From the Department of Anesthesiology, First Affiliated Hospital of Anhui Medical University, Hefei, China (G.Q., Y.W., Y.L.) School of Life Science and Technology, ShanghaiTech University, Shanghai, China (X.Z., J.H.) Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shanxi, China (L.L., H.D.) Chinese Institute for Brain Research, Beijing, China (W.S.) Department of Anesthesiology, International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (Z.Y.) Department of Anesthesiology, Anhui No. 2 Provincial People's Hospital, Hefei, Anhui, China (Y.W.) Coinnovation Center of Neuroregeneration, Nantong University, Nantong, China (J.H.).
Anesthesiology. 2020 Aug;133(2):377-392. doi: 10.1097/ALN.0000000000003347.
Dexmedetomidine induces a sedative response that is associated with rapid arousal. To elucidate the underlying mechanisms, the authors hypothesized that dexmedetomidine increases the activity of dopaminergic neurons in the ventral tegmental area, and that this action contributes to the unique sedative properties of dexmedetomidine.
Only male mice were used. The activity of ventral tegmental area dopamine neurons was measured by a genetically encoded Ca indicator and patch-clamp recording. Dopamine neurotransmitter dynamics in the medial prefrontal cortex and nucleus accumbens were measured by a genetically encoded dopamine sensor. Ventral tegmental area dopamine neurons were inhibited or activated by a chemogenetic approach, and the depth of sedation was estimated by electroencephalography.
Ca signals in dopamine neurons in the ventral tegmental area increased after intraperitoneal injection of dexmedetomidine (40 μg/kg; dexmedetomidine, 16.917 [14.882; 21.748], median [25%; 75%], vs. saline, -0.745 [-1.547; 0.359], normalized data, P = 0.001; n = 6 mice). Dopamine transmission increased in the medial prefrontal cortex after intraperitoneal injection of dexmedetomidine (40 μg/kg; dexmedetomidine, 10.812 [9.713; 15.104], median [25%; 75%], vs. saline, -0.498 [-0.664; -0.355], normalized data, P = 0.001; n = 6 mice) and in the nucleus accumbens (dexmedetomidine, 8.543 [7.135; 11.828], median [25%; 75%], vs. saline, -0.329 [-1.220; -0.047], normalized data, P = 0.001; n = 6 mice). Chemogenetic inhibition or activation of ventral tegmental area dopamine neurons increased or decreased slow waves, respectively, after intraperitoneal injection of dexmedetomidine (40 μg/kg; delta wave: two-way repeated measures ANOVA, F[2, 33] = 8.016, P = 0.002; n = 12 mice; theta wave: two-way repeated measures ANOVA, F[2, 33] = 22.800, P < 0.0001; n = 12 mice).
Dexmedetomidine activates dopamine neurons in the ventral tegmental area and increases dopamine concentrations in the related forebrain projection areas. This mechanism may explain rapid arousability upon dexmedetomidine sedation.
右美托咪定诱导的镇静反应与快速觉醒有关。为了阐明潜在的机制，作者假设右美托咪定增加腹侧被盖区多巴胺能神经元的活性，并且这种作用有助于右美托咪定独特的镇静特性。
仅使用雄性小鼠。通过基因编码 Ca 指示剂和膜片钳记录测量腹侧被盖区多巴胺神经元的活性。通过基因编码多巴胺传感器测量内侧前额叶皮层和伏隔核中的多巴胺神经递质动力学。通过化学遗传方法抑制或激活腹侧被盖区多巴胺神经元，并通过脑电图估计镇静深度。
腹腔注射右美托咪定（40μg/kg；右美托咪定，16.917[14.882；21.748]，中位数[25%；75%]，与盐水相比，-0.745[-1.547；0.359]，归一化数据，P=0.001；n=6 只小鼠）后，腹侧被盖区多巴胺神经元的 Ca 信号增加。腹腔注射右美托咪定（40μg/kg；右美托咪定，10.812[9.713；15.104]，中位数[25%；75%]，与盐水相比，-0.498[-0.664；-0.355]，归一化数据，P=0.001；n=6 只小鼠）后，内侧前额叶皮层中的多巴胺传递增加，伏隔核中的多巴胺传递也增加（右美托咪定，8.543[7.135；11.828]，中位数[25%；75%]，与盐水相比，-0.329[-1.220；-0.047]，归一化数据，P=0.001；n=6 只小鼠）。腹腔注射右美托咪定（40μg/kg）后，腹侧被盖区多巴胺神经元的化学遗传抑制或激活分别增加或减少慢波（右美托咪定：双因素重复测量方差分析，F[2,33]=8.016，P=0.002；n=12 只小鼠；θ波：双因素重复测量方差分析，F[2,33]=22.800，P<0.0001；n=12 只小鼠）。
右美托咪定激活腹侧被盖区多巴胺能神经元，并增加相关前脑投射区的多巴胺浓度。这种机制可能解释了右美托咪定镇静后快速觉醒的能力。
