Lac-Phe elicits anxiolytic-like effects associated with monoaminergic signaling in mice

Anxiety disorders are a growing public health concern in modern societies burdened with chronic stress and diminishing work motivation, imposing a substantial disease burden across all age groups. Lactoyl-phenylalanine (Lac-Phe), an endogenous metabolite produced during exercise and found in fermented foods, has recently gained attention for its metabolic regulatory functions, yet its potential anxiolytic effects remain unclear. In this study, we report that Lac-Phe administration elicits anxiolytic-like behavior in mice. Oral administration of Lac-Phe significantly increased open-arm exploration in the elevated plus maze (EPM), indicating anxiolytic-like activity. Similar behavioral effects were observed following intraperitoneal and intracerebroventricular administration in the EPM and the novelty-suppressed feeding test. Pharmacological blockade experiments indicated that dopamine D1 and serotonin 5-HT1A receptor signaling contribute to Lac-Phe-induced anxiolytic-like effects. Consistently, intraperitoneal administration of Lac-Phe increased dopamine tissue content in the hypothalamus and striatum and reduced hippocampal IL-1β and IL-6 mRNA expression. Together, these results suggest that Lac-Phe exerts anxiolytic-like effects, potentially involving monoaminergic signaling in the brain, and support further investigation of Lac-Phe as a food-derived metabolite in the context of stress- and anxiety-related outcomes.