Abstract
BackgroundClinical 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 FindingsAdult 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/SignificanceThese findings suggest that a single administration of ketamine, but not GSK-3 inhibitor SB216763, produces a long-lasting antidepressant action in CMS model mice.
Highlights
Accumulating evidence suggests that dysfunction of the glutamate neurotransmitter system is associated with the pathophysiology of mood disorders, such as major depressive disorder (MDD) and bipolar disorder (BP) [1,2,3,4,5,6,7]
We found that ketamine (10 mg/kg), but not SB216763 (10 mg/kg), exerted antidepressant-like effects, as scored in the TST, forced swimming test (FST), and anhedonia tests, in mice subjected to the chronic mild stress (CMS) model
This effect was detectable at 24 hours, and interestingly, in CMS-induced anhedonia, it was still detectable 8 days after a single dose of ketamine
Summary
Accumulating evidence suggests that dysfunction of the glutamate neurotransmitter system is associated with the pathophysiology of mood disorders, such as major depressive disorder (MDD) and bipolar disorder (BP) [1,2,3,4,5,6,7]. Several lines of evidence suggest a role for glycogen synthase kinase-3 (GSK-3) in the pathophysiology of mood disorders, such as MDD and BP [25,26,27,28]. Beurel et al reported that a subanesthetic dose (10 mg/kg) of ketamine reduced symptoms of depression in mice subjected to the depression model of learned helplessness [32] They found that ketamine increased the serinephosphorylation of GSK-3a and GSK-3b, two isoforms of GSK3. 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, those who do not typically respond to therapy. We examined the effects of ketamine and GSK-3 inhibitor SB216763 in the unpredictable, chronic mild stress (CMS) mouse model of mice
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