Fishberg Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Pharmacology, Vanderbilt Center for Addiction Research, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA.
Nat Commun. 2018 Jan 16;9(1):9. doi: 10.1038/s41467-017-01881-x.
Cocaine addiction is characterized by dysfunction in reward-related brain circuits, leading to maladaptive motivation to seek and take the drug. There are currently no clinically available pharmacotherapies to treat cocaine addiction. Through a broad screen of innate immune mediators, we identify granulocyte-colony stimulating factor (G-CSF) as a potent mediator of cocaine-induced adaptations. Here we report that G-CSF potentiates cocaine-induced increases in neural activity in the nucleus accumbens (NAc) and prefrontal cortex. In addition, G-CSF injections potentiate cocaine place preference and enhance motivation to self-administer cocaine, while not affecting responses to natural rewards. Infusion of G-CSF neutralizing antibody into NAc blocks the ability of G-CSF to modulate cocaine's behavioral effects, providing a direct link between central G-CSF action in NAc and cocaine reward. These results demonstrate that manipulating G-CSF is sufficient to alter the motivation for cocaine, but not natural rewards, providing a pharmacotherapeutic avenue to manipulate addictive behaviors without abuse potential.
可卡因成瘾的特征是奖励相关脑回路功能障碍，导致寻求和使用药物的适应不良动机。目前尚无临床可用的药物治疗可卡因成瘾。通过对先天免疫介质的广泛筛选，我们发现粒细胞集落刺激因子（G-CSF）是可卡因诱导适应的有效介质。在这里，我们报告 G-CSF 增强了可卡因诱导的伏隔核（NAc）和前额叶皮层中神经活动的增加。此外，G-CSF 注射增强了可卡因的位置偏好，并增强了对可卡因的自我给药动机，而不影响对自然奖励的反应。将 G-CSF 中和抗体注入 NAc 阻断了 G-CSF 调节可卡因行为效应的能力，为 NAc 中中枢 G-CSF 作用与可卡因奖励之间提供了直接联系。这些结果表明，操纵 G-CSF 足以改变对可卡因的动机，但不会改变对自然奖励的动机，为操纵成瘾行为提供了一种药理学途径，而不会产生滥用潜力。
