Dopamine activates astrocytes in prefrontal cortex via α1-adrenergic receptors

The prefrontal cortex (PFC) is a hub for cognitive control, and dopamine profoundly influences its functions. In other brain regions, astrocytes sense diverse neurotransmitters and neuromodulators and, in turn, orchestrate regulation of neuroactive substances. However, basic physiology of PFC astrocytes, including which neuromodulatory signals they respond to and how they contribute to PFC function, is unclear. Here, we characterize divergent signaling signatures in mouse astrocytes of the PFC and primary sensory cortex, which show differential responsiveness to locomotion. We find that PFC astrocytes express receptors for dopamine but are unresponsive through the Gs/Gi-cAMP pathway. Instead, fast calcium signals in PFC astrocytes are time locked to dopamine release and are mediated by α1-adrenergic receptors both ex vivo and in vivo. Further, we describe dopamine-triggered regulation of extracellular ATP at PFC astrocyte territories. Thus, we identify astrocytes as active players in dopaminergic signaling in the PFC, contributing to PFC function though neuromodulator receptor crosstalk. [Display omitted] •Prefrontal and visual cortex astrocytes display different Ca2+ signatures in vivo•Dopamine recruits PFC astrocyte Ca2+—but not cAMP—within seconds•Dopamine induces ATP release at PFC astrocyte territories•α1-Adrenergic receptors are involved in the response of PFC astrocytes to dopamine Pittolo et al. demonstrate that the neuromodulator dopamine targets astrocytes, a type of brain cell, via receptors specific to another neuromodulator—norepinephrine. This study provides groundwork on how dopamine affects non-neuronal brain cells and suggests that crosstalk between neuromodulatory pathways occurs in vivo, with possible clinical implications.