Impact of Pharmacological Manipulation of the κ-Opioid Receptor System on Self-grooming and Anhedonic-like Behaviors in Male Mice

The kappa (kappa) opioid receptor/dynorphin system modulates depression-like states and anhedonia, as well adaptations to stress and exposure to drugs of abuse. Several relatively short-acting small molecule kappa-receptor antagonists have been synthesized, and their behavioral profile has been examined under some conditions. The hypothesis of this study is that pharmacological manipulations of the kappa-receptor system will result in changes in ethologically relevant anhedonic-like behaviors in mice. Adult male C57BL/6j mice (n = 6-8) were examined for self-grooming behavior in the splash test (in which robust self-grooming is elicited by spraying the dorsum of the mouse with a sucrose solution). The kappa-agonist salvinorin A (0.56-1.8 mg/kg) produced dose-dependent decreases in self-grooming, a marker of anhedonia. The selectivity, potency, and duration of action of two relatively short-acting kappa-antagonists, LY2444296 [(S)-3-fluoro-4-(4-((2-(3-fluorophenyl)pyrrolidin-1-yl)methyl)phenoxy)benzamide] and LY2795050 [3-chloro-4-(4-(((2S)-2-pyridin-3- ylpyrrolidin-1-yl)methyl) phenoxy)benzamide], were studied for their effectiveness in preventing grooming deficits caused by salvinorin A (1.8 mg/kg). kappa-selective doses of both LY2444296 (0.032-1 mg/kg) and LY2795050 (0.032-0.32 mg/kg) dose- and time-dependently prevented the grooming deficits caused by salvinorin A (1.8 m/kg). We also found that a kappa-selective dose of each of these antagonists decreased immobility in the forced swim test, a common test of anti-anhedonia effects. This study shows that the kappa-receptor system is involved in an ethologically relevant measure of anhedonia, and that kappa-selective doses of these antagonists can produce effects consistent with rapid anti-anhedonia.