Chen Hui, Xu Dan, Zhang Yu, Yan Yan, Liu JunXiao, Liu ChengXi, Shen Wei, Yu Tian, Liu Jin
Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, China.
Guizhou Key Laboratory of Anesthesia and Organ Protection, Zunyi Medical University, Guizhou, China.
Front Neurosci. 2021 Mar 9;15:636901. doi: 10.3389/fnins.2021.636901. eCollection 2021.
Propofol is a worldwide-used intravenous general anesthetic with ideal effects, but hedonic effects of propofol have been reported and cause addictive issue. There is little known about the neurobiological mechanism of hedonic effects of propofol. Increasing researches have shown that the dopaminergic nervous system of the ventral tegmental area (VTA) and the noradrenergic system of locus coeruleus (LC) play a crucial role in hedonic experiences, which are putative sites for mediating the hedonic effects of propofol. In the present study, rat hedonic response scale and place conditioning paradigm were employed to examine the euphoric effects of propofol. GCaMP-based (AVV-hSyn-GCaMP6s) fiber photometry calcium imaging was used to monitor the real-time neuronal activity in VTA and LC area in rats exhibiting propofol-induced euphoric behaviors. Then DREADDs (designer receptors exclusively activated by designer drugs) modulation using rAAV-hSyn-hM4D(Gi)-EGFP was performed to confirm the neuronal substrate that mediates the euphoric effects of propofol. The score of hedonic facial responses was significantly increased in the 4 mg/kg group compared with that of the 0 mg/kg group. The locomotor activity in the propofol-paired compartment was significantly increased at the 4 mg/kg dose compared with that of the saline-paired group. When compared with the 0 mg/kg group, the place preference increased in the 4 mg/kg group. Administration of 4 mg/kg of propofol triggers reliable increases in GcaMP fluorescence. However, in the VTA GcaMP-expressing rats, administration of 4 mg/kg of propofol did not induce any change of GcaMP signals. The facial score and the place preference, which increased by 4 mg/kg propofol were abolished by chemogenetic inhibition of the neuronal activity in the LC area. Our results suggest that LC noradrenergic neurons, not VTA dopaminergic neurons, are directly involved in the hedonic effects of sub-anesthetic dose of propofol.
丙泊酚是一种在全球范围内使用的静脉全身麻醉药，效果理想，但有报道称丙泊酚具有享乐效应并引发成瘾问题。关于丙泊酚享乐效应的神经生物学机制知之甚少。越来越多的研究表明，腹侧被盖区（VTA）的多巴胺能神经系统和蓝斑（LC）的去甲肾上腺素能系统在享乐体验中起关键作用，它们被认为是介导丙泊酚享乐效应的部位。在本研究中，采用大鼠享乐反应量表和位置条件反射范式来检测丙泊酚的欣快效应。基于GCaMP（AVV-hSyn-GCaMP6s）的光纤光度法钙成像用于监测表现出丙泊酚诱导欣快行为的大鼠VTA和LC区域的实时神经元活动。然后使用rAAV-hSyn-hM4D（Gi）-EGFP进行DREADDs（仅由设计药物激活的设计受体）调节，以确认介导丙泊酚欣快效应的神经元底物。与0 mg/kg组相比，4 mg/kg组的享乐性面部反应评分显著增加。与生理盐水配对组相比，4 mg/kg剂量的丙泊酚配对隔室中的运动活性显著增加。与0 mg/kg组相比，4 mg/kg组的位置偏好增加。给予4 mg/kg丙泊酚会引发GCaMP荧光可靠增加。然而，在VTA表达GCaMP的大鼠中，给予4 mg/kg丙泊酚并未诱导GCaMP信号的任何变化。4 mg/kg丙泊酚增加的面部评分和位置偏好通过化学遗传学抑制LC区域的神经元活动而被消除。我们的结果表明，LC去甲肾上腺素能神经元而非VTA多巴胺能神经元直接参与亚麻醉剂量丙泊酚的享乐效应。
