Dopamine D4 receptors in the lateral habenula regulate anxiety-related behaviors in a rat model of Parkinson's disease

IF 3.5 3区医学 Q2 NEUROSCIENCES

Brain Research Bulletin Pub Date : 2024-11-08 DOI:10.1016/j.brainresbull.2024.111122

Chengxue Du , Jiachen Wang , Huihui Tan , Nannan Han , Xiaobo Li , Baihua Sun , Gejuan Zhang , Mingze Chang

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Abstract

Although the output of the lateral habenula (LHb) controls the activity of midbrain dopamine (DA) and 5-hydroxytryptamine (5-HT) containing systems, which are implicated in the pathophysiology of anxiety, it is not clear how activation and blockade of LHb D₄ receptors affects anxiety-like behaviors, particularly in Parkinson’s disease related anxiety. In this study, unilateral 6-hydroxydopamine lesions of the substantia nigra pars compacta (SNc) in rats induced anxiety-like behaviors, which attribute to hyperactivity of LHb neurons and decrease in the level of DA in the medial prefrontal cortex (mPFC), amygdala and ventral hippocampus (vHip) compared to sham-operated rats. Intra-LHb injection of D₄ receptor agonist A412997 induced or increased the expression of anxiety-like behaviors, while injection of D₄ receptor antagonist L741742 showed anxiolytic effects in sham-operated and the SNc-lesioned rats. However, the doses producing behavioral effects in the lesioned rats were higher than those of sham-operated rats. Intra-LHb injection of A412997 increased firing rate of LHb neurons, and decreased levels of DA and 5-HT in the mPFC, amygdala and vHip; conversely, L741742 decreased firing rate of LHb neurons, and increased levels of DA and 5-HT in two groups of rats. Compared to sham-operated rats, the duration of A412997 and L741742 action on the firing rate of neurons was markedly shortened in the lesioned rats. Collectively, these findings suggest that D₄ receptors in the LHb are involved in the regulation of anxiety-like behaviors, and degeneration of the nigrostriatal pathway down-regulates function and/or expression of these receptors.

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外侧哈文脑中的多巴胺 D4 受体调节帕金森病大鼠模型中的焦虑相关行为

虽然外侧哈文脑（LHb）的输出控制着中脑多巴胺（DA）和含有5-羟色胺（5-HT）的系统的活动，而这些系统与焦虑的病理生理学有关，但目前还不清楚激活和阻断LHb D4受体如何影响焦虑样行为，尤其是与帕金森病有关的焦虑。与假手术大鼠相比，单侧黑质(SNc)6-羟基多巴胺损伤会诱发焦虑样行为，这归因于LHb神经元的过度活跃以及内侧前额叶皮层(mPFC)、杏仁核和腹侧海马(vHip)中DA水平的下降。在假手术大鼠和SNc缺失大鼠体内注射D4受体激动剂A412997会诱导或增加焦虑样行为的表达，而注射D4受体拮抗剂L741742则会产生抗焦虑作用。然而，对病变大鼠产生行为效应的剂量高于假手术大鼠。LHb内注射A412997可提高LHb神经元的发射率，降低mPFC、杏仁核和vHip中DA和5-HT的水平；相反，L741742可降低LHb神经元的发射率，提高两组大鼠DA和5-HT的水平。与假手术大鼠相比，A412997 和 L741742 对病变大鼠神经元发射率的作用持续时间明显缩短。总之，这些研究结果表明，LHb中的D4受体参与了焦虑样行为的调节，而黑质通路的退化会下调这些受体的功能和/或表达。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Brain Research Bulletin 医学-神经科学

CiteScore

6.90

自引率

2.60%

发文量

253

审稿时长

67 days

期刊介绍： The Brain Research Bulletin (BRB) aims to publish novel work that advances our knowledge of molecular and cellular mechanisms that underlie neural network properties associated with behavior, cognition and other brain functions during neurodevelopment and in the adult. Although clinical research is out of the Journal''s scope, the BRB also aims to publish translation research that provides insight into biological mechanisms and processes associated with neurodegeneration mechanisms, neurological diseases and neuropsychiatric disorders. The Journal is especially interested in research using novel methodologies, such as optogenetics, multielectrode array recordings and life imaging in wild-type and genetically-modified animal models, with the goal to advance our understanding of how neurons, glia and networks function in vivo.