Long-Lasting Antidepressant Action of Ketamine, but Not Glycogen Synthase Kinase-3 Inhibitor SB216763, in the Chronic Mild Stress Model of Mice

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.

GSK-3 Inhibition Potentiates the Synaptogenic and Antidepressant-Like Effects of Subthreshold Doses of Ketamine

“…Similarly, while selective GSK-3 inhibitors produce antidepressant-like activity when given alone (Gould et al, 2004;KaidanovichBeilin et al, 2004), only short-term behavioral tests (30 min) were conducted in these studies. A more recent study reported that after selective GSK-3 inhibition alone, antidepressant effects were not observed after 24 h or 1 week (Ma et al, 2013). The latter results are consistent with our present finding that single acute doses of lithium or the selective GSK-3 inhibitor SB 216763 are not sufficient to produce a more prolonged phase of antidepressant-like effects.…”

“…To determine whether combined administration of a lowdose GSK-3 inhibitor and ketamine would be sufficient to evoke synaptogenesis and antidepressant effects similar to Ket-1/Li-10, we tested the effects of a combination of Ket-1 plus 2.5 mg/kg of SB 216763 (Ket-1/SB-2.5), previously shown to be ineffective by itself in reducing immobility 24 h after injection (Ma et al, 2013). Statistical analysis revealed a significant effect of the combination treatment on immobility time in the FST (F2,23 ¼ 18.299, po0.0001).…”

Short‐ and long‐term antidepressant effects of ketamine in a rat chronic unpredictable stress model

“…In rodents, the CUS paradigms produces anhedonia, the loss of interest in normally pleasurable and rewarding activities, which are a core symptom of depression (Ma et al, 2013;Willner, Muscat, & Papp, 1992). As based upon the results of our sucrose preference test, the CUS paradigm used in this report induced anhedonia, as rats exposed to chronic stress consumed significantly lower amounts of sucrose (Figure 3a).…”

The Prodrug 4-Chlorokynurenine Causes Ketamine-Like Antidepressant Effects, but Not Side Effects, by NMDA/GlycineB-Site Inhibition

“…Ketamine was used as a positive control in all of the behavioral experiments. The dose used routinely (10 mg/kg) was previously shown to exert antidepressant effects in mice (Maeng et al, 2008;Ma et al, 2013;Antony et al, 2014).…”

“…and quantitatively very similar, to those of ketamine, which was tested in parallel using a well-established antidepressant dose for mice [10 mg/kg;Maeng et al (2008); Ma et al (2013)]. We confirmed that the antidepressant-like action of 4-Cl-KYN in the acute FST involves the glycine B site, since pretreatment with glycine prevented the effects at the same dose shown to increase concentrations of glycine in the brain (albeit by less than a 2-fold difference) and to reverse the behavioral effects of NMDA channel blockers (Trullas and Skolnick, 1990;Evoniuk et al, 1991;Javitt et al, 1999).…”