Department of Pharmacology and Toxicology.
Exp Clin Psychopharmacol. 2020 Feb;28(1):44-54. doi: 10.1037/pha0000287.
Repeated drug administration results in sensitization, tolerance, or no change in subsequent drug-induced alterations of motivated behaviors, such as intracranial self-stimulation (ICSS). For example, repeated mu-opioid agonist administration results in increased expression of mu agonist-induced facilitation of ICSS. Acute kappa-opioid receptor (KOR) agonist administration depresses ICSS; however, effects of repeated KOR agonist administration on ICSS are unknown. This study determined effects of daily KOR agonist U-50488 administration and subsequent termination on ICSS in male and female rats. Female (n = 5) and male (n = 6) Sprague-Dawley rats were trained to respond for electrical brain stimulation under a frequency-rate ICSS procedure. Sequential U-50488 dose-effect functions (1-5.6 mg/kg, intraperitoneal) were determined every 7 days over a 21-day experimental period during which saline and increasing U-50488 doses (3.2-5.6 mg/kg, intraperitoneal) were administered on intervening days. Sequential U-50488 dose-effect functions were also determined 7 and 28 days after termination of repeated U-50488 administration. U-50488 dose-dependently depressed ICSS in both female and male rats. There were no sex differences on either initial or repeated U-50488 treatment effects. Repeated 5.6 mg/kg U-50488 administration produced selective tolerance to the rate-decreasing, but not threshold-altering, effects of 5.6 mg/kg U-50488 during sequential dose-effect test sessions. Neither repeated U-50488 administration nor termination of U-50488 significantly altered baseline ICSS. Overall, these results suggest neither tolerance nor sensitization develops to the depressive-like effects of repeated KOR agonist activation. Selective tolerance to the rate-decreasing effects of repeated KOR agonist administration may have implications for elucidating the neurobiological processes involved in long-term abused drug self-administration. (PsycINFO Database Record (c) 2020 APA, all rights reserved).
重复给予药物会导致敏化、耐受或对随后的药物诱导的动机行为改变（如颅内自我刺激[ICSS]）没有变化。例如，重复给予μ阿片激动剂会导致μ激动剂诱导的 ICSS 易化表达增加。急性κ阿片受体（KOR）激动剂给药会抑制 ICSS；然而，重复 KOR 激动剂给药对 ICSS 的影响尚不清楚。本研究旨在确定每日 KOR 激动剂 U-50488 给药及其随后终止对雄性和雌性大鼠 ICSS 的影响。雌性（n=5）和雄性（n=6）Sprague-Dawley 大鼠接受训练，在频率-率 ICSS 程序下对电脑刺激作出反应。在 21 天的实验期间，每隔 7 天确定一次 U-50488 的剂量-效应关系（1-5.6mg/kg，腹腔内），在此期间，在间隔日给予盐水和递增的 U-50488 剂量（3.2-5.6mg/kg，腹腔内）。在重复 U-50488 给药终止后 7 天和 28 天，也确定了 U-50488 的剂量-效应关系。U-50488 剂量依赖性地抑制了雌性和雄性大鼠的 ICSS。在初始或重复 U-50488 治疗效果上，均没有性别差异。重复给予 5.6mg/kg U-50488 导致对 5.6mg/kg U-50488 的序贯剂量-效应测试过程中的速率降低但不改变阈值的作用产生选择性耐受。重复给予 U-50488 或终止 U-50488 均未显著改变基线 ICSS。总体而言，这些结果表明，重复 KOR 激动剂激活不会产生对抑郁样作用的耐受或敏化。对重复 KOR 激动剂给药的速率降低作用的选择性耐受可能对阐明涉及长期滥用药物自我给药的神经生物学过程具有重要意义。
