Effects of ketamine and LY341495 on the depressive-like behavior of repeated corticosterone-injected rats
Introduction
Excessive activity of the hypothalamic–pituitary–adrenal (HPA) axis, which modulates the stress response, is often observed in depression. The overactivation and dysfunction of the HPA axis have been observed in patients with severe depression who are resistant to currently prescribed antidepressants (Juruena et al., 2009).
Chronic corticosterone (CORT)-injected rodents have been proposed as an animal model of depression that mimics the dysfunction of the HPA axis in depression. This procedure produced depressive-like behaviors and neuronal abnormalities in rodents similar to those observed in depression (Gourley and Taylor, 2009, Sterner and Kalynchuk, 2010). We previously reported that repeated CORT-injected rats showed an increase in immobility time during the forced swim test (FST) and demonstrated that imipramine (a tricyclic antidepressant; TCA) and fluvoxamine (a selective serotonin reuptake inhibitor; SSRI) did not correct the depressive-like behavior in the repeated CORT-injected rats, while mifepristone (a glucocorticoid receptor antagonist) did (Iijima et al., 2010). Our findings are supported by a previous report that repeated CORT injections in mice also increased the immobility time during the FST and the tail suspension test, and that desipramine (a TCA) and fluoxetine (an SSRI) were not effective, while RU43044 (a glucocorticoid receptor antagonist) improved depressive-like behaviors (Ago et al., 2008). Consistent with these preclinical findings, mifepristone has been reported to be an effective treatment for treatment-resistant depression (TRD) (Murphy et al., 1991). Thus, repeated CORT-injected rodents may represent a pharmacological animal model of TRD.
Dysfunctions of the glutamatergic system in the central nervous system, including glutamate levels (both in blood and brain), glutamate receptors and transporters, have been reported in patients with depression (Auer et al., 2000, Pfleiderer et al., 2003, Nudmamud-Thanoi and Reynolds, 2004, Sanacora et al., 2004, Choudary et al., 2005, Mitani et al., 2006, Hashimoto et al., 2007). Recently, ketamine, a noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, has been reported to exert antidepressant effects in patients with TRD (Price et al., 2009, aan het Rot et al., 2010, DiazGranados et al., 2010, Zarate et al., 2006, Zarate et al., 2012). In addition, ketamine has been reported to be effective in several animal models of depression, and the mechanisms underlying its effects are being revealed (Li et al., 2010, Autry et al., 2011, Koike et al., 2011a, Koike et al., 2011b, Liu et al., 2012). However, the effects of ketamine in repeated CORT injection rodents have not been investigated. Therefore, in the present study, we examined the effect of ketamine on the depressive-like behavior in repeated CORT-injected rats to further validate whether this procedure can be used as an animal model of TRD. Moreover, we investigated the effect of LY341495, a group ΙΙ metabotropic glutamate (mGlu2/3) receptor antagonist, on this animal model, since we recently found that mGlu2/3 receptor antagonists share some neural mechanisms with ketamine in the exertion of antidepressant-like effects (Koike et al., 2011a, Koike et al., 2011b, Chaki et al., 2013).
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Animals
Male Sprague–Dawley rats (4 weeks old at the beginning of the experiments, 65–105 g; Charles River, Yokohama, Japan) were used for this study. After treatment with CORT or a vehicle for 21 consecutive days, 7-week-old rats (185–325 g) were used for the FST. The animals were maintained under controlled temperature (25 ± 1 °C) and humidity (30%–40%) conditions with a 12-h light–dark cycle (lights on at 07:00). Food and water were provided ad libitum except during the tests. All the experiments were
Effect of ketamine on the increased immobility time during the FST in response to repeated CORT injection
Repeated CORT injection significantly increased the immobility time during the FST [t(14) = 3.01, P < 0.01; Fig. 1]. A sub-anesthesia dose of ketamine significantly reduced the increase in the immobility time in the repeated CORT-injected rats [F(3, 28) = 4.03, P < 0.05; Fig. 1]. Ketamine did not affect the immobility time in the repeated vehicle-treated rats (Fig. 1).
Effect of LY341495 on the increased immobility time during the FST in response to repeated CORT injection
Repeated CORT injection significantly increased the immobility time during the FST, [t(14) = 4.03, P < 0.01; Fig. 2]. LY341495 significantly
Discussion
The first aim of the present study was to further validate repeated CORT-injected rats as an animal model of TRD by examining the efficacy of ketamine, which is known to be effective for patients with TRD. We demonstrated that a sub-anesthesia dose of ketamine reduced the increased immobility time of repeated CORT-injected rats without affecting the immobility time of the repeated vehicle injected rats. In a previous study, we reported that mifepristone, which has also been reported to be
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