Abstract
Administration of a single low dose of the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has been demonstrated to elicit long-lasting antidepressant effects in humans with depression, as well as in rodent models of depression. Although pharmacological studies have implicated the GluN2B subunit of the NMDA receptor in these effects, drugs targeting this subunit have off-target actions, and systemic administration of these compounds does not allow for delineation of specific brain regions involved. In this study, we assessed the role of GluN2B in the bed nucleus of the stria terminalis (BNST) in novelty-induced hypophagia (NIH) in mice. First, we verified that ketamine, as well as the GluN2B antagonist Ro25–6981, decreased the latency to consume food in a novel environment in a version of the NIH test. We then hypothesized that GluN2B-containing receptors within the BNST may be a target of systemic ketamine and contribute to behavioral effects. Through the combination of a GluN2B-floxed mouse line and stereotaxic delivery of lentiviral Cre recombinase, we found that targeted knockdown of this subunit within the BNST mimicked the reduction in affective behavior observed with systemic ketamine or Ro25–6981 in the NIH test. These data suggest a role for GluN2B-containing NMDARs within the BNST in the affective effects of systemic ketamine.
Highlights
A single, subanesthetic dose of the N-methyl D-aspartate receptor (NMDAR) antagonist ketamine exerts a rapid antidepressant action in patients with depression,[1] and has been associated with a number of adaptations throughout the brain
Ketamine acts as a psychotomimetic and has abuse potential, so understanding which specific adaptations are contributing to its positive behavioral effects is crucial for safer treatment options for depression
We propose that GluN2B subunitcontaining NMDARs within the bed nucleus of the stria terminalis (BNST) contribute to the actions of ketamine in a novelty-induced hypophagia (NIH) task used to test antidepressant efficacy
Summary
A single, subanesthetic dose of the N-methyl D-aspartate receptor (NMDAR) antagonist ketamine exerts a rapid antidepressant action in patients with depression,[1] and has been associated with a number of adaptations throughout the brain. We propose that GluN2B subunitcontaining NMDARs within the bed nucleus of the stria terminalis (BNST) contribute to the actions of ketamine in a novelty-induced hypophagia (NIH) task used to test antidepressant efficacy. The BNST is a component of the extended amygdala that modulates affective behavior, has been implicated in depression and anxiety, and has relatively high adult expression of GluN2B-containing NMDARs.[4–6] Further, activation of glutamate synapses in the BNST drives negative affect-related behaviors.[7] Given the evidence for GluN2B-containing NMDARs in the antidepressant effects of ketamine, we hypothesized that these receptors within the BNST might govern affective behaviors.
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