Abstract
The kappa (κ) 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 κreceptor 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 κ receptor system will result in changes 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" (an ethologically relevant behavior, in which robust self-grooming is elicited by spraying the dorsum of the mouse with a sucrose solution). The κ 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 κ 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). κ 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 κ selective dose of each of these antagonists decreased immobility in the forced swim test (FST), a common test of anti-anhedonia effects. This study shows that the κ receptor system is involved in an ethologically relevant measure of anhedonia, and that κ selective doses of these antagonists can produce effects consistent with rapid anti-anhedonia.
SIGNIFICANCE STATEMENT Shorter-acting k antagonists can produce actions consistent with rapid anti-anhedonia, in an ethologically relevant assay.
- The American Society for Pharmacology and Experimental Therapeutics