L-Lactate as an Overlooked Neuromodulator and Antidepressant Factor: The Role of the Astrocyte–Neuron Lactate Shuttle (ANLS) in Exercise-Induced Synaptic Plasticity in Athletes
DOI:
https://doi.org/10.12775/QS.2026.60.72924Keywords
L-lactate, astrocyte–neuron lactate shuttle, HCA1/GPR81, exercise, BDNF, depression, neuroplasticityAbstract
Background: Throughout most of the twentieth century, L-lactate was regarded largely as a metabolic waste product held responsible for muscular fatigue and acidosis. A growing body of evidence now reframes it as a signalling molecule, an exercise-released metabokine and a preferred oxidative substrate for the brain.
Aim: This narrative review considers whether high-intensity, glycolytic exercise, by generating a large peripheral lactate load, may exert central antidepressant and neuroprotective effects through direct neuromodulation, with a focus on the astrocyte–neuron lactate shuttle (ANLS) and the lactate receptor HCA1/GPR81.
Material and methods: PubMed, Scopus and Web of Science were searched for preclinical and translational studies, with priority given to work published between 2018 and 2026. Search terms included L-lactate, ANLS, HCA1/GPR81, exercise-induced neuroplasticity and depression.
Results: The reviewed literature suggests that peripheral lactate crosses the blood–brain barrier via monocarboxylate transporters and may support neuronal energetics through the ANLS. Beyond its fuelling role, lactate appears to engage HCA1 and downstream ERK1/2 and Akt signalling, and is associated with increased BDNF and VEGF expression, facilitated long-term potentiation and antidepressant-like behaviour in animal models.
Conclusions: Exercise-derived lactate may act as a non-pharmacological stimulus of neuroplasticity, combining energetic support with receptor-mediated signalling. Glycolytic protocols such as HIIT might complement pharmacotherapy in affective disorders, although human in vivo evidence remains limited.
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