Subanesthetic propofol alleviates chronic stress-induced anxiety by enhancing VTADA neurons' activity

Anxiety, a common mental disorder, imposes significant clinical and economic burdens. Previous studies indicate that propofol has anxiolytic effects at anesthetic doses. However, the risks associated with general anesthesia limit its application in anxiety treatment. The feasibility of using subanesthetic doses of propofol to alleviate chronic stress-induced anxiety and the underlying neural mechanisms remain unknown. Here, we found that subanesthetic dose (20 mg/kg and 40 mg/kg) of propofol alleviated anxiety-like behaviors induced by chronic unpredictable mild stress (CUMS) in mice, and the anxiolytic effects were maintained for at least 6 h. In vivo calcium imaging study showed that propofol significantly enhanced Ca²⁺ signals in ventral tegmental area dopaminergic (VTA^DA) neurons. Whole-cell patch-clamp recordings confirmed that subanesthetic propofol increased the excitability of VTA^DA neurons while inhibiting VTA GABAergic (VTA^GABA) neurons. Propofol suppressed spontaneous inhibitory postsynaptic currents (sIPSCs) in VTA^DA neurons, accompanied by a decline in the ability of GABAergic neurons to transmit inhibitory signals. These findings suggests that a subanesthetic dose of propofol enhances the excitability of VTA^DA neurons through disinhibition, demonstrating its potential for the treatment of CUMS-associated anxiety-like behaviors.