Involvement of AMPA receptor in both the rapid and sustained antidepressant-like effects of ketamine in animal models of depression

Abstract

A growing body of evidence has suggested that the dysfunction of glutamatergic systems plays a pivotal role in major depressive disorder (MDD). In clinical studies, an N-methyl-d-aspartate receptor antagonist, ketamine, was shown to exert both rapid and sustained antidepressant effects in patients with treatment-resistant MDD. The objective of the present study was to confirm the rapid onset of action of ketamine and to investigate the mechanisms underlying both the rapid and sustained antidepressant-like effects of ketamine in rodent models of depression. The intraperitoneal administration of ketamine (10 mg/kg) 30 min prior to testing significantly reduced the number of escape failures in the learned helplessness (LH) paradigm in rats in which currently prescribed antidepressants exerted an effect only after repeated administrations. Ketamine also significantly reduced the immobility time in the tail suspension test (TST), and this effect lasted for 72 h, indicating that ketamine may possess a sustained antidepressant-like effect. The rapid antidepressant-like effects of ketamine in both the LH paradigm and the TST were significantly blocked by subcutaneous treatment with 2,3-dihydroxy-6-nitro-7-sulfoamoylbenzo(f)quinoxaline (NBQX), an α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor antagonist. In addition, the sustained antidepressant-like effect of ketamine in the TST was partially abolished by treatment with NBQX. In conclusion, we confirmed the faster onset of the action of ketamine, compared with clinically prescribed antidepressants. Moreover, the present results suggested that direct AMPA receptor activation may play an important role in both the rapid and sustained antidepressant-like effects of ketamine in animal models of depression, although other mechanisms might be involved in the sustained action.

Introduction

The dysregulation of glutamatergic systems has been implicated in various stages of psychiatric disorders. Abnormalities in glutamatergic systems have been consistently identified in major depressive disorder (MDD) [15], [20], [21], [29], [32]. For example, the glutamate levels in the occipital cortex are abnormally elevated in MDD patients [28]. In contrast, a reduction in Glx levels (a marker for combined glutamate and glutamine) has been observed in the anterior cingulate cortex of patients with MDD [1]. A similar reduction was also reported in the anterior cingulated cortex in children with major depression [17], [27].

Clinical studies have demonstrated that a noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, ketamine, produced both rapid and sustained antidepressant effects in patients with treatment-resistant MDD [4], [36]. Of note, recent clinical studies have reported that ketamine also decreased suicidal ideation in patients with treatment-resistant MDD [7], [26]. Thus, the elucidation of the mechanism underlying agents acting on glutamatergic systems, such as ketamine may lead to novel therapies for MDD.

Accumulating evidence has shown that NMDA receptor antagonists also exert antidepressant-like effects in several animal models of depression [21]. Ketamine has been reported to exert antidepressant-like effects after acute treatment in behavioral despair models examined using the forced swim test and the tail suspension test (TST) [9], [14], [22], both of which are commonly used tests for assessing antidepressant activity [23], [24], [31]. Interestingly, the antidepressant-like effect of ketamine has been reported to be sustained for up to 2 weeks in animals examined using the forced swim test [14], [35], despite the short serum half-life of ketamine (approximately 13 min) in mice [16]. The acute antidepressant-like effect of ketamine is thought to be mediated by the stimulation of α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors during the forced swimming test [14]. However, whether AMPA receptor stimulation is the common mechanism underlying both the rapid and sustained antidepressant-like effects of ketamine remains unknown. In the present study, we first confirmed the rapid antidepressant-like effects of ketamine in the learned helplessness (LH) paradigm in rats in which clinically prescribed antidepressants exerted an effect only after repeated administration [30]. Moreover, the involvement of AMPA receptor stimulation in both the acute and sustained antidepressant effects of ketamine was investigated in the LH paradigm and the TST.