Lin A M, Freund R K, Palmer M R
Department of Pharmacology, University of Colorado Health Sciences Center, Denver.
J Pharmacol Exp Ther. 1993 Apr;265(1):426-32.
We previously reported that both systemic administration and brief local application of ethanol potentiated gamma-aminobutyric acid (GABA)-induced depressions of cerebellar Purkinje neurons when the GABA responses were concomitantly facilitated (modulated) by catecholaminergic agonists. In the present study, we further investigated the effects of prolonged local applications of ethanol, which more closely mimic the systemic application of ethanol, and we characterized the pharmacological specificity of the catecholaminergic interaction with these ethanol effects. As has been previously observed, iontophoretic applications of isoproterenol (ISO), a beta adrenergic agonist, facilitated GABA-induced depressions of cerebellar Purkinje neurons. The prolonged local application of ethanol produced a long-lasting potentiation of the ISO-modulated GABA responses that was similar in duration to that caused by systemic ethanol administration. The ethanol-induced augmentation of the ISO-modulated GABA responses was diminished both by terminating the beta adrenergic agonist application as well as by administering the beta adrenergic antagonist timolol. The alpha adrenergic agonist phenylephrine, on the other hand, either attenuated or had no effects on the GABA-induced depressions of cerebellar Purkinje neurons, and a subsequent application of ethanol did not potentiate GABA responses in the presence of phenylephrine. We conclude that prolonged local application of ethanol mimics the interaction of systemic ethanol with GABA-induced depressions of cerebellar Purkinje neurons. Furthermore, the catecholaminergic sensitization of GABA responses to these potentiative effects of ethanol is mediated by a beta adrenergic mechanism.
我们先前报道，当γ-氨基丁酸（GABA）反应同时被儿茶酚胺能激动剂促进（调制）时，全身给予乙醇和短暂局部应用乙醇均可增强GABA诱导的小脑浦肯野神经元抑制。在本研究中，我们进一步研究了更接近全身应用乙醇的乙醇长时间局部应用的效果，并对儿茶酚胺能与这些乙醇作用相互作用的药理学特异性进行了表征。如先前观察到的，β肾上腺素能激动剂异丙肾上腺素（ISO）的离子电渗应用促进了GABA诱导的小脑浦肯野神经元抑制。乙醇的长时间局部应用产生了ISO调制的GABA反应的持久增强，其持续时间与全身给予乙醇所引起的相似。通过终止β肾上腺素能激动剂应用以及给予β肾上腺素能拮抗剂噻吗洛尔，均可减弱乙醇诱导的ISO调制的GABA反应增强。另一方面，α肾上腺素能激动剂去氧肾上腺素要么减弱要么对GABA诱导的小脑浦肯野神经元抑制没有影响，并且在存在去氧肾上腺素的情况下随后应用乙醇不会增强GABA反应。我们得出结论，乙醇的长时间局部应用模拟了全身乙醇与GABA诱导的小脑浦肯野神经元抑制之间的相互作用。此外，GABA反应对乙醇这些增强作用的儿茶酚胺能致敏是由β肾上腺素能机制介导的。
