Meng Z H, Pennington S N, Dar M S
Department of Pharmacology, School of Medicine, East Carolina University, Greenville, NC 27858, USA.
Neuroscience. 1998 Aug;85(3):919-30. doi: 10.1016/s0306-4522(97)00627-1.
We have previously reported the involvement of the striatum in acute ethanol-induced motor incoordination and the striatal adenosinergic modulation of ethanol-induced motor incoordination through A1 receptor-mediated mechanism(s). The present study, a continuation of our previous work, was carried out to investigate the possible functional correlation between striatal cyclic AMP and ethanol-induced motor incoordination, and its modulation by striatal adenosine in Sprague-Dawley rats. Forskolin (0.1, 0.5 and 1.0 pmol), a known activator of adenylate cyclase, significantly attenuated ethanol-induced motor incoordination in a dose-dependent manner following its direct intrastriatal microinfusion. Forskolin also antagonized the accentuating effect of intrastriatal N6-cyclohexyladenosine on ethanol-induced motor incoordination. These results suggested that ethanol-induced motor incoordination might be functionally correlated to a decrease in the striatal cyclic AMP levels and that the striatal adenosine A1 receptors might modulate ethanol-induced motor incoordination through cyclic AMP signaling mechanism(s). Further support to this hypothesis was obtained by the actual measurement of the striatal cyclic AMP levels in the same experimental conditions as in motor coordination studies using high-performance liquid chromatography with fluoroscence detection. Regardless of the method (focused microwave irradiation, cervical dislocation or decapitation into a dry ice-ethanol mixture) used to kill the animals, a significant decrease in the striatal cyclic AMP levels was observed due to ethanol. Intrastriatal adenosine A1-selective agonist, N6-cyclohexyladenosine (24 ng), caused a further significant decrease in the striatal cyclic AMP levels in the ethanol- but not in the vehicle-treated animals. The further enhancement in the ethanol-induced decrease in the striatal cyclic AMP levels by intrastriatal N6-cyclohexyladenosine, therefore, functionally correlated with the observed potentiating effect of intrastriatal N6-cyclohexyladenosine on ethanol-induced motor incoordination. The effects of intrastriatal N6-cyclohexyladenosine+ethanol and of ethanol alone on the striatal cyclic AMP levels were blocked by intrastriatal pertussis toxin (500 ng) pretreatment, indicating the involvement of pertussis toxin-sensitive G-proteins (Gi, Go) and possibly of the adenosine A1 receptor coupled to the G-proteins in the striatum. Furthermore, ethanol alone significantly decreased the basal as well as the cyclic AMP-stimulated catalytic activities of the striatal cyclic AMP protein kinase, which were further reduced by intrastriatal N6-cyclohexyladenosine. The results of the present study therefore support an involvement of a cyclic AMP signaling pathway in the striatal adenosinergic modulation of ethanol-induced motor incoordination at the post-adenosine A1 receptor level.
我们之前曾报道，纹状体参与急性乙醇诱导的运动不协调，且纹状体通过A1受体介导的机制对乙醇诱导的运动不协调进行腺苷能调节。本研究是我们之前工作的延续，旨在探讨纹状体环磷酸腺苷（cAMP）与乙醇诱导的运动不协调之间可能的功能相关性，以及纹状体腺苷对其的调节作用，实验采用Sprague-Dawley大鼠。已知的腺苷酸环化酶激活剂福司可林（0.1、0.5和1.0 pmol）直接纹状体内微量注射后，能以剂量依赖的方式显著减轻乙醇诱导的运动不协调。福司可林还拮抗了纹状体内N6-环己基腺苷对乙醇诱导的运动不协调的增强作用。这些结果表明，乙醇诱导的运动不协调可能在功能上与纹状体cAMP水平降低相关，且纹状体腺苷A1受体可能通过cAMP信号机制调节乙醇诱导的运动不协调。在与运动协调性研究相同的实验条件下，使用高效液相色谱荧光检测法实际测量纹状体cAMP水平，进一步支持了这一假设。无论采用何种方法（聚焦微波辐射、颈椎脱臼或断头后放入干冰-乙醇混合物）处死动物，乙醇均导致纹状体cAMP水平显著降低。纹状体内腺苷A1选择性激动剂N6-环己基腺苷（24 ng）使乙醇处理组动物纹状体cAMP水平进一步显著降低，但对溶剂处理组动物无此作用。因此，纹状体内N6-环己基腺苷进一步增强乙醇诱导的纹状体cAMP水平降低，在功能上与纹状体内N6-环己基腺苷对乙醇诱导的运动不协调的增强作用相关。纹状体内百日咳毒素（500 ng）预处理可阻断纹状体内N6-环己基腺苷+乙醇以及单独乙醇对纹状体cAMP水平的影响，表明百日咳毒素敏感的G蛋白（Gi、Go）以及可能与纹状体中G蛋白偶联的腺苷A1受体参与其中。此外，单独乙醇显著降低纹状体cAMP蛋白激酶的基础活性以及cAMP刺激的催化活性，纹状体内N6-环己基腺苷进一步降低这些活性。因此，本研究结果支持cAMP信号通路参与纹状体在腺苷A1受体后水平对乙醇诱导的运动不协调的腺苷能调节。
