Long-lasting antidepressant action of ketamine, but not glycogen synthase kinase-3 inhibitor SB216763, in the chronic mild stress model of mice

Abstract

Background: Clinical studies demonstrate that the N-methyl-D-aspartate (NMDA) receptor antagonist, ketamine, induces rapid antidepressant effects in patients with refractive major depressive disorder and bipolar depression. This rapid onset of action makes ketamine a highly attractive drug for patients, particularly those who do not typically respond to therapy. A recent study suggested that glycogen synthase kinase (GSK)-3 may underlie the rapid antidepressant action of ketamine, although the precise mechanisms are unclear. In this study, we examined the effects of ketamine and GSK-3 inhibitor SB216763 in the unpredictable, chronic mild stress (CMS) mouse model of mice.

Methodology/principal findings: Adult C57/B6 male mice were divided into 2 groups, a non-stressed control group and the unpredictable CMS (35 days) group. Then, either vehicle, ketamine (10 mg/kg), or the established GSK-3 inhibitor, SB216763 (10 mg/kg), were administered into mice in the CMS group, while vehicle was administered to controls. In the open field test, there was no difference between the four groups (control+vehicle, CMS+vehicle, CMS+ketamine, CMS+SB216763). In the sucrose intake test, a 1% sucrose intake drop, seen in CMS mice, was significantly attenuated after a single dose of ketamine, but not SB216763. In the tail suspension test (TST) and forced swimming test (FST), the increased immobility time seen in CMS mice was significantly attenuated by a single dose of ketamine, but not SB216763. Interestingly, the ketamine-induced increase in the sucrose intake test persisted for 8 days after a single dose of ketamine. Furthermore, a single administration of ketamine, but not SB216763, significantly attenuated the immobility time of the TST and FST in the control (non-stressed) mice.

Conclusions/significance: These findings suggest that a single administration of ketamine, but not GSK-3 inhibitor SB216763, produces a long-lasting antidepressant action in CMS model mice.

Figure 1. Experimental protocol.

(A): CMS paradigm. CMS procedures were performed for 5-weeks. Drug treatment was performed day 36. The 1% sucrose intake test (SIT) was performed at baseline, days 3, 10, 17, 24, 31, 37, 40, 42 and 44. Vehicle, ketamine (10 mg/kg), or SB216763 (10 mg/kg) were administered at day 36. The open field test (OFT) was performed at day 37. The tail suspension test (TST) and the forced swimming test (FST) was performed at day 38. (B): Acute effects of ketamine and SB216763 in control mice. Vehicle, ketamine (10 mg/kg, i.p.), or SB216763 (2.5, 5.0, or 10 mg/kg, i.p.) were administered into control mice. The behavioral tests, OFT, TST, and FST, were performed 3 and 24 hours after a single administration.

Figure 2. Effects of ketamine and the established GSK-3 inhibitor SB216763 in the CMS model.

(A) Locomotion: There were no differences between the four groups. Data show the mean±SEM (n = 8 or 9). (B) Tail-suspension test (TST): The increased immobility time of mice in the CMS groups, decreased significantly 48 hours (day 38) after a single dose of ketamine (10 mg/kg, i.p.), but not SB216763 (10 mg/kg, i.p.). Data show the mean±SEM (n = 5–8). (C) Forced swimming test (FST): The increased immobility time of mice in the CMS groups decreased significantly 48 hours (day 38) after a single dose of ketamine (10 mg/kg, i.p.), but not SB216763 (10 mg/kg, i.p.). Data show the mean±SEM (n = 8 or 9). *p<0.05, **p<0.01 as compared to CMS+Vehicle group.

Figure 3. Effects of ketamine and the established GSK-3 inhibitor SB216763 in the anhedonia model.

The decreased intake of 1% sucrose in the CMS groups was significantly attenuated 24 hours, 4 days, 6 days and 8 days after a single dose of ketamine (10 mg/kg, i.p.), but not of SB216763 (10 mg/kg, i.p.). Data show the mean±SEM (n = 8 or 9). **p<0.01, ***p<0.001 as compared to Control group.

Figure 4. Effects of ketamine and SB216763 on control mice.

Behavioral tests in control mice were performed 3 hours and 24 hours after a single administration of vehicle, ketamine (10 mg/kg, i.p.) or SB216763 (2.5, 5.0, or 10 mg/kg, i.p.). (A): Locomotion: There were no differences between the five groups. Data show the mean±SEM (n = 14–16). (B) Tail-suspension test (TST): There were no differences between the five groups. Data show the mean±SEM (n = 13–16). (C) Forced swimming test (FST): There were no differences between the five groups. Data show the mean±SEM (n = 13–15). (D) Locomotion: There were no differences between the five groups. Data show the mean±SEM (n = 15 or 16). (E) Tail-suspension test (TST): Ketamine significantly (p = 0.001) decreased immobility time, 24 hours after administration. Data show the mean±SEM (n = 15 or 16). (C) Forced swimming test (FST): Ketamine significantly (p = 0.037) decreased immobility time, 24 hours after administration. Data show the mean±SEM (n = 15 or 16). *p<0.05, **p<0.01 as compared with the control group.