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

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.