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Regulating serotonin expression can be used to treat psychotic depression. Mifepristone, a glucocorticoid receptor antagonist, is an effective candidate for psychotic depression treatment. However, the underlying mechanism related to serotonin transporter expression is poorly understood. In this study, we cloned the human brain serotonin transporter into Xenopus oocytes, to establish an in vitro expression system. Two-electrode voltage clamp recordings were used to detect serotonin transporter activity. Our results show that mifepristone attenuates serotonin transporter activity by directly inhibiting the serotonin transporter, and suggests that the serotonin transporter is a pharmacological target of mifepristone for the treatment of psychotic depression.
Figure 1. Expression of human brain serotonin transporter (SERT) in Xenopus oocytes.(A) Dose-response curves for varied serotonin concentrations (3.16–1,000 μmol/L) on SERT channels. (B) No serotonin response in control oo-cytes injected with water. (C) Normalized serotonin dose response on SERT channels. The half-maximal effect (EC50) was observed at a concentra-tion of 35.52 ± 3.63 μmol/L. Data are expressed as mean ± SEM. Each experiment was repeated six times. I: Current intensity; Sweeps 1–6: 3.16, 10, 31.6, 100, 316, and 1,000 μmol/L serotonin (5-HT).
Figure 2. Effect of glucocorticoids and RU-486 on serotonin transporter (SERT) activity.Response curves of Ringer control, cortisol, dexamethasone, corticos-terone, and glucocorticoid receptor antagonist, mifepristone (RU-486) (10 μmol/L) in 100 μmol/L serotonin (5-HT) activated SERT channels, after the serotonin response reached a steady-state plateau. Each exper-iment was repeated six times. Sweeps 1–5: 100 μmol/L 5-HT + control, cortisol, dexamethasome, corticosterone, or RU-486.
Figure 3. RU-486 blocked serotonin-elicited serotonin transporter (SERT) activity.(A) Serotonin (50 μmol/L) response in SERT-expressing oocytes, when co-applied with varied glucocorticoid receptor antagonist, mifepristone (RU-486) concentrations. Sweeps 1–6: 3.16, 10, 31.6, 100, 316, and 1,000 μmol/L serotonin. (B) SERT currents were recorded in response to sero-tonin (50 μmol/L). After the serotonin response reached a steady-state plateau, addition of RU-486 (1–100 μmol/L) produced concentration-de-pendent outward currents of SERT. Each experiment was repeated six times. Sweeps 1–6: 3.16, 10, 31.6, 100, 316, and 1,000 μmol/L serotonin + 100 μmol/L RU-486.
Figure 4. Effect of RU-486 on serotonin (5-HT) dose-response curves.(A) Serotonin dose-response curves from serotonin transporter (SERT)-expressing Xenopus oocytes. (B) Comparison of serotonin dose-response curves when glucocorticoid receptor antagonist, mifepristone (RU-486) (100 μmol/L) co-applied in the same oocyte. Each experiment was repeated six times. Sweeps 1–6: 50 μmol/L serotonin + 0, 1 3.16, 10, 31.6, and 100 μmol/L RU-486.
Figure 5. Comparison of normalized serotonin (5-HT) dose-response curves in the absence or presence of 100 μmol/L RU-486.(A) Data obtained in controls with 100 μmol/L glucocorticoid receptor antagonist, mifepristone (RU-486) were normalized to individually saturated serotonin response values. (B) Data normalized to the maximal response elicited by 1,000 μmol/L serotonin in the absence of RU-486. Data are expressed as mean ± SEM. Each experiment was repeated six times.
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