A bright future of researching AMPA receptor agonists for depression treatment

Keywords::

• AMPA receptor agonists
• depression
• ketamine
• N-methyl-d-aspartate receptor

Ketamine, an N-methyl-d-aspartate (NMDA) receptor antagonist, is a widely used drug for anesthesia. However, increasing studies have focused on the potential antidepressant effects of ketamine. As mentioned in the review of Szewczyk et al. [1], subunit selective NMDA receptor antagonists exert the same antidepressant efficacy of ketamine but with fewer adverse effects. Indeed, the authors make a good comment and indicate a bright research future of developing novel antidepressants. However, we cannot neglect another vital receptor modulator α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor agonist.

Compared with conventional antidepressants, the most eye-catching superiority of NMDA receptor antagonists is their fast-acting and robust therapeutic effects for depression and even for treatment-resistant depression [2]. However, with regard to AMPA agonists, large previous studies have shown that they also exert exact antidepressant effects with a rapid onset time [3]. Moreover, mounting evidences indicate that ketamine-elicited antidepressant effects require the activation of AMPA receptors [4,5]. And until now, the researches on antidepressant action of AMPA agonists are not enough and there is no study reporting the severe side effects of AMPA agonists. In conclusion, further researches on AMPA receptor agonists for depression treatment will bring us a bright future for developing novel antidepressants.

Bibliography

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Authors' response: the differences in AMPA receptor dependence on antidepressant-like activity

Yang et al. (above) commented on our article [1] and pointed to the AMPA receptors as an important target for antidepressant research. In the above-mentioned review [1], we only briefly described the AMPA issue, since there is no clinical evidence indicating this mechanism in human depression.

However, recent preclinical data show the AMPA receptor as a target for antidepressant drugs. Thus, we examined the role of the AMPA receptor in the antidepressant-like activity of zinc, magnesium, chromium, MTEP, CGP 37849, MGS0039 as well as some antidepressants, both AMPA-dependent and AMPA-independent mechanisms were demonstrated (Table 1). Our data, together with data from other groups [2-5], indicate that AMPA-dependence may be related to drugs that influence NMDA receptors (or its subunits), or which block metabotropic mGlu2/3 receptors, or which influence the serotonergic (5-HT) rather than the noradrenergic (NA) transmission (Table1). This issue, however, requires further detailed studies.

Table 1. The AMPA receptor dependence of activity in the forced swim test or tail suspension test in mice.

Agent	Characteristic mechanism	AMPA dependence	Ref.
Ro25-6981	NR2B antagonist	+	Maeng et al. [2]
Ketamine	NMDA antagonist	+	Maeng et al. [2]; Koike et al. [5]
CGP 37849	NMDA antagonist	-	Dybała et al. [6]
Zinc	NMDA antagonist	+	Szewczyk et al. [7]
Magnesium	NMDA antagonist	+	Our unpublished
MTEP	mGluR5 antagonist	-	Pomierny-Chamioło et al. [8]
Imipramine	5-HT/NA uptake inhibition	-(+ partial?)	Maeng et al. [2]; our unpublished
Citalopram	5-HT uptake inhibition	+	Our unpublished
Reboxetine	NA uptake inhibition	-	Our unpublished
Tianeptine	5-HT uptake enhancer	+	Wlaz et al. [9]
Lithium	Uncertain	+	Gould et al. [3]
Chromium	Uncertain	+	Piotrowska et al. [10]
MGS0039	mGlu2/3 antagonist	+	Karasawa et al. [4]
			Pałucha-Poniewiera et al. [11]

The AMPA receptor dependence was assessed with the use of NBQX, an AMPA receptor antagonist.

5-HT: serotonergic; AMPA: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; CGP 37849: (dl-(E)amino-4-methyl-5-phosphono-3-pentenoic acid; MGS0039: (1R,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid; MTEP: 3-[(2-methyl-1,3-thiazol 4-yl)ethynyl]-pyridine; NA: noradrenergic; NBQX: 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)-quinoxaline-2,3-dione; NMDA: N-methyl-d-aspartate; Ro25-6981: (R-(R,S)-α-(4-hydroxyphenyl)-β-methyl-4-(phenylmethyl)-1-piperidine propanol.

Bibliography

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