title: Evaluation of sigma (σ) receptors in the antidepressant-like effects of ketamine in vitro and in vivo.
abstract: 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 σ 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 σ receptors in the antidepressant-like actions of ketamine. Competition binding assays were performed to assess the affinity of ketamine for σ(1) and σ(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 σ receptor antagonists, NE-100 and BD1047, were evaluated in conjunction with ketamine in these assays to determine the involvement of σ receptors in the antidepressant-like effects of ketamine. Ketamine bound to both σ(1) and σ(2) receptors with μM 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 σ receptor-mediated neuronal remodeling may contribute to the antidepressant effects of ketamine.
authors.affiliation: Department of Basic Pharmaceutical Sciences, West Virginia University, Morgantown, WV 26506, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Robson
authors.forename: Meenal
authors.initials: M
authors.lastname: Elliott
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Seminerio
authors.forename: Rae R
authors.initials: RR
authors.lastname: Matsumoto
mesh_terms: D000818:Animals; D000840:Anisoles / Q000494:pharmacology; D000928:Antidepressive Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005029:Ethylenediamines / Q000494:pharmacology; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D020932:Nerve Growth Factor / Q000819:agonists / Q000494:pharmacology; D016501:Neurites / Q000187:drug effects / Q000378:metabolism; D016716:PC12 Cells; D011437:Propylamines / Q000494:pharmacology; D011869:Radioligand Assay / Q000379:methods; D051381:Rats; D017480:Receptors, sigma / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000840:Anisoles; D000928:Antidepressive Agents; D005029:Ethylenediamines; D011437:Propylamines; D017480:Receptors, sigma; C083832:N,N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)ethylamine monohydrochloride; C097963:N-(2-(3,4-Dichlorphenyl)ethyl)-N,N',N'-trimethyl-1,2-ethandiamin; D007649:Ketamine; D020932:Nerve Growth Factor