摘要目的:探讨大鼠丙泊酚精神依赖形成的机制与腺苷A2A受体-神经递质-细胞外信号调节激酶(ERK)通路的关系。方法:健康雄性SD大鼠48只，采用间断腹腔注射丙泊酚40 mg/kg，连续14 d的方法建立丙泊酚依赖模型。采用随机数字表法将大鼠分为6组( n＝8)：中枢对照组(c-C组)、中枢激动剂组(c-CGS组)、中枢拮抗剂组(c-DMPX组)、外周对照组(p-C组)、外周激动剂组(p-CGS组)和外周拮抗剂组(p-DMPX组)。c-CGS组和c-C组于建模后立即颅内注射腺苷A2A激动剂CGS-21680 2.5 ng/0.5 μl或等量生理盐水，p-CGS组和p-C组腹腔注射CGS-21680 0.1 mg/kg或等量生理盐水；c-DMPX组于每次丙泊酚注射前20 min颅内注射腺苷A2A受体拮抗剂DMPX 50 ng/0.5 μl，p-DMPX组腹腔注射DMPX 0.25 mg/kg。分别于建模前、建模后即刻、激动剂或生理盐水给药后(干预后)测定位置偏爱值(CPP值)。建模后1 d时处死大鼠取血标本及脑组织，采用ELISA法检测血浆及海马多巴胺(DA)、谷氨酸(Glu)及大脑皮层5-羟色胺(5-HT)水平，采用Western blot法检测大脑皮层磷酸化ERK1/2(p-ERK1/2)的表达。 结果:与建模前比较，建模后即刻c-C组、c-CGS组、p-C组和p-CGS组CPP值升高( P <0.05)，c-DMPX组和p-DMPX组CPP值差异无统计学意义( P>0.05)；与造模后即刻比较，干预后c-C组和p-C组CPP值差异无统计学意义( P>0.05)，c-CGS组和p-CGS组CPP值升高( P<0.05)。与c-C组比较，c-CGS组海马DA和Glu含量增加，c-DMPX组海马Glu含量减少，大脑皮层5-HT含量增加，p-ERK1/2表达下调( P<0.05)；与p-C组比较，p-CGS组血浆及海马DA和Glu、大脑皮层5-HT和p-ERK1/2水平差异无统计学意义( P>0.05)，p-DMPX组海马DA和Glu含量减少，大脑皮层5-HT含量增加，p-ERK1/2表达下调( P<0.05)。 结论:大鼠丙泊酚精神依赖形成的机制可能与激活腺苷A2A受体，增加脑内兴奋性神经递质，进而上调ERK活性有关。

abstractsObjective:To investigate the relationship between the mechanism of mental dependence of propofol and adenosine A2A receptor-neurotransmitter-extracellular signal-regulated kinase (ERK) pathway in rats.Methods:Forty-eight healthy male Sprague-Dawley rats, aged about 7 weeks, weighing 200-300 g, were used in this study.The model of propofol dependence was established by intraperitoneal injection of propofol 40 mg/kg for 14 consecutive days.The rats were divided into 6 groups ( n=8 each) using a random number table method: central control group (group c-C), central agonist group (group c-CGS), central antagonist group (group c-DMPX), peripheral control group (group p-C), peripheral agonist group (group p-CGS) and peripheral antagonist group (group p-DMPX). Adenosine A2A agonist CGS-21680 2.5 ng/0.5 μl was intracranially injected immediately after establishing the model in group c-CGS, while the equal volume of normal saline was given instead in c-C group.CGS-21680 0.1 mg/kg was intraperitoneally injected in group p-CGS, while the equal volume of normal saline was given instead in group p-C.Adenosine A2A receptor antagonist DMPX 50 ng/0.5 μl was intracranially injected at 20 min before each propofol injection in group c-DMPX, and DMPX 0.25 mg/kg was intraperitoneally injected in group p-DMPX.The position preference value (CPP value) was determined before establishing the model, immediately after establishing the model, and after administration of agonist or normal saline (after intervention). The animals were sacrificed at 1 day after establishing the model, and blood samples and brain tissues were obtained for determination of the levels of dopamine (DA) and glutamate (Glu) in plasma and hippocampus and content of serotonin (5-HT) in cerebral cortex (by enzyme-linked immunosorbent assay) and expression of phosphorylated ERK1/2 (p-ERK1/2) in cerebral cortex (by Western blot). Results:Compared with the baseline before establishing the model, CPP value was increased immediately after establishing the model in c-C, c-CGS, p-C and p-CGS groups ( P<0.05), and no significant change was found in CPP value immediately after establishing the model in c-DMPX and p-DMPX groups ( P>0.05). Compared with the value immediately after establishing the model, no significant change was found in CPP value after intervention in c-C and p-C groups ( P>0.05), and CPP value was increased after intervention in c-CGS and p-CGS groups ( P<0.05). Compared with group c-C, the contents of hippocampal DA and Glu were significantly increased in group c-CGS, and the contents of hippocampal Glu were decreased, the content of 5-HT in cerebral cortex was increased, and the expression of p-ERK1/2 was down-regulated in group c-DMPX ( P<0.05). Compared with group p-C, no significant change was found in levels of DA and glutamate (Glu) in plasma and hippocampus and 5-HT and p-ERK1/2 in cerebral cortex in group p-CGS ( P>0.05), and the contents of hippocampal DA and Glu were significantly decreased, the content of 5-HT in cerebral cortex was increased, and the expression of p-ERK1/2 was down-regulated in group p-DMPX ( P<0.05). Conclusion:The mechanism underlying the development of propofol mental dependence may be related to activating adenosine A2A receptors, increasing excitatory neurotransmitters in brain, and thus up-regulating ERK activity in rats.