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

Abstract

Recent pharmacological studies indicated that the modulation of tripartite-synaptic transmission plays important roles in the pathophysiology of schizophrenia, mood disorders and adverse reactions. Therefore, to explore the mechanisms underlying the clinical and adverse reactions to atypical antipsychotics, the present study determined the effects of the sub-chronic administration of quetiapine (QTP: 3~30 μM) on the protein expression of 5-HT7 receptor (5-HT7R), connexin43 (Cx43), cAMP level and intracellular signalling, Akt, Erk and adenosine monophosphate-activated protein kinase (AMPK) in cultured astrocytes and the rat hypothalamus, using ultra-high-pressure liquid chromatography with mass spectrometry and capillary immunoblotting systems. QTP biphasically increased physiological ripple-burst evoked astroglial D-serine release in a concentration-dependent manner, peaking at 10 μM. QTP enhanced the astroglial signalling of Erk concentration-dependently, whereas both Akt and AMPK signalling’s were biphasically enhanced by QTP, peaking at 10 μM and 3 μM, respectively. QTP downregulated astroglial 5-HT7R in the plasma membrane concentration-dependently. Protein expression of Cx43 in astroglial cytosol and intracellular cAMP levels were decreased and increased by QTP also biphasically, peaking at 3 μM. The dose-dependent effects of QTP on the protein expression of 5-HT7R and Cx43, AMPK signalling and intracellular cAMP levels in the hypothalamus were similar to those in astrocytes. These results suggest several complicated pharmacological features of QTP. A therapeutically relevant concentration/dose of QTP activates Akt, Erk and AMPK signalling, whereas a higher concentration/dose of QTP suppresses AMPK signalling via its low-affinity 5-HT7R inverse agonistic action. Therefore, 5-HT7R inverse agonistic action probably plays important roles in the prevention of a part of adverse reactions of QTP, such as weight gain and metabolic complications.

A Candidate Gliotransmitter, L-β-Aminoisobutyrate, Contributes to Weight Gain and Metabolic Complication Induced by Atypical Antipsychotics

“…Therapeutic-relevant and supratherapeutic serum concentrations of lurasidone are ranged from 30–100 nM and higher than 500 nM, respectively [ 25 , 26 ]. Therapeutic-relevant and supratherapeutic serum concentrations of quetiapine ranged from 0.3–10 μM and higher than 30 μM, respectively [ 19 , 25 , 26 , 27 ]. Based on these clinical findings and preclinical demonstrations, in this study, primary cultured cortical astrocytes were chronically (for 14 d) exposed to supratherapeutic concentration of lurasidone (500 nM) and quetiapine (30 μM) and therapeutic-relevant concentration of lurasidone (100 nM) and quetiapine (3 μM) [ 19 , 20 , 27 , 28 ].…”

“…Therapeutic-relevant and supratherapeutic serum concentrations of quetiapine ranged from 0.3–10 μM and higher than 30 μM, respectively [ 19 , 25 , 26 , 27 ]. Based on these clinical findings and preclinical demonstrations, in this study, primary cultured cortical astrocytes were chronically (for 14 d) exposed to supratherapeutic concentration of lurasidone (500 nM) and quetiapine (30 μM) and therapeutic-relevant concentration of lurasidone (100 nM) and quetiapine (3 μM) [ 19 , 20 , 27 , 28 ]. Previously, pharmacodynamic studies reported that the effective dose of systemic administration of lurasidone [ 29 , 30 ] and quetiapine [ 31 ] to schizophrenic models were 1 and 10 mg/kg, respectively.…”

“…Previously, pharmacodynamic studies reported that the effective dose of systemic administration of lurasidone [ 29 , 30 ] and quetiapine [ 31 ] to schizophrenic models were 1 and 10 mg/kg, respectively. Based on these previous studies, rats were chronically administered lurasidone (1 and 3 mg/kg/day) and quetiapine (10 and 30 mg/kg/day) for 14 d, using subcutaneously osmotic pumps (2ML_1; Alzet, Cupertino, CA, USA) [ 19 , 20 ].…”

“…These discrepancies between brexpiprazole and clozapine can provide a candidate hypothetical pathophysiology of antipsychotics-induced weight gain that increasing BAIBA plays important roles in the antipsychotics-induced activation of AMPK signalings. On the contrary, inhibition of 5-HT7 receptor suppresses AMPK signalings via decreasing cAMP synthesis [ 6 , 19 , 20 , 21 ]. Considering these preclinical findings, the interaction between stimulatory effects of increasing L-BAIBA and inhibitory effects of 5-HT7 receptor inhibition on AMPK signalings contributes to the bell-shaped dose–response curve of weight gain induced by several atypical antipsychotics, such as quetiapine [ 4 , 15 ].…”

Opposing effects of clozapine and brexpiprazole on β-aminoisobutyric acid: Pathophysiology of antipsychotics-induced weight gain

“…AMPK controls the metabolism of individual cells in peripheral organs; however, hypothalamic AMPK seems to play fundamental roles in regulating both sides of the energy balances equation (feeding and energy expenditure) in whole-body 5 . Indeed, antipsychotics with a high-risk for weight gain (clozapine and olanzapine) enhance hypothalamic AMPK signalling, whereas lower-risk antipsychotics (lurasidone and brexpiprazole) suppress AMPK signalling [10][11][12][13] .…”