Mouse cerebellar adenosinergic modulation of ethanol-induced motor incoordination: Possible involvement of cAMP
Mouse cerebellar adenosinergic modulation of ethanol-induced motor incoordination: Possible involvement of cAMP
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DOI：
10.1016/s0006-8993(96)01263-2
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发表时间：
1997-02-28
期刊：
影响因子：
2.9
通讯作者：
Dar, MS
中科院分区：
文献类型：
--
作者：
Dar, MS
作为我们之前关于乙醇引起的运动不协调的脑腺苷能调节的工作的延伸，评估了直接小脑内施用 A(1)-选择性腺苷激动剂 N-6-环己基腺苷 (CHA) 对乙醇引起的运动不协调的影响。观察到 CHA 显着加重乙醇引起的运动障碍。当 CHA 给药后用盐水代替乙醇时，正常运动协调没有变化。小脑内 cAMP 或其类似物 8-(4-氯苯硫基)-cAMP 以剂量相关的方式显着抑制乙醇的运动损伤，并消除 CHA 对乙醇引起的运动不协调的加重作用。这些观察结果表明 cAMP 可能参与腺苷能调节和乙醇诱导的运动不协调的表达。通过观察到乙醇引起的运动损伤以剂量相关的方式显着增强和减弱，以及 CHA 分别通过小脑内咪康唑和毛喉素增强乙醇运动损伤，提供了进一步的支持。然而，等摩尔小脑内剂量的咪康唑和毛喉素（分别为腺苷酸环化酶的抑制剂和刺激剂）未能显着改变乙醇引起的运动不协调，可能是由于它们相互的功能拮抗作用。腺苷能调节的表达和乙醇诱导的运动障碍的表达很可能涉及 G(i) 蛋白偶联受体（例如腺苷受体）。与百日咳毒素敏感的 G 蛋白相关的受体的参与被认为是因为小脑内百日咳毒素预处理显着抑制了乙醇引起的运动不协调以及 CHA 对乙醇运动损伤的加重。最后，与cAMP对CHA加重的拮抗作用不同，cAMP不能拮抗小脑内GABA(A)激动剂(+)-蝇蕈醇对乙醇诱导的运动损伤的加重。这表明cAMP选择性参与G蛋白偶联受体（例如腺苷）介导的反应，而不参与离子通道偶联受体（例如GABA(A)）介导的机制。总体而言，数据表明小脑腺苷酸环化酶-cAMP信号通路可能参与乙醇共济失调的腺苷能调节。
As an extension of our previous work pertaining to brain adenosinergic modulation of ethanol-induced motor incoordination, the effect of direct intracerebellar administration of the A(1)-selective adenosine agonist, N-6-cyclohexyladenosine (CHA) on ethanol-induced motor incoordination was evaluated. Marked accentuation of ethanol-induced motor impairment by CHA was observed. No change in the normal motor coordination was noted when CHA administration was followed by saline instead of ethanol. Intracerebellar cAMP or its analog, 8-(4-chlorophenylthio)-cAMP, significantly inhibited ethanol's motor impairment in a dose-related manner as well as abolished CHA's accentuating effect on ethanol-induced motor incoordination. These observations suggested a possible involvement of cAMP in the adenosinergic modulation and in the expression of ethanol-induced motor incoordination. Further support was provided by the observation of a marked accentuation and attenuation in a dose-related manner of ethanol-induced motor impairment as well as CHA's accentuation of ethanol's motor impairment by intracerebellar miconazole and forskolin, respectively. However, equimolar intracerebellar doses of miconazole and forskolin (inhibitor and stimulator of adenylyl cyclase, respectively) failed to significantly alter ethanol-induced motor incoordination probably due to their mutual functional antagonism. The expression of adenosinergic modulation and that of ethanol-induced motor impairment most likely involved G(i) protein-coupled receptor(s) (such as adenosine receptors). The involvement of receptors linked to pertussis toxin-sensitive G-proteins was suggested because intracerebellar pertussis toxin pretreatment markedly inhibited ethanol-induced motor incoordination as well as CHA's accentuation of ethanol's motor impairment. Finally, cAMP, unlike its antagonism to CHA's accentuation, failed to antagonize the accentuation of ethanol-induced motor impairment by intracerebellar GABA(A) agonist (+)-muscimol. This indicated selectivity of cAMP participation in G protein coupled receptor (such as adenosine)-mediated response and not in ionic channel coupled receptor (such as GABA(A))-mediated mechanism. Overall, the data suggested a possible involvement of cerebellar adenylyl cyclase-cAMP signalling pathway in the adenosinergic modulation of ethanol's ataxia.