Semester

Summer

Date of Graduation

2013

Document Type

Dissertation

Degree Type

PhD

College

School of Pharmacy

Department

Pharmaceutical Sciences

Committee Chair

Rae R. Matsumoto.

Abstract

Depression is estimated to affect at least 30% of the world's population at some point during their lives. Currently marketed antidepressants require a period of at least 2 to 3 weeks to display any antidepressant effects in clinical populations and rates of clinical resistance to the antidepressant effects of these drugs are high. Ketamine is an N-methyl-D-aspartate (NMDA) antagonist and dissociative anesthetic that has been shown to display rapid acting and prolonged antidepressant activity in smallscale 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 and 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, 4- methoxy-3-(2-phenylethoxy)-N,N-dipropylbenzeneethanamine hydrochloride (NE-100) and N-[2-(3,4- dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine dihydrobromide (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 iM affinities. Additionally, ketamine potentiated nerve growth factor (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.

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