Dexmedetomidine elicits a prolonged anxiolytic effect by inhibiting adrenergic neurons in the locus coeruleus in mice.

Anxiety disorders impose a substantial global burden, yet current pharmacotherapies often lack sustained efficacy and carry risks of dependence. Dexmedetomidine (Dex), a selective α2 adrenergic receptor agonist primarily used for sedation, demonstrates promising anxiolytic properties, but its long-term neural mechanisms remain unclear. Here, using a chronic restraint stress (CRS) mouse model, we reveal that tyrosine hydroxylase (TH)-positive neurons in the locus coeruleus (LC) are persistently hyperactivated during chronic anxiety states, driving elevated norepinephrine (NE) release in the medial prefrontal cortex (mPFC). A single low dose of Dex (50 µg/kg) produced anxiolytic effects lasting ≥3 days, evidenced by improved performance in open-field, light-dark box, and elevated plus maze tests. In vivo fiber photometry and chemogenetic approaches demonstrated that Dex suppresses LC-NE neuronal hyperactivity and normalizes mPFC NE levels. Crucially, neuron-specific knockdown of α2 receptors in the LC abolished Dex's anxiolytic effects, confirming their essential role. These findings elucidate a neural mechanism wherein Dex sustains anxiety relief via α2 receptor-mediated inhibition of the LC-NE-mPFC circuit, highlighting its potential as a novel long-acting therapeutic strategy for anxiety disorders.