EFFECTS OF CONVULSANTS ON HANDLING-INDUCED CONVULSIONS IN MICE SELECTED FOR ETHANOL WITHDRAWAL SEVERITY
EFFECTS OF CONVULSANTS ON HANDLING-INDUCED CONVULSIONS IN MICE SELECTED FOR ETHANOL WITHDRAWAL SEVERITY
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DOI：
10.1016/0006-8993(91)90397-e
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发表时间：
1991-05-31
期刊：
影响因子：
2.9
通讯作者：
BELKNAP, JK
中科院分区：
文献类型：
--
作者：
CRABBE, JC;MERRILL, CD;BELKNAP, JK
戒断癫痫易感(WSP)小鼠在停止慢性乙醇蒸气吸入后表现出严重的手把性惊厥(HIC)。HIC是中枢神经系统兴奋性的敏感指标，本文比较了11种惊厥药物对WSP和WSR(戒断发作抵抗)小鼠HIC的影响，后者被选为最小酒精戒断HIC。如果WSP和WSR小鼠对测试药物的一个子集具有不同的敏感性，那么该子集的共同作用机制将意味着影响该机制的基因在确定乙醇戒断严重程度方面非常重要。所有药物均能显著提高WSP小鼠的HIC。N-甲基-D-天冬氨酸(NMDA)、海人酸、BAY K 8644、RO15-4513和士的宁的增强幅度较小；在WSP小鼠中，尼古丁、直接和间接的伽马氨基丁酸(GABA)拮抗剂荷包牡丹碱、3-巯基丙酸、印防己毒素、环磷硫酸叔丁酯(TBP)和戊四唑的增强作用更强。只有两种药物对WSR小鼠有显著效果：这两种药物对WSP和WSR小鼠的最大作用相当。然而，印防己毒素和戊四氮在WSP小鼠中的效力强于WSR小鼠。另外三种GABA拮抗剂，荷包牡丹碱、3-巯基丙酸和TBP，对WSR小鼠的影响非常小：这些药物在WSP小鼠中似乎也比在WSR小鼠中更有效。对于所有其他受试药物，WSP小鼠的最大作用比WSR小鼠的大得多。考虑到WSR小鼠对这些其他药物的最小反应，无法估计其效力，或将其与WSP小鼠的效力进行比较。WSP小鼠明显比WSR小鼠对所有测试药物更敏感。由于WSP和WSR小鼠对GABA相关化合物的敏感性差异最小，这些结果表明，大脑GABA系统的差异可能不是表达对酒精戒断严重程度的遗传易感性或抵抗力的关键。然而，在戒酒动物身上进行的类似研究可能会为评估戒酒的潜在神经药理学相关性提供更好的方法。
Withdrawal seizure-prone (WSP) mice were genetically selected to express severe handling-induced convulsions (HIC) upon cessation of chronic ethanol vapor inhalation. The HIC is a sensitive measure of CNS excitability, and the current paper compares the effects of eleven convulsant drugs on the HIC in WSP and WSR (withdrawal seizure-resistant) mice, the latter selected for minimal alcohol withdrawal HIC. If WSP and WSR mice were differentially sensitive to a subset of the tested drugs, a common mechanism of action for that subset would imply that genes influencing that mechanism were important in determining ethanol withdrawal severity. All drugs significantly enhanced HIC in WSP mice. The magnitude of enhancement was small for N-methyl-D-aspartate (NMDA), kainic acid, BAY K 8644, Ro 15-4513, and strychnine; greater enhancement in WSP mice was seen after nicotine, and the direct and indirect gamma-aminobutyric acid (GABA) antagonists bicuculline, 3-mercaptopropionic acid, picrotoxin, t-butylcyclophosphorothionate (TBPS), and pentylenetetrazol. Only two drugs, picrotoxin and pentylenetetrazol, had a marked effect on WSR mice: maximal effect of these drugs was equivalent in WSP and WSR mice. However, picrotoxin and pentylenetetrazol were more potent in WSP than in WSR mice. Three other GABA antagonists, bicuculline, 3-mercaptopropionic acid, and TBPS, had a very small effect in WSR mice: these drugs also seemed to be more potent in WSP than in WSR mice. For all other tested drugs, maximal effect in WSP mice was much greater in WSP than in WSR mice. Given the minimal response of WSR mice to these other drugs, it was not possible to estimate potency, or to compare it with potency in WSP mice. WSP mice were clearly more sensitive to all tested drugs than WSR mice. Since WSP and WSR mice differed least in sensitivity to GABA-related compounds, these results suggest that differences in brain GABA systems may not be critical for the expression of genetic susceptibility or resistance to ethanol withdrawal severity. However, similar studies in animals withdrawing from ethanol may provide a better method for evaluating potential neuropharmacological correlates of withdrawal.