Central kappa-opioid receptor-mediated antidepressant-like effects of nor-Binaltorphimine: behavioral and BDNF mRNA expression studies

Abstract

kappa-opioid receptor antagonists such as nor-Binaltorphimine (nor-BNI) have been shown to produce antidepressant-like behavioral effects in animal models of depression. The aim of this study was to investigate further the duration of centrally administered nor-BNI-induced antidepressant-like actions measured by both behavior and brain-derived neurotrophic factor (BDNF) gene expression. In addition, antagonist studies were conducted to determine the role of opioid receptor subtypes and the time course of nor-BNI's pharmacological actions. Antidepressant-like behavioral effects were measured by decreased immobility in the rat forced swim test and BDNF mRNA expression was determined by in situ hybridization. Centrally administered nor-BNI (20 microg, i.c.v.) decreased immobility and increased BDNF mRNA expression in the hippocampus on day 1, not on days 3-14, post-administration. Systemic administration of selective mu-, delta- and kappa-opioid receptor antagonists did not block nor-BNI-induced antidepressant-like effects. In contrast, i.c.v. administration of nor-BNI 7 or 14 days earlier significantly blocked subsequent nor-BNI-induced decreased immobility and upregulation of BDNF mRNA expression. Although the duration of nor-BNI's antidepressant-like effects did not synchronize with that of its kappa-opioid receptor antagonist effects, this study is the first to show that centrally administered nor-BNI, like most clinically used antidepressants, can upregulate BDNF mRNA expression in the rat hippocampus. These findings further demonstrate that central kappa-opioid receptor mediates antidepressant-like effects of nor-BNI measured by both behavior and BDNF gene expression.

Fig. 1

Effects of central administration of nor-BNI on behavior in the forced swim test and on BDNF mRNA expression in rats. nor-BNI (μg) was administrated i.c.v. 24 h before the behavioral measurement (top panel) and brain collection for in situ hybridization (bottom panel). Quantification of BDNF mRNA signals in different brain regions including the frontal cortex, CA1, CA3, and dentate gyrus of hippocampus, and amygdala are represented as mean percent of control (no treatment). Each value represents mean ± S.E.M. (n=4-6). *, p<0.05 compared with the vehicle condition.

Fig. 2

Time course of centrally administered nor-BNI-induced antidepressant-like effects and increases of BDNF mRNA expression. Effects of i.c.v. nor-BNI 20 μg on behavior in the forced swim test and on BDNF mRNA expression were measured. nor-BNI was administered 1, 3, 7, or 14 days before the behavioral measurement (top panel) and brain collection for in situ hybridization (bottom panel) in different groups of rats. Each value represents mean ± S.E.M. (n=4-6). *, p<0.05 compared with the vehicle condition. See Fig. 1. for other details.

Fig. 3

Effects of systemic opioid receptor antagonists on centrally administered nor-BNI-induced effects. nor-BNI (20 μg) decreased immobility in the forced swim test and increased BDNF mRNA expression 24 h following i.c.v. administration. Sterile water (1 mL/kg, Veh), naltrindole (1 mg/kg) or naltrexone (0.1 mg/kg) was administered s.c. 15 min before i.c.v. administration of nor-BNI (i.e., Veh+nor-BNI, Naltrindole+nor-BNI, and Naltrexone+nor-BNI). nor-BNI (10 mg/kg) was administered s.c. 24 h before i.c.v. administration of nor-BNI (i.e., nor-BNI+nor-BNI). Each value represents mean ± S.E.M. (n=4-6). *, p<0.05 compared with the Veh+Veh condition. See Fig. 1. for other details.

Fig. 4

Effects of 7-day central pretreatment with nor-BNI on i.c.v. nor-BNI-induced antidepressant-like effects and increases brain BDNF mRNA expression. Sterile water (Vehicle, 10 μL) or nor-BNI (20 μg) was administrated i.c.v. 7 days prior to i.c.v. administration of nor-BNI 20 μg (i.e., Veh+nor-BNI and nor-BNI+nor-BNI). Last nor-BNI was administered 24 h before the behavioral measurement (top panel) and brain collection for in situ hybridization (bottom panel). Each value represents mean ± S.E.M. (n=4-6). *, p<0.05 compared with the Veh+Veh condition; #, p<0.05 compared with the Veh+nor-BNI condition. See Fig. 1 & 3 for other details.

Fig. 5

Effects of 14-day central pretreatment with nor-BNI on i.c.v. nor-BNI-induced antidepressant-like effects and increases brain BDNF mRNA expression. Sterile water (Vehicle, 10 μL) or nor-BNI (20 μg) was administrated i.c.v. 14 days prior to i.c.v. administration of nor-BNI 20 μg (i.e., Veh+nor-BNI and nor-BNI+nor-BNI). Last nor-BNI was administered 24 h before the behavioral measurement (top panel) and brain collection for in situ hybridization (bottom panel). Each value represents mean ± S.E.M. (n=4-6). *, p<0.05 compared with the Veh+Veh condition; #, p<0.05 compared with the Veh+nor-BNI condition. See Fig. 1 & 4 for other details.