Research reportRequirement of AMPA receptor stimulation for the sustained antidepressant activity of ketamine and LY341495 during the forced swim test in rats
Introduction
Accumulating evidence has indicated that modulation of the glutamatergic system is an attractive strategy for treating mood disorders. Indeed, ketamine, a non-competitive N-methyl-d-aspartate receptor antagonist, has been reported to relieve the symptoms of patients with treatment-resistant major depressive disorder and bipolar disorder [1], [2], [3], [4], [5], [6]. However, a number of adverse effects, including psychotomimetic symptoms and abuse potential, preclude the routine use of ketamine, and demands for alternatives to ketamine are increasing. These demands have facilitated efforts to understand the mechanisms underlying the antidepressant action of ketamine.
We and others have previously shown the transient activation of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA) receptor after ketamine administration is needed to trigger the rapid and sustained antidepressant effects of ketamine [7], [8], [9], [10], [11]. In addition, transient AMPA receptor stimulation has been demonstrated to activate brain-derived neurotrophic factor/tropomyosin-related kinase B (TrkB) and mammalian target of rapamycin complex (mTORC) 1 signaling pathways, which subsequently increase the expression of synaptic proteins (e.g., GluR1, PSD-95, and Synapsin I) and excitatory synaptic transmission in the medial prefrontal cortex (mPFC) [8], [12]. Importantly, not only pretreatment with the AMPA receptor antagonist 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide (NBQX), but also the blockade of synaptic plasticity using the mTORC1 inhibitor rapamycin abrogated the antidepressant effects of ketamine [8], [13], [14], suggesting that the delayed up-regulation of excitatory synaptic transmission in the mPFC may play an important role in exerting the antidepressant effects of ketamine.
Group II metabotropic glutamate (mGlu2/3) receptor antagonists exert ketamine-like antidepressant effects in animal models of depression [15], which is mediated through transient AMPA receptor stimulation [9], [16]. Moreover, we and others have previously demonstrated that the antidepressant effects of mGlu2/3 receptor antagonists, similarly to ketamine, can be prevented by the inhibition of the TrkB and mTORC1 pathways [17], [18], [19] and that an mGlu2/3 receptor antagonist (2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl)propanoic acid (LY341495) increases the expression of synaptic proteins including GluR1 (an AMPA receptor subunit) in the mPFC [19], thereby indicating that synaptic plasticity in the mPFC may also be involved in the antidepressant effects of mGlu2/3 receptor antagonists. Thus, in addition to transient stimulation of AMPA receptor, the increase in AMPA receptor expression (and presumably transmission) might be associated with the antidepressant effects of both ketamine and mGlu2/3 receptor antagonists.
However, little is known about whether the delayed increase in AMPA receptor-mediated synaptic transmission is required for the antidepressant activities of ketamine and mGlu2/3 receptor antagonists. To address this issue, we first confirmed that the antidepressant effects of ketamine and LY341495 are observed at 24 h after the administration using the forced swim test (FST), which is widely used for assessing antidepressant activity. We then used NBQX to examine the relationship between the delayed AMPA receptor stimulation and the antidepressant effects of ketamine and LY341495.
Section snippets
Animals
Male 6-week-old Sprague-Dawley rats were purchased and were used for this study at an age of 7 weeks (Charles River, Yokohama, Japan). 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 conducted in accordance with the criteria of the Taisho Pharmaceutical Co., Ltd. Animal Care Committee and met the Japanese
Antidepressant effect of ketamine
We examined the anti-immobility effect of ketamine in the FST (Fig. 1B). An ANOVA showed a significant effect of treatment on the immobility time (F(3,36) = 3.88; P < 0.05, n = 10 each). A post hoc analysis indicated that ketamine at a dose of 10 mg/kg significantly reduced the immobility time (P < 0.05). To examine whether excitatory synaptic transmission through the AMPA receptor during the FST contributed to the anti-immobility effect of ketamine, NBQX was injected 30 min before the test (Fig. 1C).
Discussion
In the present study, we demonstrated for the first time that excitatory synaptic transmission through the AMPA receptor at 24 h after a single injection of ketamine or LY341495 is required to produce the anti-immobility effects of these compounds in the FST.
First, consistent with the results of previous studies [8], [19], [20], we confirmed that the administration of a sub-anesthetic dose of ketamine (at dose of 10 mg/kg) or LY341495 at 24 h prior to the test reduced the immobility time in the
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