Antagonism at the NR2B subunit of NMDA receptors induces increased connectivity of the prefrontal and subcortical regions regulating reward behavior

Major depressive disorder afflicts ~16 percent of the world population at some point in their lives. Despite a number of available monoaminergic-based antidepressants, most patients require many weeks, if not months, to respond to these treatments, and many patients never attain sustained remission of their symptoms. The non-competitive glutamatergic N-methyl-D-aspartate receptor (NMDAR) antagonist, (R,S)-ketamine (ketamine), exerts rapid and sustained antidepressant effects following a single dose in depressed patients. Here we show that the metabolism of ketamine to (2S,6S;2R,6R)-hydroxynorketamine (HNK) is essential for its antidepressant effects, and that the (2R,6R)-HNK enantiomer exerts behavioural, electroencephalographic, electrophysiological and cellular antidepressant actions in vivo. Notably, we demonstrate that these antidepressant actions are NMDAR inhibition-independent but they involve early and sustained α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor activation. We also establish that (2R,6R)-HNK lacks ketamine-related side-effects. Our results indicate a novel mechanism underlying ketamine’s unique antidepressant properties, which involves the required activity of a distinct metabolite and is independent of NMDAR inhibition. These findings have relevance for the development of next generation, rapid-acting antidepressants.

Neuroimaging studies have shown that major depressive disorder (MDD) is accompanied by structural and functional abnormalities in specific brain regions and connections; yet, little is known about alterations of the topological organization of whole-brain networks in MDD patients. Thirty drug-naive, first-episode MDD patients and 63 healthy control subjects underwent a resting-state functional magnetic resonance imaging scan. The whole-brain functional networks were constructed by thresholding partial correlation matrices of 90 brain regions, and their topological properties (e.g., small-world, efficiency, and nodal centrality) were analyzed using graph theory-based approaches. Nonparametric permutation tests were further used for group comparisons of topological metrics. Both the MDD and control groups showed small-world architecture in brain functional networks, suggesting a balance between functional segregation and integration. However, compared with control subjects, the MDD patients showed altered quantitative values in the global properties, characterized by lower path length and higher global efficiency, implying a shift toward randomization in their brain networks. The MDD patients exhibited increased nodal centralities, predominately in the caudate nucleus and default-mode regions, including the hippocampus, inferior parietal, medial frontal, and parietal regions, and reduced nodal centralities in the occipital, frontal (orbital part), and temporal regions. The altered nodal centralities in the left hippocampus and the left caudate nucleus were correlated with disease duration and severity. These results suggest that depressive disorder is associated with disruptions in the topological organization of functional brain networks and that this disruption may contribute to disturbances in mood and cognition in MDD patients. Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

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