Elsevier

Biological Psychiatry

Volume 63, Issue 4, 15 February 2008, Pages 349-352
Biological Psychiatry

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

https://doi.org/10.1016/j.biopsych.2007.05.028Get rights and content

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.

Section snippets

Animals and Treatments

Mice (male, 20–25 g, Jackson Labs, Bar Harbor, Maine) were housed in a standard National Institutes of Health (NIH) animal facility and subjected to experiments after a 1-week accommodation period. Ketamine (.5, 2.5, 10 mg/kg, Sigma, St. Louis, Missouri), MK-801 (also known as Dizocilpine; .05, .1, .2 mg/kg, Sigma), Ro25-6981 (1, 3, 10 mg/kg, Sigma), imipramine (20 mg/kg, Sigma), and 2,3-dihydroxy-6-nitro-7-sulfoamoylbenzo(f)-quinozaline (NBQX; 10 mg/kg, Toronto Research Chemicals, Ontario,

Acute Ketamine Effective in a Model That Requires Repeated Administration of Monoaminergic Antidepressant Drugs

The acute antidepressant-like effect of ketamine was tested with the learned helplessness (LH) paradigm. Mice undergoing the LH paradigm are generally only responsive to monoaminergic antidepressant drugs after repeated administration over several days (16). Significant differences were observed among naïve (without prior helplessness induction), saline-treated, and ketamine-treated groups on escape failures (Figure 1A) and on latency to escape (Figure 1B). In the mice that developed

Discussion

In conclusion, the findings presented here suggest that both nonselective NMDA antagonists as well as NR2B selective antagonists exert their antidepressant effects by regulating the functional interplay between AMPA and NMDA throughput. The results also raise the possibility that the combination of AMPA potentiating agents with even lower doses of NMDA antagonists might have utility in the treatment of depression and is worthy of further study.

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