Dopamine-induced L-lactate production in cortical astrocytes cross-reacts with β1-adrenoceptor-mediated cAMP signalling

Sugiyama, Keita (author), Horvat, Anemari (author), Dolinar, Klemen (author), Pirkmajer, Sergej (author), Furlani, Borut (author), Jorgačevski, Jernej (author), Vardjan, Nina (author), Zorec, Robert (author)

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.

• Language: English
• Keywords: astrocytes, dopamine, volumen transmitter, cyclic AMP, L-lactate, energy metabolism
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: MF - Faculty of Medicine
• Publication status: Published
• Publication version: Version of Record
• Year: 2026
• Number of pages: 16 str.
• Numbering: Vol. 18, iss. 3
• PID: 20.500.12556/RUL-183556
• UDC: 616-092
• ISSN on article: 2152-5250
• DOI: 10.14336/AD.2025.1442
• COBISS.SI-ID: 275352323
• Publication date in RUL: 15.06.2026

Record is a part of a journal

• Title: Aging and disease
• Shortened title: Aging dis.
• Publisher: ISOAD
• ISSN: 2152-5250
• COBISS.SI-ID: 517906713

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

• Language: Slovenian
• Keywords: astrociti, dopamin, volumski transmiter, ciklični AMP, L-laktat, energijski metabolizem