PT  - JOURNAL ARTICLE
AU  - Eduardo R. Butelman
AU  - Bryan D. McElroy
AU  - Thomas E. Prisinzano
AU  - Mary Jeanne Kreek
TI  - Impact of Pharmacological Manipulation of the <em>κ</em>-Opioid Receptor System on Self-grooming and Anhedonic-like Behaviors in Male Mice
AID  - 10.1124/jpet.119.256354
DP  - 2019 Jul 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 1--8
VI  - 370
IP  - 1
4099  - http://jpet.aspetjournals.org/content/370/1/1.short
4100  - http://jpet.aspetjournals.org/content/370/1/1.full
SO  - J Pharmacol Exp Ther2019 Jul 01; 370
AB  - 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 κ-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 κ-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 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, 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 Activation of the κ-opioid receptor system results in grooming deficits in mice, an ethologically relevant marker of anhedonia. Shorter acting κ-antagonists are able to cause effects consistent with rapid antianhedonia.