Propofol Regulates Arousal by Enhancing Inhibitory Synaptic Transmission of Noradrenergic Neurons in the Locus Coeruleus of Adult Male Mice

Locus coeruleus-noradrenergic (LC-NA) neurons have been implicated to be involved in the effects of general anesthetics. However, the contribution of LC-NA neurons during propofol anesthesia remains unknown. We aimed to elucidate the mechanism of action of propofol in the LC-NA neurons. LC-NA neurons from adult male mice were identified by targeted expression of fluorescent proteins. Whole-cell patch-clamp recordings were performed to analyze the effects of propofol on action potentials and synaptic transmission. The results showed that propofol concentration-dependently decreased action potential frequencies. Propofol also increased the frequency of spontaneous inhibitory postsynaptic currents and prolonged their decay time. The presence of GABA _A receptor antagonist bicuculline prevented these effects. Inhibitory tonic currents were evoked only at high concentration of propofol. In behavioral experiments, bicuculline injection into the LC significantly shortened the return of righting reflex time following propofol anesthesia. We demonstrated that clinical doses of propofol induce a facilitatory effect on phasic GABAergic neural currents and direct action on GABAA receptors in LC-NA neurons. The enhancement of inhibitory effects mediated by GABA _A receptors in LC-NA neurons is considered one of the mechanisms underlying the anesthetic effects of propofol.