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.)
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.).
J Pharmacol Exp Ther. 2019 Jul;370(1):1-8. doi: 10.1124/jpet.119.256354. Epub 2019 Apr 11.
The 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 -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 -receptor system will result in changes in ethologically relevant anhedonic-like behaviors in mice. Adult male C57BL/6j mice ( = 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 -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 -antagonists, LY2444296 [()-3-fluoro-4-(4-((2-(3-fluorophenyl) pyrrolidin-1-yl)methyl)phenoxy)benzamide] and LY2795050 [3-chloro-4-(4-(((2)-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). -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 -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 -receptor system is involved in an ethologically relevant measure of anhedonia, and that -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.
κ 阿片受体/强啡肽系统调节抑郁状态和快感缺失，以及对压力和滥用药物的适应。已经合成了几种相对短半衰期的小分子 - 受体拮抗剂，并在某些条件下检查了它们的行为特征。本研究的假设是，κ-受体系统的药理学操作将导致在老鼠中产生与行为相关的快感缺失样行为的变化。成年雄性 C57BL/6j 小鼠（n = 6-8）在飞溅测试中检查自我梳理行为（通过向小鼠背部喷洒蔗糖溶液来引起强烈的自我梳理）。κ-激动剂沙利洛芬 A（0.56-1.8 mg/kg）产生剂量依赖性的自我梳理减少，这是快感缺失的标志物。两种相对短半衰期的κ-拮抗剂 LY2444296[()-3-氟-4-（（2-（3-氟苯基）吡咯烷-1-基）甲基）苯氧基）苯甲酰胺]和 LY2795050[3-氯-4-（4-（（2-）-2-吡啶-3-基吡咯烷-1-基）甲基）苯氧基）苯甲酰胺]的选择性、效力和作用持续时间研究了它们预防沙利洛芬 A（1.8mg/kg）引起的梳理缺陷的有效性。LY2444296（0.032-1mg/kg）和 LY2795050（0.032-0.32mg/kg）的 - 选择性剂量均剂量和时间依赖性地预防了沙利洛芬 A（1.8m/kg）引起的梳理缺陷。我们还发现，这些拮抗剂中的每一种的 - 选择性剂量都降低了强制游泳试验中的不动性，这是一种常见的抗快感缺失效应测试。这项研究表明，κ-受体系统参与了一种与行为相关的快感缺失测量，并且这些 - 选择性剂量的拮抗剂可以产生与快速抗快感缺失一致的效果。意义声明：κ-阿片受体系统的激活导致小鼠梳理缺陷，这是快感缺失的一种与行为相关的标志物。作用时间较短的拮抗剂能够产生与快速抗快感缺失一致的效果。
