Dexmedetomidine Activation Of Dopamine Neurons In The Ventral Tegmental Area Attenuates The Depth Of Sedation In Mice

Background: Dexmedetomidine is a highly selective α2 adrenergic receptor agonist with a sedative characteristic similar to natural sleep(easy to be awakened).Based on this,dexmedetomidine can provide "cooperative sedation" and is widely used in functional neurosurgery and ICU.However,the mechanism of dexmedetomidine sedation has not been studied thoroughly.In recent years,the ventral tegmental area(VTA)has proven to be highly related to sleep and awakening.About 65% of the neurons in the VTA are dopamine(DA)neurons.Direct electrical stimulation of VTA or optogenetic activation of VTA DA neurons or using of dopamine transporter(DAT)reuptake inhibitors can awaken mice from anesthesia.However,the relationship between the VTA DA system and dexmedetomidine sedation has not been studied.Whether the VTA DA system participates in the sedative characteristics of dexmedetomidine that is easily awakened remains to be studied.Methods: Stereotactic instrument and micro-injection pump were used to inject the virus to the specific brain areas.The effect of dexmedetomidine on VTA DA neurons was studied using a calcium indicator(GCa MP6m)in vivo.Using patch-clamp to study the effect and mechanism of dexmedetomidine on VTA DA neurons in vitro.The effects of dexmedetomidine on DA neurotransmitters in the projected brain regions(nucleus accumbens(NAc)and medial prefrontal cortex(m PFC))of VTA DA neurons were studied in vivo using DA neurotransmitter sensors.Chemogenetics were used to activate or inhibit VTA DA neurons.EEG was used to test the sedation depth of the mice.Results: After intraperitoneal injection of normal saline in mice,the calcium signal of VTA DA neurons did not change significantly.After intraperitoneal injection of dexmedetomidine in mice,the calcium signal of VTA DA neurons increased significantly.After intraperitoneal injection of normal saline in mice,the DA neurotransmitters in m PFC and NAc did not change significantly.After intraperitoneal injection of dexmedetomidine in mice,DA neurotransmitters in m PFC and NAc increased significantly.Patch-clamp recordings show that after giving dexmedetomidine,the frequency of spontaneous firing of VTA DA neurons significantly increased,the potassium ion current was significantly suppressed,and these results disappeared after perfusion of α2 adrenergic receptor antagonists(RS79948).After chemical genetics inhibited VTA DA neurons,the δ wave and θ wave caused by dexmedetomidine increased significantly.After VTA DA neurons were activated by chemical genetics,theδ wave and θ wave caused by dexmedetomidine reduced significantly.Conclusion: Dexmedetomidine activates VTA DA neurons and increases the DA neurotransmitters in projected brain areas(NAc,m PFC)of VTA DA neurons.Inhibition of VTA DA neurons increased the sedation depth of dexmedetomidine.Activation of VTA DA neurons reduced the sedation depth of dexmedetomidine.Therefore,dexmedetomidine activates VTA DA system which attenuates the sedation depth in mice.This mechanism may be involved in its unique sedation characteristics that are easily awakened.