纳曲酮剂量选择性调节大鼠目标定向行为和下丘脑蛋白质组。

IF 3.6 3区 医学 Q2 PHARMACOLOGY & PHARMACY
Natalia Malikowska-Racia, Przemysław Mielczarek, Piotr Popik
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引用次数: 0

摘要

背景:纳曲酮是一种阿片受体拮抗剂,可以根据剂量调节相反方向的奖励加工。纳曲酮是否也会对动机产生类似的影响尚不清楚。本研究探讨了纳曲酮对动机行为测量的影响,并寻找潜在的机制,包括依赖于propropiomanocortin (POMC)的内源性阿片途径。方法:雄性sd大鼠给予纳曲酮(0.01、0.1、1 mg/kg, ig)治疗2周。在此期间,每天对大鼠进行递进比例强化(PR)测试和基于努力的选择(EBC)测试,以解决动机活力、方向性和基于努力的决策。测试后,收集下丘脑进行蛋白质组学分析,使用数据独立采集(DIA)。结果:低剂量纳曲酮(0.01 mg/kg;LDN在不改变EBC决策的情况下短暂地增加了PR反应活力。当剂量为0.1 mg/kg时,而不是高剂量为1 mg/kg时,它会损害基于努力的决策和目标导向。蛋白质组学分析将LDN与生长激素(GH)通路下调和G蛋白偶联受体(GPCR)信号通路改变相关。纳曲酮的中剂量主要影响与神经生长有关的蛋白质,而1mg /kg剂量影响与基因调控有关的蛋白质。结论:不同剂量纳曲酮对大鼠的动机测量和下丘脑蛋白质组有不同的影响。纳曲酮0.1 mg/kg会损害动机方向性和基于努力的决策,这与阿片类药物阻断导致的奖励信号减少相对应。相比之下,LDN增强活力,但仅在治疗早期。纳曲酮对pomc依赖性内源性阿片通路没有影响,表明其动机作用背后有不同的机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Naltrexone dose-selectively modulates goal-directed behavior and the hypothalamic proteome in rats.

Background: Naltrexone is an opioid receptor antagonist that can modulate reward processing in opposite directions depending on the dose. Whether naltrexone similarly affects motivation remains unexplored. This study investigates the effects of naltrexone on behavioral measures of motivation and search for potential mechanisms, including the endogenous opioid pathway dependent on proopiomelanocortin (POMC).

Methods: Male Sprague Dawley rats received naltrexone (0.01, 0.1, or 1 mg/kg, ip) for two weeks. During this period, rats were tested daily using a progressive ratio schedule of reinforcement (PR) test and effort-based choice (EBC) that address motivational vigor, directedness, and effort-based decision-making. After tests, the hypothalami were collected for proteomic analysis using data-independent acquisition (DIA).

Results: Low-dose naltrexone (0.01 mg/kg; LDN) transiently increased PR response vigor without altering decision-making in EBC. At 0.1 mg/kg, but not at the high dose of 1 mg/kg, it impaired effort-based decision-making and goal-directedness. Proteomic analysis correlated LDN with the downregulation of a growth hormone (GH) pathway and altered G protein-coupled receptors (GPCR) signaling. Naltrexone's intermediate dose predominantly impacted proteins involved in neural growth, while the 1 mg/kg dose affected proteins related to gene regulation.

Conclusions: Different doses of naltrexone had varying effects on motivational measures and the rat's hypothalamic proteome. Naltrexone 0.1 mg/kg impaired motivational directedness and effort-based decision-making that corresponds to reduced reward signaling due to opioid blockade. In contrast, LDN enhanced vigor, but only early in the treatment. Naltrexone had no effects on the POMC-dependent endogenous opioid pathway, suggesting that a different mechanism underlies its motivational effects.

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来源期刊
Pharmacological Reports
Pharmacological Reports 医学-药学
CiteScore
8.40
自引率
0.00%
发文量
91
审稿时长
6 months
期刊介绍: Pharmacological Reports publishes articles concerning all aspects of pharmacology, dealing with the action of drugs at a cellular and molecular level, and papers on the relationship between molecular structure and biological activity as well as reports on compounds with well-defined chemical structures. Pharmacological Reports is an open forum to disseminate recent developments in: pharmacology, behavioural brain research, evidence-based complementary biochemical pharmacology, medicinal chemistry and biochemistry, drug discovery, neuro-psychopharmacology and biological psychiatry, neuroscience and neuropharmacology, cellular and molecular neuroscience, molecular biology, cell biology, toxicology. Studies of plant extracts are not suitable for Pharmacological Reports.
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