Dexmedetomidine Activation of Dopamine Neurons in the Ventral Tegmental Area Attenuates the Depth of Sedation in Mice
Dexmedetomidine Activation of Dopamine Neurons in the Ventral Tegmental Area Attenuates the Depth of Sedation in Mice
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PubMed 右美托咪定激活腹侧被盖区多巴胺神经元可减弱小鼠的镇静深度
DOI：
10.1097/aln.0000000000003347
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发表时间：
2020-08-01
期刊：
影响因子：
8.8
通讯作者：
Hu, Ji
中科院分区：
文献类型：
--
作者：
Qiu, Gaolin;Wu, Ying;Hu, Ji
背景：右美托咪定诱导与快速觉醒相关的镇静反应。为了阐明其潜在的机制，作者假设右美托咪定增加了腹侧被盖区多巴胺能神经元的活性，这一作用有助于右美托咪定独特的镇静特性。方法：只使用雄性小鼠。通过基因编码的Ca2+指示剂和膜片钳记录来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的多巴胺神经递质动态。通过化学发生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。结果：腹腔注射右美托咪定（40 μ g/kg；右美托咪定，16.917[14.882;21.748]，中位数[25%；75%]，相对于生理盐水，-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Ca2+信号升高。腹腔注射右美托咪定（40 μ g/kg；右美托咪定，10.812[9.713;15.104]，中位数[25%；75%]，与生理盐水相比，-0.498[-0.664;-0.355]，归一化数据，P = 0.001, n = 6只小鼠）和伏隔核多巴胺传递增加（右美托咪定，8.543[7.135;11.828]，中位数[25%；75%]，与生理盐水相比，-0.329[-1.220;-0.047]，归一化数据，P = 0.001, n = 6只小鼠）。右美托咪定（40 μ g/kg）腹腔注射后，化学抑制或激活腹侧被盖区多巴胺神经元分别增加或减少慢波；δ波：双向重复测量方差分析，F[2,33] = 8.016, P = 0.002, n = 12只小鼠；θ波：双向重复测量方差分析，F[2,33] = 22.800, P < 0.0001, n = 12只小鼠)。结论：右美托咪定激活腹侧被盖区多巴胺神经元，增加相关前脑投射区多巴胺浓度。这一机制可以解释右美托咪定镇静后的快速觉醒。
Background: 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.Methods: Only male mice were used. The activity of ventral tegmental area dopamine neurons was measured by a genetically encoded Ca2+ 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.Results: Ca2+ signals in dopamine neurons in the ventral tegmental area increased after intraperitoneal injection of dexmedetomidine (40 mu g/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 mu g/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 mu g/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).Conclusions: Dexmedetomidine activates dopamine neurons in the ventral tegmental area and increases dopamine concentrations in the related fore-brain projection areas. This mechanism may explain rapid arousability upon dexmedetomidine sedation.