Granulocyte-Colony Stimulating Factor Reduces Cocaine-Seeking and Downregulates Glutamatergic Synaptic Proteins in Medial Prefrontal Cortex
Granulocyte-Colony Stimulating Factor Reduces Cocaine-Seeking and Downregulates Glutamatergic Synaptic Proteins in Medial Prefrontal Cortex
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DOI：
10.1523/jneurosci.1452-20.2020
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发表时间：
2021-02-17
影响因子：
5.3
通讯作者：
Kiraly, Drew D.
中科院分区：
文献类型：
--
作者：
Hofford, Rebecca S.;Euston, Tanner J.;Kiraly, Drew D.
精神兴奋剂使用障碍是一个重大的公共卫生问题，尽管问题范围很广，但目前尚无美国食品和药物管理局 (FDA) 批准的治疗方法。开发一种可以帮助患者实现并维持禁欲的治疗方法将具有巨大的效用。我们小组之前的工作已经确定粒细胞集落刺激因子（G-CSF）是一种神经活性细胞因子，可以改变对可卡因的行为反应，增加突触多巴胺的释放，并增强认知灵活性。在这里，我们研究了 G-CSF 在影响可卡因寻求的消失和恢复中的作用，并对其在多个边缘亚结构中的蛋白质组效应进行了详细表征。雄性Sprague Dawley大鼠在(1)可卡因自我施用灭绝或(2)戒断期间注射PBS或G-CSF，并测量药物寻求行为。通过数据独立采集（DIA）质谱分析对伏隔核（NAc）和内侧前额叶皮层（mPFC）蛋白质组景观的变化进行定量评估。在戒断期间给予G-CSF会加速戒断速度，而在戒断期间给予G-CSF会减弱线索诱导的可卡因寻求。对整体蛋白表达的分析表明，G-CSF 主要调节 mPFC 中的蛋白，这些蛋白对于谷氨酸信号传导和突触维持至关重要。总而言之，这些发现支持 G-CSF 作为可行的转化研究目标，具有减少药物渴望或寻求行为的潜力。重要的是，重组 G-CSF 作为 FDA 批准的药物存在，可促进快速临床转化。此外，利用尖端的多区域发现蛋白质组学分析，这些研究确定了 G-CSF 对行为可塑性影响的新机制。
Psychostimulant use disorder is a major public health issue, and despite the scope of the problem there are currently no Food and Drug Administration (FDA)-approved treatments. There would be tremendous utility in development of a treatment that could help patients both achieve and maintain abstinence. Previous work from our group has identified granulocyte-colony stimulating factor (G-CSF) as a neuroactive cytokine that alters behavioral response to cocaine, increases synaptic dopamine release, and enhances cognitive flexibility. Here, we investigate the role of G-CSF in affecting extinction and reinstatement of cocaine-seeking and perform detailed characterization of its proteomic effects in multiple limbic substructures. Male Sprague Dawley rats were injected with PBS or G-CSF during (1) extinction or (2) abstinence from cocaine self-administration, and drug seeking behavior was measured. Quantitative assessment of changes in the proteomic landscape in the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) were performed via data-independent acquisition (DIA) mass spectrometry analysis. Administration of G-CSF during extinction accelerated the rate of extinction, and administration during abstinence attenuated cue-induced cocaine-seeking. Analysis of global protein expression demonstrated that G-CSF regulated proteins primarily in mPFC that are critical to glutamate signaling and synapse maintenance. Taken together, these findings support G-CSF as a viable translational research target with the potential to reduce drug craving or seeking behaviors. Importantly, recombinant G-CSF exists as an FDA-approved medication which may facilitate rapid clinical translation. Additionally, using cutting-edge multiregion discovery proteomics analyses, these studies identify a novel mechanism underlying G-CSF effects on behavioral plasticity.