Ripley Tamzin L, Dunworth Sarah J, Stephens David N
Sussex Centre for Research in Alcohol, Alcoholism and Drug Dependence, School of Biological Sciences, University of Sussex, Falmer, Brighton BN1 9QG, UK.
Psychopharmacology (Berl). 2002 Sep;163(2):157-65. doi: 10.1007/s00213-002-1138-7. Epub 2002 Jul 13.
It has previously been shown that drugs, such as benzodiazepines, that inhibit seizure activity during ethanol withdrawal, fail to alleviate the potentiated withdrawal seen following repeated episodes of withdrawal when administered during each withdrawal episode. Acute administration of the N-methyl- D-aspartate (NMDA) receptor competitive antagonist, CGP39551, has been shown to inhibit seizure activity during ethanol withdrawal, and, when administered during the periods of repeated diazepam withdrawal, it blocked the reduction in pentylenetetrazol (PTZ) seizure threshold seen following a final, untreated withdrawal.
The aim of the current study was to determine if CGP39551 could alter final ethanol-withdrawal symptoms when administered during the acute intermittent withdrawal periods.
Mice were chronically treated with ethanol-containing liquid diet for either 30 days continuously (single withdrawal) or with 8-h withdrawal periods on day 16 and day 23 of treatment (repeated withdrawal). Control animals received a control diet for the same period of time. On the final withdrawal animals were tested for behavioural signs of withdrawal. The effect of CGP39551 administered acutely on withdrawal [up to 5 mg/kg, intraperitoneally (i.p.)] or during the intermittent withdrawal periods (10 mg/kg, i.p.) was examined.
Acute administration of CGP39551 failed to inhibit handling-induced convulsions in the single-withdrawal or repeated-withdrawal group and had no effect on either decreased exploration or increased sensitivity to PTZ seen in withdrawal. Surprisingly, when CGP39551 was administered during periods of repeated ethanol withdrawal a potentiation of seizure activity was seen in the final, untreated withdrawal. This potentiation of seizure activity, compared with vehicle-treated animals, was not seen when CGP39551 was given whilst animals had access to ethanol (single-withdrawal group and repeated-withdrawal group where CGP39551 treatment was non-contingent with withdrawal episodes). However, the decrease in exploration seen during withdrawal was potentiated in repeated-withdrawal animals treated with CGP39551 irrespective of the time at which the CGP39551 was administered.
Treatment with an NMDA receptor-competitive antagonist potentiated the ethanol-withdrawal syndrome in animals with previous experience of ethanol withdrawal.
先前的研究表明，诸如苯二氮䓬类等在乙醇戒断期间抑制癫痫活动的药物，在每次戒断发作时给药，无法缓解反复戒断发作后出现的增强戒断反应。N-甲基-D-天冬氨酸（NMDA）受体竞争性拮抗剂CGP39551的急性给药已被证明可在乙醇戒断期间抑制癫痫活动，并且在反复地西泮戒断期间给药时，它能阻止在最后一次未经治疗的戒断后出现的戊四氮（PTZ）癫痫阈值降低。
本研究的目的是确定CGP39551在急性间歇性戒断期间给药时是否能改变最终的乙醇戒断症状。
小鼠连续用含乙醇的液体饲料慢性治疗30天（单次戒断），或在治疗的第16天和第23天进行8小时的戒断期（反复戒断）。对照动物在相同时间段接受对照饲料。在最后一次戒断时，对动物进行戒断行为体征测试。检查急性给予CGP39551（腹腔注射，最高5mg/kg）或在间歇性戒断期间（腹腔注射，10mg/kg）给药对戒断的影响。
急性给予CGP39551未能抑制单次戒断或反复戒断组中处理诱导的惊厥，并且对戒断时观察到的探索减少或对PTZ敏感性增加均无影响。令人惊讶的是，当在反复乙醇戒断期间给予CGP39551时，在最后一次未经治疗的戒断中出现癫痫活动增强。与给予溶媒的动物相比，当动物可获取乙醇时给予CGP39551（单次戒断组和反复戒断组中CGP39551治疗与戒断发作无关），未观察到癫痫活动增强。然而，无论CGP39551何时给药，在接受CGP39551治疗的反复戒断动物中，戒断期间观察到的探索减少均增强。
用NMDA受体竞争性拮抗剂治疗会使有乙醇戒断既往史的动物的乙醇戒断综合征增强。
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