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

• Published in: Neuropharmacology 2024-12, Vol.265, p.110264, Article 110264
• Main Authors: Jiang, Shaolei, Ge, Dengyun, Song, Bo, Deng, Xiaofei, Liu, Zhongdong, He, Jian, Sun, Jing, Zhu, Zhi, Meng, Zhiqiang, Zhu, Yingjie
• Format: Article
• Language: English
• Subjects: Anxiety; Disinhibition; Dopaminergic neurons; Propofol; Subanesthetic dose
• ISSN: 0028-3908; 1873-7064; 1873-7064
• DOI: 10.1016/j.neuropharm.2024.110264

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 hours. In vivo calcium imaging study showed that propofol significantly enhanced Ca2+ signals in ventral tegmental area dopaminergic (VTADA) neurons. Whole-cell patch-clamp recordings confirmed that subanesthetic propofol increased the excitability of VTADA neurons while inhibiting VTA GABAergic (VTAGABA) neurons. Propofol suppressed spontaneous inhibitory postsynaptic currents (sIPSCs) in VTADA 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 VTADA neurons through disinhibition, demonstrating its potential for the treatment of CUMS-associated anxiety-like behaviors. •Subanesthetic doses of propofol alleviated anxiety-like behaviors in mice subjected to chronic stress through non-sedative effects.•Subanesthetic doses of propofol activated VTADA neurons in vivo in mice.•Subanesthetic doses of propofol attenuated the inhibitory inputs to VTADA neurons.•Subanesthetic doses of propofol inhibited VTAGABA neurons and enhanced the excitability of VTADA neurons through disinhibition.