Depression is associated with alterations in brain glucose metabolism and impairments in processes associated with the astrocyte-neuron lactate shuttle (ANLS). Within this framework, lactate emerges as a promising therapeutic avenue, demonstrating antidepressant efficacy in diverse mouse models of depression, including the forced swim test and chronic corticosterone treatment. Our study explores the impact of stress and elevated corticosterone on astrocyte-neuron metabolic coupling, examining restoration potential of lactate treatment in controlled in vitro and complex in vivo settings. Prolonged corticosterone exposure in mouse neocortical astrocytic cultures revealed significant ANLS impairment, including upregulated thioredoxin-interacting protein (TXNIP), a marker associated with glucose and lipid metabolism disruptions, diminished glucose uptake, downregulated glucose transporter-1 (GLUT-1) expression at the cell membrane, alterations in lactate monocarboxylate transporter-4 (MCT-4) at both mRNA and protein levels, and reduced lactate release from astrocytes. In vivo experiments with mouse models exposed to chronic unpredictable stress (CUS) or corticosterone-induced depression, demonstrated heightened anxiety and social avoidance, observed through various behavioral tests. Lactate treatment emerged as a potent intervention, promoting resilience to stress and rescuing social avoidance behaviors. Ongoing investigations explore nuanced changes in gene expression related to energy metabolism in the hippocampus and prefrontal cortex in the two depression models, with and without lactate treatment. The observed alterations in astrocytes strongly suggest that targeting the ANLS pathway is crucial in understanding and addressing the complex landscape of stress and mood disorders.