R inhibition probably plays an important role in the underlying effects of vortioxetine, brexpiprazole and lurasidone on the suppression of Cx43 trafficking [ 31 , 38 , 39 ].…”

“…Similar to vortioxetine, mood-stabilising antipsychotics, such as brexpiprazole and lurasidone, which are effective for bipolar depression but not for mania, also suppress astroglial L-glutamate release due to the same mechanism [ 18 , 28 , 38 , 39 , 40 , 41 ]. It has been demonstrated that 5-HT7R inhibition probably plays an important role in the underlying effects of vortioxetine, brexpiprazole and lurasidone on the suppression of Cx43 trafficking [ 31 , 38 , 39 ]. Contrarily, several mood-stabilising atypical antipsychotics, such as clozapine, QTP and zotepine, which are effective for a wide spectrum of mood disorders, including unipolar depression, bipolar depression and mania, increase astroglial L-glutamate release via activation of Cx43 trafficking [ 18 , 26 , 28 , 40 , 41 ].…”

“…Both antidepressive mood-stabilising antipsychotics, lurasidone and brexpiprazole, are evaluated to be the safest option in patients with a risk of developing metabolic complications, since they are listed among the best atypical antipsychotics associated with metabolic outcomes [ 14 , 42 ]. The mechanisms of similar clinical features between lurasidone and brexpiprazole, which are of low risk for the development of metabolic complication, are also probably involved in the 5-HT7R inverse agonistic action of these atypical antipsychotics [ 38 , 39 ]. In particular, the 5-HT7R inverse agonistic actions of lurasidone and brexpiprazole are speculated to contribute to the suppression of adenosine monophosphate-activated protein kinase (AMPK) signalling, resulting in a low risk of developing metabolic complications [ 38 , 39 , 43 ]; however, clozapine is also known to be a 5-HT7R inverse agonist [ 44 ].…”

“…The mechanisms of similar clinical features between lurasidone and brexpiprazole, which are of low risk for the development of metabolic complication, are also probably involved in the 5-HT7R inverse agonistic action of these atypical antipsychotics [ 38 , 39 ]. In particular, the 5-HT7R inverse agonistic actions of lurasidone and brexpiprazole are speculated to contribute to the suppression of adenosine monophosphate-activated protein kinase (AMPK) signalling, resulting in a low risk of developing metabolic complications [ 38 , 39 , 43 ]; however, clozapine is also known to be a 5-HT7R inverse agonist [ 44 ]. Clozapine acutely inhibits 5-HT7R functions and chronically downregulates 5-HT7R [ 44 ], whereas the binding affinity of clozapine to 5-HT7R (Ki = 18 nM) is relatively lower compared to H1R (Ki = 1.1 nM) [ 22 , 23 ] ( Table 1 ).…”