The α(2) Adrenoceptor Agonist and Sedative/Anaesthetic Dexmedetomidine Excites Diverse Neuronal Types in the Ventrolateral Preoptic Area of Male Mice

The unique sedative activities with rapid arousal of dexmedetomidine (Dex) are not fully understood. Growing evidence suggests the involvement of the ventrolateral preoptic area (VLPO) in sleep–wake cycle. The major type in the VLPO is sleep-active neurons, inhibited by noradrenaline (NA(−) neurons). The other type of neurons is activated by NA (NA(+) neurons), which are wake-active. Previous research showed that Dex-induced sedation and sleep homeostasis likely share common mechanisms. To explore the underlying mechanisms of Dex in the VLPO, in vivo polysomnography recording and in vitro electrophysiological recording were used in our study. Bath application of Dex (2 μM) increased the firing rate of both VLPO NA(−) and NA(+) neurons. Compared to the control group, there was no difference in the firing rate of both VLPO NA(−) and NA(+) neurons after Dex (2 μM) and RS79948 (1 mM) administration, an α(2) receptor antagonist. No difference was detected regarding resting membrane potential (RMP) amplitude of both VLPO NA (−) and NA(+) neurons after application of Dex (2 μM). Moreover, Dex (2 μM) significantly reduced the frequency of miniature inhibitory postsynaptic currents (mIPSCs) in both VLPO NA(−) and NA(+) neurons. These electrophysiology results were consistent with behavioral sedation, with increased nonrapid eye movement sleep (NREM sleep) and increased expression of c-Fos in the VLPO during the dark phase after intraperitoneal injection with Dex (80 μg/kg). In conclusion, Dex activates NA(−) and NA(+) neurons in the VLPO via presynaptic α(2) receptors. This mechanism may explain the unique sedative properties with rapid arousal. SUMMARY STATEMENT: Dexmedetomidine is an important ICU sedative. The mechanism of dexmedetomidine is not fully understood. Activating NA(−) and NA(+) neurons in the VLPO by dexmedetomidine using polysomnography and electrophysiological recording, this may explain the unique sedative properties with rapid arousal.