Nanomolar propofol stimulates glutamate transmission to dopamine neurons: A possible mechanism of abuse potential?
Nanomolar propofol stimulates glutamate transmission to dopamine neurons: A possible mechanism of abuse potential?
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DOI：
10.1124/jpet.107.132472
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发表时间：
2008-04-01
影响因子：
3.5
通讯作者：
Ye, Jiang-Hong
中科院分区：
文献类型：
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作者：
Li, Ke-Yong;Xiao, Cheng;Ye, Jiang-Hong
麻醉师在医生滥用药物的名单上名列前茅，其机制尚不清楚。最近的研究表明，与职业相关的静脉注射药物（包括异丙酚）的二手暴露可能起作用。越来越多的证据表明，异丙酚是被滥用的药物之一。在这项研究中，我们发现微量浓度的异丙酚增加了腹侧被盖区（VTA）的谷氨酸能兴奋性突触传递和多巴胺神经元的放电。我们发现，异丙酚（0.1-10 nM）急性应用于大鼠中脑VTA切片，增加了α -氨基-3-羟基-5-甲基异恶唑-4-丙酸受体介导的自发兴奋性突触后电流（EPSCs）的频率，但未增加其振幅。我们观察到，异丙酚增加了在GABA a受体拮抗剂gabazine （SR 95531）存在和不存在的情况下刺激引起的EPSCs的振幅，但降低了配对脉冲比。此外,propofol-induced便利化EPSCs模仿了6-phenyl-4-azabicyclo 5.4.0 undeca-7, 9日11-triene-9, 10-diol (SKF38393)、多巴胺d1受体的激动剂,通过1 - [2 - (diphenylmethoxy)乙基]4 - (3-phenylpropyl)哌嗪盐酸盐(GBR 12935),多巴胺再摄取抑制剂,但被7-bromo-8-hydroxy-3-methyl-1-phenyl-2 (+ / -), 3, 4, 5-tetrahydro-1H-3-benzazepine盐酸盐(SKF83566), d 1拮抗剂或耗尽多巴胺与利血平商店。最后，1 nM异丙酚增加了多巴胺神经元的自发放电率。这些发现表明，微小浓度的异丙酚可能通过增加细胞外多巴胺水平，增强突触前D-1受体介导的谷氨酸能突触传递的促进作用和VTA多巴胺神经元的兴奋性。这些突触可塑性的变化可能导致异丙酚滥用的发展和对其他药物成瘾的易感性增加。
Anesthesiologists among physicians are on the top of the drug abuse list, and the mechanism is unclear. Recent studies suggest occupation-related second-hand exposure to i.v. drugs, including propofol, may play a role. Growing evidence indicates that propofol is one of the choices of drugs being abused. In this study, we show that propofol at minute concentrations increases glutamatergic excitatory synaptic transmission and discharges of dopamine neurons in the ventral tegmental area (VTA). We found that acute application of propofol (0.1-10 nM) to the VTA in midbrain slices of rats increased the frequency but not the amplitude of spontaneous excitatory postsynaptic currents (EPSCs) mediated by alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors. We observed that propofol increased the amplitude but decreased the paired-pulse ratio of EPSCs evoked by stimulation in the absence and the presence of gabazine (SR 95531), a GABA A receptor antagonist. Moreover, the propofol-induced facilitation of EPSCs was mimicked by 6-phenyl-4-azabicyclo[5.4.0]undeca-7,9,11-triene-9,10-diol (SKF38393), an agonist of dopamine D-1 receptor, and by 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine dihydrochloride (GBR 12935), a dopamine reuptake inhibitor, but blocked by (+/-)-7-bromo-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SKF83566), a D-1 antagonist, or by depleting dopamine stores with reserpine. Finally, 1 nM propofol increased the spontaneous discharge rate of dopamine neurons. These findings suggest that propofol at minute concentrations enhances presynaptic D-1 receptor-mediated facilitation of glutamatergic synaptic transmission and the excitability of VTA dopamine neurons, probably by increasing extracellular dopamine levels. These changes in synaptic plasticity in the VTA, an addiction-related brain area might contribute to the development of propofol abuse and the increased susceptibility to addiction of other drugs.