慢性鲁拉西酮治疗对慢性不可避免应激大鼠情绪功能障碍的恢复作用:内侧前额叶皮层-伏隔核网络的作用。

IF 4.6 2区 医学 Q1 NEUROSCIENCES
Eleonora Corridori, Sara Salviati, Veronica Begni, Alessia Marchesin, Carla Gambarana, Marco Andrea Riva, Simona Scheggi
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引用次数: 0

摘要

快感缺乏是一种普遍存在于抑郁症和精神病中的跨诊断症状,由于其与动机受损相关,因此对药物干预提出了重大挑战。了解精神药物如何调节这种病理领域并阐明这种作用背后的分子机制是精神病学研究的关键努力。在这项研究中,我们旨在研究鲁拉西酮在快感缺乏大鼠(Sprague Dawley雄性)模型中的促进动机特性,并揭示鲁拉西酮与大脑奖励处理关键区域之间的相互作用。暴露于不可预测的慢性应激(UCS)导致动机显著降低,这种缺陷可以通过3 mg/kg的鲁拉西酮治疗恢复,但10 mg/kg的鲁拉西酮治疗不能恢复。有趣的是,两种剂量的鲁拉西酮都逆转了应激引起的对负刺激的反应性下降。在分子水平上,应激动物表现出神经可塑性标志物的表达降低,鲁拉西酮给药后神经可塑性标志物的表达增加。此外,UCS暴露损害了内侧前额叶皮层(mPFC)和伏隔核(NAc)对享乐刺激的反应,鲁拉西酮治疗改善了这一效应。此外,鲁拉西酮恢复了暴露于享乐刺激的UCS大鼠mPFC和NAc中受损的DARPP-32的磷酸化,DARPP-32是多巴胺信号的关键调节因子。这些发现强调了鲁拉西酮在改善各种精神病理领域的潜力,如动机受损和情绪反应性受损,这是导致精神障碍相关残疾的核心因素。这些作用突出了鲁拉西酮在解决与快感缺乏和相关情绪障碍相关的复杂行为和神经化学改变方面的治疗潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Restorative properties of chronic lurasidone treatment on emotional dysfunction in rats exposed to chronic unavoidable stress: A role for medial prefrontal cortex - nucleus accumbens network.

Anhedonia, a transdiagnostic symptom prevalent in depressive and psychotic disorders, poses a significant challenge for pharmacological intervention due to its association with impaired motivation. Understanding how psychotropic drugs can modulate this pathological domain and elucidating the molecular mechanisms underlying such effects are crucial endeavors in psychiatric research. In this study, we aimed to investigate the pro-motivational properties of lurasidone in a rat (Sprague Dawley males) model of anhedonia and to unravel the interplay between lurasidone and the brain regions critical for reward processing. Exposure to unpredictable chronic stress (UCS) led to a marked reduction in motivation, a deficit that was restored by lurasidone treatment at 3 mg/kg, but not at 10 mg/kg. Interestingly, the stress-induced decrease in reactivity to negative stimuli was reversed by both doses of lurasidone. At the molecular level, stressed animals exhibited reduced expression of neuroplastic markers, that was increased following lurasidone administration. Furthermore, UCS exposure impaired the activation of the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) in response to hedonic stimuli, an effect amended by lurasidone treatment. Additionally, lurasidone restored the impaired phosphorylation of DARPP-32, a key regulator of dopamine signaling, in mPFC and NAc of UCS rats exposed to a hedonic stimulus. These findings underscore the potential of lurasidone in improving various psychopathological domains, like impaired motivation and emotional reactivity, core elements contributing to the disability associated with mental disorders. These effects highlight the therapeutic potential of lurasidone in addressing the intricate behavioral and neurochemical alterations associated with anhedonia and related mood disorders.

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来源期刊
Neuropharmacology
Neuropharmacology 医学-神经科学
CiteScore
10.00
自引率
4.30%
发文量
288
审稿时长
45 days
期刊介绍: Neuropharmacology publishes high quality, original research and review articles within the discipline of neuroscience, especially articles with a neuropharmacological component. However, papers within any area of neuroscience will be considered. The journal does not usually accept clinical research, although preclinical neuropharmacological studies in humans may be considered. The journal only considers submissions in which the chemical structures and compositions of experimental agents are readily available in the literature or disclosed by the authors in the submitted manuscript. Only in exceptional circumstances will natural products be considered, and then only if the preparation is well defined by scientific means. Neuropharmacology publishes articles of any length (original research and reviews).
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