Evaluation of sigma (σ) receptors in the antidepressant-like effects of ketamine in vitro and in vivo

Ketamine is an NMDA antagonist and dissociative anesthetic that has been shown to display rapid acting and prolonged antidepressant activity in small-scale human clinical trials. Ketamine also binds to sigma receptors, which are believed to be protein targets for a potential new class of antidepressant medications. The purpose of this study was to determine the involvement of sigma receptors in the antidepressant-like actions of ketamine. Competition binding assays were performed to assess the affinity of ketamine for sigma(1) land sigma(2) receptors. The antidepressant-like effects of ketamine were assessed in vitro using a neurite outgrowth model and PC12 cells, and in vivo using the forced swim test. The sigma receptor antagonists, NE-100 and BD1047, were evaluated in conjunction with ketamine in these assays to determine the involvement of sigma receptors in the antidepressant-like effects of ketamine. Ketamine bound to both sigma(1) and sigma(2) receptors with mu M affinities. Additionally, ketamine potentiated NGF-induced neurite outgrowth in PC12 cells and this effect was attenuated in the presence of NE-100. Ketamine also displayed antidepressant-like effects in the forced swim test; however, these effects were not attenuated by pretreatment with NE-100 or BD1047. Taken together, these data suggest that sigma receptor-mediated neuronal remodeling may contribute to the antidepressant effects of ketamine. (C) 2011 Elsevier B.V. and ECNP. All rights reserved.