Cellular mechanisms underlying the antidepressant effects of ketamine: role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors.
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 alpha-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.
Maeng
Sungho
S
Laboratory of Molecular Pathophysiology and Experimental Therapeutics, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Department of Health & Human Services, Bethesda, MD 20892, USA.
Zarate
Carlos A
CA
Du
Jing
J
Schloesser
Robert J
RJ
McCammon
Joseph
J
Chen
Guang
G
Manji
Husseini K
HK
D000818:Animals; D003865:Major Depressive Disorder / Q000188:drug therapy*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D006380:Helplessness, Learned; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology*; D007649:Ketamine / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D011597:Psychomotor Performance / Q000187:drug effects; D018091:Receptors, AMPA / Q000187:drug effects; D013550:Swimming; D013997:Time Factors; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000378:metabolism*
D018691:Excitatory Amino Acid Antagonists; D007649:Ketamine; D018091:Receptors, AMPA; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid