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J Pharmacol Exp Ther. 2019 Jul;370(1):1-8. doi: 10.1124/jpet.119.256354. Epub 2019 Apr 11.

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

Author information

1
Laboratory on the Biology of Addictive Diseases, the Rockefeller University, New York, New York (E.R.B., B.D.M., M.J.K.), and Department of Medicinal Chemistry, School of Pharmacy, University of Kansas, Lawrence, Kansas (T.E.P.) butelme@rockefeller.edu.
2
Laboratory on the Biology of Addictive Diseases, the Rockefeller University, New York, New York (E.R.B., B.D.M., M.J.K.), and Department of Medicinal Chemistry, School of Pharmacy, University of Kansas, Lawrence, Kansas (T.E.P.).

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 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.

PMID:
30975792
PMCID:
PMC6538891
[Available on 2020-07-01]
DOI:
10.1124/jpet.119.256354

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