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Volume 63, Issue 4, Pages 349-352 (15 February 2008)


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Cellular Mechanisms Underlying the Antidepressant Effects of Ketamine: Role of α-Amino-3-Hydroxy-5-Methylisoxazole-4-Propionic Acid Receptors

Sungho Maeng, Carlos A. Zarate Jr, Jing Du, Robert J. Schloesser, Joseph McCammon, Guang Chen, Husseini K. ManjiCorresponding Author Informationemail address

Received 7 August 2006; received in revised form 14 May 2007; accepted 23 May 2007. published online 28 July 2007.

Background

Ketamine exerts a robust, rapid, and relatively sustained antidepressant effect in patients with major depression. Understanding the mechanisms underlying the intriguing effects of N-methyl d-aspartate (NMDA) antagonists could lead to novel treatments with a rapid onset of action.

Methods

The learned helplessness, forced swim, and passive avoidance tests were used to investigate ketamine’s behavioral effects in mice. Additional biochemical and behavioral experiments were undertaken to determine whether the antidepressant-like properties of ketamine and other NMDA antagonists involve α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor throughput.

Results

Subanesthetic doses of ketamine treatment caused acute and sustained antidepressant-like effects. At these doses, ketamine did not impair fear memory retention. MK-801 (dizocilpine) and Ro25-6981, an NR2B selective antagonist, also exerted antidepressant-like effects; these effects, however, were not sustained as long as those of ketamine. Pre-treatment with NBQX, an AMPA receptor antagonist, attenuated both ketamine-induced antidepressant-like behavior and regulation of hippocampal phosphorylated GluR1 AMPA receptors.

Conclusions

NMDA antagonists might exert rapid antidepressant-like effects by enhancing AMPA relative to NMDA throughput in critical neuronal circuits.

Laboratory of Molecular Pathophysiology and Experimental Therapeutics, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, and Department of Health & Human Services, Bethesda, Maryland.

Corresponding Author InformationAddress reprint requests to Husseini K. Manji, M.D., F.R.C.P.C., Mood and Anxiety Disorders Program, NIMH, Bldg 35, 1C-912, 35 Convent Drive. Bethesda, MD 20892

PII: S0006-3223(07)00547-1

doi:10.1016/j.biopsych.2007.05.028


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