Dopamine triggers dose-dependent cAMP increases and delayed L-lactate production in cultured rat cortical astrocytes via a receptor- and cAMP-dependent mechanism that is largely mediated by β1-adrenoceptors despite limited D1–β1 nanoscale colocalization.

By revealing a dopaminergic pathway that drives astrocytic glycolysis via β1-adrenergic signalling, the work highlights a novel metabolic mechanism potentially relevant to Parkinson's disease (where noradrenergic loss may impair astrocyte support) and points to astrocytic β1 signalling and lactate…

Astrocytes maintain homeostasis of the central nervous system and supply neurons with metabolic substrates essential for synaptic plasticity and learning. Upon stimulation by noradrenaline (NA), released primarily by locus coeruleus (LC) neurons and acting via volume transmission, astrocytes enhance aerobic glycolysis and produce L-lactate, a process critical for energy support yet dependent on β-adrenoceptor-mediated cyclic adenosine monophosphate (cAMP) signalling. In neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, early degeneration of the LC diminishes noradrenergic tone, potentially impairing astrocyte metabolic function. Dopamine (DA), acting via volume transmission like NA, released from the substantia nigra pars compacta, may also modulate astrocytic metabolism; however, this has not yet been investigated at the cellular level. Using fluorescence resonance energy transfer-based nanosensor imaging in cultured rat cortical astrocytes, we investigated DA-induced cAMP signalling and L-lactate production. DA elicited a dose-dependent increase in cytosolic cAMP (EC50 = 1.25 μM) and stimulated delayed L-lactate production in a receptor-mediated, cAMP-dependent manner. Knockdown of β1-adrenoceptors (Adrb1) significantly reduced these effects. At the same time, super-resolution stimulated emission depletion microscopy revealed minimal nanoscale colocalization between D1 and β1 receptors, suggesting that at least at higher DA concentrations, β1-adrenoceptors contribute to DA-mediated metabolic regulation. These findings identify a novel dopaminergic pathway for astrocytic glycolytic activation, informing future studies examining dysregulation of monoaminergic-astrocytic signalling in neurodegenerative diseases.