GABAergic systems modulate nicotinic receptor-mediated seizures in mice
GABAergic systems modulate nicotinic receptor-mediated seizures in mice
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DOI：
10.1124/jpet.103.053066
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发表时间：
2003-09-01
影响因子：
3.5
通讯作者：
Collins, AC
中科院分区：
文献类型：
--
作者：
Dobelis, P;Hutton, S;Collins, AC
本文研究了烟碱受体介导的小鼠癫痫发作的药理作用。11种尼古丁激动剂和6种拮抗剂被中枢注射(i.c.v)。Epibatidine和epboxidine是最有效的激动剂，而乙酰胆碱和α7*选择性化合物3-(2，4-二甲氧基亚甲基)-anabaseine(GTS-21)和anabasine的作用最弱。尼古丁诱导的癫痫发作可通过与非选择性拮抗剂甲氨基甲胺或α7*选择性拮抗剂甲基琥珀酸乙酯联合治疗而被阻断。α-β2*-选择性拮抗剂二氢-β-乙酸乙二胺对癫痫发作的阻断作用无效。然而，所测试的所有六种拮抗剂的高剂量都能完全有效地导致癫痫发作，其中d-Tubocurarine的效力最强，甲基苯丙胺的效力最弱。此外，还研究了烟碱受体介导的癫痫发作与药物对GABA功能的影响之间的潜在关系。没有发现激动剂引起癫痫发作和刺激[H-3]GABA释放的效力之间或拮抗剂引起癫痫发作的效力和拮抗剂抑制尼古丁刺激的[H-3]GABA释放之间的相关性。然而，激动剂引起癫痫发作的效力与抑制由激动剂诱导的受体脱敏产生的尼古丁刺激的[H-3]GABA释放的IC50值之间存在强烈的相关性。我们还比较了近交系小鼠对尼古丁、印防己毒素、荷包牡丹碱和红藻氨酸诱导的癫痫发作的敏感性。尼古丁诱导的癫痫发作与印防己毒素或荷包牡丹碱诱发的癫痫发作呈显著正相关，两者都是GABA A受体拮抗剂。未发现尼古丁诱发的惊厥与兴奋性氨基酸受体激动剂海人酸诱发的惊厥之间存在相关性。基于这些发现，我们提出了一个通过GABA能系统介导的尼古丁受体介导的癫痫模型。
The pharmacology of nicotinic receptor-mediated seizures was investigated in C3H mice. Eleven nicotinic agonists and six antagonists were administered centrally (i.c.v.). Epibatidine and epiboxidine were the most potent agonists tested, whereas acetylcholine and the alpha7*-selective compounds 3-(2,4-dimethoxybenzylidene)-anabaseine (GTS-21) and anabasine, were the least potent. Nicotine-induced seizures were blocked by cotreatment with either the nonselective antagonist mecamylamine or the alpha7*-selective antagonist methyllycaconitine. The alpha4beta2*-selective antagonist dihydro-beta-erythroidine was ineffective at blocking seizures. However, high doses of all six antagonists tested were fully efficacious in producing seizures, with d-tubocurarine being the most potent and mecamylamine the least potent. Potential relationships between nicotinic receptor-mediated seizures and drug effects on GABA function were also investigated. No correlation was seen between potencies of the agonists in producing seizures and stimulating [H-3] GABA release or between potencies of the antagonists in producing seizures and antagonist inhibition of nicotine-stimulated [H-3] GABA release. However, a robust correlation was detected between potencies of the agonists in producing seizures and the IC50 values for inhibition of nicotine-stimulated [H-3] GABA release produced by agonist-induced receptor desensitization. We also compared inbred mouse strain sensitivity to nicotine, picrotoxin, bicuculline, and kainate-induced seizures. Robust positive correlations were revealed for nicotine-induced seizures and seizures induced by either picrotoxin or bicuculline, both GABA A receptor antagonists. No correlation was found between nicotine-induced seizures and those induced by the excitatory amino acid receptor agonist kainate. Based on these findings, we present a model for nicotinic receptor-mediated seizures mediated through GABAergic systems.