The role of protein kinase A in acute ethanol-induced neurobehavioral actions in rats
The role of protein kinase A in acute ethanol-induced neurobehavioral actions in rats
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DOI：
10.1213/01.ane.0000263030.13249.36
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发表时间：
2007-07-01
影响因子：
5.7
通讯作者：
Lin, Hsun-Husn
中科院分区：
文献类型：
--
作者：
Lai, Chih-Chia;Kuo, Ting-In;Lin, Hsun-Husn
背景：camp依赖性蛋白激酶（PKA）信号通路参与敲除小鼠模型中乙醇诱导的镇静作用的调节。在本研究中，我们研究了PKA对乙醇引起的大鼠行为行为的作用。方法：采用翻正反射丧失（LORR）试验研究腹腔注射乙醇的急性镇静作用。采用旋转杆性能研究乙醇对大鼠运动损伤的影响。采用脑室内n -甲基- d -天冬氨酸（NMDA）诱导惊厥，评价乙醇对NMDA受体的影响。Western blot法检测NR1和NR1亚基上磷酸化丝氨酸897的蛋白水平。结果：经LORR评估，H-9（一种非特异性PK抑制剂）或KT 5720（一种特异性PKA抑制剂）的ICV预处理能剂量依赖地减弱乙醇诱导的睡眠时间。ICV KT 5720不减少氯胺酮或戊巴比妥诱导的睡眠时间。用福斯克林（腺苷酸环化酶活化剂）或车车草碱（一种选择性PKC抑制剂）预处理对乙醇诱导的LORR没有影响。经KT 5720预处理后，乙醇诱导的运动损伤也有所减轻。乙醇显著抑制nmda诱导的惊厥；先前的ICV KT 5720降低了乙醇的抑制作用，并且对我们检测的几个脑区NMDA NR1亚基的磷酸化丝氨酸897水平没有显著影响。结论：我们的研究结果提示PKA通路可能参与了乙醇诱导的神经行为改变，NMDA受体可能参与了PKA对乙醇作用的调节。
BACKGROUND: cAMP-dependent protein kinase (PKA) signaling pathways are involved in the regulation of ethanol-induced sedative effects in knockout mouse models. In the present study, we examined the role of PKA on the behavioral action caused by ethanol in Sprague Dawley rats.METHODS: A loss of righting reflex (LORR) test was used to study the acute sedative effects of intraperitoneally injected ethanol. Rotarod performance was used to study the motor impairment caused by ethanol. Convulsions induced by intrace-rebroventricular (ICV) N-methyl-D-aspartate (NMDA) were used to evaluate ethanol's effect on NMDA receptors. Western blot analysis was used to assay protein levels for NR1 and phosphoserine 897 on NR1 subnuits.RESULTS: ICV pretreatment with H-9 (a nonspecific PK inhibitor) or KT 5720 (a specific PKA inhibitor) dose-dependently attenuated ethanol-induced sleeping time as assessed by LORR. ICV KT 5720 did not reduce ketamine or pentobarbital-induced sleeping time. Pretreatment with forskolin (an activator of adenylyl cyclase) or chelerythrine (a selective PKC inhibitor) had no effect on ethanol-induced LORR. Ethanol-induced motor impairment was also attenuated after pretreatment with KT 5720. Ethanol significantly inhibited NMDA-induced convulsions; the inhibitory effects of ethanol were reduced by prior ICV KT 5720, which had no significant effects on the levels of phosphoserine 897 on NMDA NR1 subunits in the several brain areas we examined.CONCLUSIONS: Our results suggest that the PKA pathway may participate in ethanol-induced neurobehavioral changes and that NMDA receptors may be involved in the PKA regulation of ethanol's actions.