Elsevier

Behavioural Brain Research

Volume 271, 1 September 2014, Pages 111-115
Behavioural Brain Research

Research report
Requirement of AMPA receptor stimulation for the sustained antidepressant activity of ketamine and LY341495 during the forced swim test in rats

https://doi.org/10.1016/j.bbr.2014.05.065Get rights and content

Highlights

  • Ketamine exhibited antidepressant effect in the forced swim test at 24 h after the injection.

  • LY341495 exhibited antidepressant effect in the forced swim test at 24 h after the injection.

  • Stimulation of AMPA receptor during the test is required the antidepressant effects.

Abstract

Ketamine, a non-competitive N-methyl-d-aspartate receptor antagonist, and group II metabotropic glutamate (mGlu2/3) receptor antagonists produce antidepressant effects in animal models of depression, which last for at least 24 h, through the transient increase in glutamate release, leading to activation of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA) receptor. Both ketamine and an mGlu2/3 receptor antagonist reportedly increase the expression of GluR1, an AMPA receptor subunit, within 24 h, which may account for the sustained enhancement of excitatory synaptic transmission following ketamine administration. However, whether the sustained increase in AMPA receptor-mediated synaptic transmission is associated with the antidepressant effects of ketamine and mGlu2/3 receptor antagonists has not yet been investigated.

In the present study, to address this question, we tested whether AMPA receptor stimulation at 24 h after a single injection of ketamine or an mGlu2/3 receptor antagonist, (2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl)propanoic acid (LY341495) was necessary for the antidepressant effect of these compounds using a forced swim test in rats.

A single injection of ketamine or LY341495 at 24 h before the test significantly decreased the immobility time. An AMPA receptor antagonist, 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide (NBQX), administered 30 min prior to the test significantly and dose-dependently reversed the antidepressant effects of ketamine and LY341495, while NBQX itself had no effect on the immobility time.

Our findings suggest that AMPA receptor stimulation at 24 h after a single injection of ketamine or LY341495 is required to produce the anti-immobility effects of these compounds. Moreover, the present results provide additional evidence that an mGlu2/3 receptor antagonist may share some of neural mechanisms with ketamine to exert antidepressant effects.

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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