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<p>Astrocytic Ca<sup>2+</sup> activity is crucial for maintaining normal brain function. However, the pathophysiological role of astrocytes in the context of addictive drugs remains largely unknown. Taking advantage of two-photon Ca<sup>2+</sup> imaging in awake mice, we show that a physiologically relevant level of cocaine induces synchronized and hyperactive Ca<sup>2+</sup> signals in frontal cortical astrocytes. Mechanistically, this process occurs primarily through the volume release of norepinephrine from locus coeruleus innervation, followed by the activation of Gq-coupled α1 adrenergic receptors in the prefrontal cortex and the subsequent IP<sub>3</sub>R2-dependent store Ca<sup>2+</sup> release, thus causing hyperactive Ca<sup>2+</sup> fluctuations in astrocytes. Importantly, interrupting the hyperactive astrocytic Ca<sup>2+</sup> signals either by blocking store Ca<sup>2+</sup> release or by conditionally knocking out the astrocytic α1AR rescued FrA neuronal activity and aggravated cocaine-induced locomotor sensitization. These findings revealed that, in addition to neurons, astrocytes can be super-activated by cocaine through the crosstalk between norepinephrine nerves and glia, providing a new perspective for the understanding and clinical treatment of cocaine addiction.</p>

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Cocaine facilitates Ca2+ fluctuations in prefrontal cortex astrocytes via norepinephrine transmission in awake mice

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月8日

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  • Suhua Sun,
  • Xi Wu,
  • Min Gao,
  • Jie Li,
  • Liyuan Sun,
  • Lun Wang,
  • Guoqing Chen,
  • Qinglong Wang,
  • Yingfei Xiong,
  • Yang Lu,
  • Bo Zhou,
  • Bing Liu,
  • Quanfeng Zhang,
  • Changhe Wang,
  • Feipeng Zhu,
  • Zhuan Zhou

摘要

Astrocytic Ca2+ activity is crucial for maintaining normal brain function. However, the pathophysiological role of astrocytes in the context of addictive drugs remains largely unknown. Taking advantage of two-photon Ca2+ imaging in awake mice, we show that a physiologically relevant level of cocaine induces synchronized and hyperactive Ca2+ signals in frontal cortical astrocytes. Mechanistically, this process occurs primarily through the volume release of norepinephrine from locus coeruleus innervation, followed by the activation of Gq-coupled α1 adrenergic receptors in the prefrontal cortex and the subsequent IP3R2-dependent store Ca2+ release, thus causing hyperactive Ca2+ fluctuations in astrocytes. Importantly, interrupting the hyperactive astrocytic Ca2+ signals either by blocking store Ca2+ release or by conditionally knocking out the astrocytic α1AR rescued FrA neuronal activity and aggravated cocaine-induced locomotor sensitization. These findings revealed that, in addition to neurons, astrocytes can be super-activated by cocaine through the crosstalk between norepinephrine nerves and glia, providing a new perspective for the understanding and clinical treatment of cocaine addiction.