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. 2018 Jan 1;21(1):84-88.
doi: 10.1093/ijnp/pyx108.

Lack of Antidepressant Effects of (2R,6R)-Hydroxynorketamine in a Rat Learned Helplessness Model: Comparison with (R)-Ketamine

Yukihiko Shirayama  1   2 , Kenji Hashimoto  2
Affiliations

Lack of Antidepressant Effects of (2R,6R)-Hydroxynorketamine in a Rat Learned Helplessness Model: Comparison with (R)-Ketamine

Yukihiko Shirayama et al. Int J Neuropsychopharmacol. .

Abstract

Background: (R)-Ketamine exhibits rapid and sustained antidepressant effects in animal models of depression. It is stereoselectively metabolized to (R)-norketamine and subsequently to (2R,6R)-hydroxynorketamine in the liver. The metabolism of ketamine to hydroxynorketamine was recently demonstrated to be essential for ketamine's antidepressant actions. However, no study has compared the antidepressant effects of these 3 compounds in animal models of depression.

Methods: The effects of a single i.p. injection of (R)-ketamine, (R)-norketamine, and (2R,6R)-hydroxynorketamine in a rat learned helplessness model were examined.

Results: A single dose of (R)-ketamine (20 mg/kg) showed an antidepressant effect in the rat learned helplessness model. In contrast, neither (R)-norketamine (20 mg/kg) nor (2R,6R)-hydroxynorketamine (20 and 40 mg/kg) did so.

Conclusions: Unlike (R)-ketamine, its metabolite (2R,6R)-hydroxynorketamine did not show antidepressant actions in the rat learned helplessness model. Therefore, it is unlikely that the metabolism of ketamine to hydroxynorketamine is essential for ketamine's antidepressant actions.

Keywords: (R)-ketamine; (R)-norketamine (2R,6R)-hydroxynorketamine; learned helplessness; metabolism.

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Figures

Figure 1.
Figure 1.
Metabolism of (R)-ketamine in the liver. In the liver, (R)-ketamine is metabolized to (R)-norketamine (major pathway) and (2R,6R)-hydroxyketamine (minor pathway), subsequently (2R,6R)-hydroxynorketamine (HNK).
Figure 2.
Figure 2.
Effects of a single injection of (R)-ketamine, (R)-norketamine, and (2R,6R)- HNK in a rat LH model. (A) Rats received inescapable electric shock (IES) treatments on 2 days (days 1 and 2), passed a post-shock test (PS) on day 3, and were designated as learned helplessness (LH) rats with depression-like phenotype. On day 3, vehicle (saline: 2 mL/kg), (R)-ketamine (20 mg/kg), (R)-norketamine (20 mg/kg), or (2R,6R)- HNK (20 and 40 mg/kg) was administered i.p. into LH rats. On day 8 (5 days after a single injection), conditioned avoidance (CA) test to study the antidepressant effect was performed. (B) The failure number of LH (1-way ANOVA: F4,24 = 3.755, P = .0167). The escape latency of LH (1-way ANOVA: F4,24 = 3.973, P = .013). Data are shown as mean ± SEM (n = 5–8). The number in the parenthesis is the dose (mg/kg). *P < .05 compared with vehicle-treated group. (C) Rats received IES treatments on 2 days (days 1 and 2), passed a PS on day 3, and were designated as LH rats with depression-like phenotype. On day 3, either vehicle (saline: 2 mL/kg), (R)-ketamine (20 mg/kg), or (2R,6R)- HNK (20 mg/kg) was administered i.p. into LH rats. CA test was performed on day 4 (24 hours after a single injection). (D) The failure number of LH (1-way ANOVA: F2,14 = 13.52, P < .0001). The escape latency of LH (1-way ANOVA: F2,14 = 14.73, P = .0004). Data are shown as mean ± SEM (n = 5 or 6). The number in the parenthesis is the dose (mg/kg). **P < .01, ***P < .001 compared with vehicle-treated group. R-KT: (R)-ketamine, R-NKT: (R)-norketamine, R-HNK: (2R,6R)-hydroxynorketamine.
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