Knockdown of BNST GluN2B-containing NMDA receptors mimics the actions of ketamine on novelty-induced hypophagia - PubMed (original) (raw)

Knockdown of BNST GluN2B-containing NMDA receptors mimics the actions of ketamine on novelty-induced hypophagia

K M Louderback et al. Transl Psychiatry. 2013.

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.

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Figures

Figure 1

Figure 1

Viral deletion of GluN2B from the bed nucleus of the stria terminalis (BNST) phenocopies systemic treatment with ketamine or Ro25–6981. (a) Timeline above. Decreased latencies with systemic ketamine (3 mg kg−1) and Ro25 (5 mg kg−1) administration in our novelty-induced feeding suppression paradigm were repeated with (R) and without (NR) restraint stress. (b) Coronal atlas image (left) showing dorsal BNST in the inset and LV-GFP injection targeting (right). (c) Viral-mediated deletion of GluN2B from BNST (LV-Cre) phenocopies systemic ketamine; (d) however, viral-mediated deletion of GR from the BNST has no such effect. Data are presented as means with s.e.m. *_P_>0.05; **_P_>0.01. _N_s are indicated on bars.

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