Journal Article

NMDAR inhibition-independent antidepressant actions of ketamine metabolites

Zanos, Panos, Dossou, Katina S. S., Morris, Patrick J., Fang, Yuhong, Mayo, Cheryl L., Gould, Todd D., Yuan, Peixiong, Alkondon, Manickavasagom, Huang, Xi-Ping, Thomas, Craig J., Georgiou, Polymnia, Wainer, Irving W., Moaddel, Ruin, Elmer, Greg I., Pribut, Heather J., Zarate Jr, Carlos A., Fischell, Jonathan, Albuquerque, Edson X., Singh, Nagendra S., Thompson, Scott M.

2016

Overview

Major depressive disorder affects around 16 per cent of the world population at some point in their lives. Despite the availability of numerous monoaminergic-based antidepressants, most patients require several weeks, if not months, to respond to these treatments, and many patients never attain sustained remission of their symptoms. The non-competitive, glutamatergic NMDAR ( N -methyl- d -aspartate receptor) antagonist ( R , S )-ketamine exerts rapid and sustained antidepressant effects after a single dose in patients with depression, but its use is associated with undesirable side effects. Here we show that the metabolism of ( R , S )-ketamine to (2 S ,6 S ;2 R ,6 R )-hydroxynorketamine (HNK) is essential for its antidepressant effects, and that the (2 R ,6 R )-HNK enantiomer exerts behavioural, electroencephalographic, electrophysiological and cellular antidepressant-related actions in mice. These antidepressant actions are independent of NMDAR inhibition but involve early and sustained activation of AMPARs (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors). We also establish that (2 R ,6 R )-HNK lacks ketamine-related side effects. Our data implicate a novel mechanism underlying the antidepressant properties of ( R , S )-ketamine and have relevance for the development of next-generation, rapid-acting antidepressants. The metabolism of ketamine to (2S,6S;2R,6R)-hydroxynorketamine (HNK) is essential for its antidepressant effects, and the (2R,6R)-HNK enantiomer lacks ketamine-related side effects but exerts rapid and sustained antidepressant actions in mice; these antidepressant effects are independent of NMDAR inhibition but require AMPAR activity. Antidepressant action of a ketamine metabolite The NMDAR antagonist ketamine has rapid and sustained antidepressant effects; this has prompted a search for alternative NMDAR antagonists that have the same antidepressant properties but lack the undesirable side effects of ketamine. Todd Gould and colleagues now show that the metabolism of ( R , S )-ketamine to (2 S ,6 S ;2 R ,6 R )-hydroxynorketamine (HNK) is essential for its antidepressant activity, and that the (2 R ,6 R )-HNK enantiomer exerts rapid and sustained antidepressant actions in mice. These effects are NMDAR-independent but require AMPAR activation. Importantly, (2 R ,6 R )-HNK lacks the side effects associated with ketamine. These findings suggest new options for the development of novel rapid-acting antidepressants.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/154/436/1729 / 631/378/1689/1333 / 631/378/1689/1414 / 64/60 / 9/30 / 9/74 / Animals / Antidepressants / Antidepressive Agents - adverse effects / Antidepressive Agents - metabolism / Antidepressive Agents - pharmacology / Brain / Cell receptors / Drug dosages / Female / Humanities and Social Sciences / Ketamine / Ketamine - adverse effects / Ketamine - analogs & derivatives / Ketamine - metabolism / Ketamine - pharmacology / Male / Mental depression / Metabolism / Metabolites / Methyl aspartate / Mice / multidisciplinary / Pharmaceutical research / Physiological aspects / Psychopharmacology / Receptors, AMPA - agonists / Receptors, AMPA - metabolism / Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors / Science / Side effects / Time Factors / World population