Marczynski T J, Urbancic M, Gadek M
Department of Pharmacology, University of Illinois Medical Center, Chicago 60612.
Neuropharmacology. 1991 Oct;30(10):1085-94. doi: 10.1016/0028-3908(91)90137-z.
The effects of chronic administration of the benzodiazepine receptor antagonist, flumazenil (Ro 15-1788; 4 mg/kg/day for 14 days in drinking water) on the performance of adult rats in the 12-arm radial maze were studied. Relative to controls, the animals treated with flumazenil showed an increase (P less than 0.002) in non-appetitively motived exploratory behavior, so called because it occurred in 88% of instances in non-baited alleys, facing the well-illuminated "enriched environment" of the center of the room, as opposed to the baited alleys, facing the "dull" corner of the room. This behavior emerged between day 5 and 7 of treatment with the drug, it continued to increase over the period of treatment with drug (P less than 0.002), and reached its peak at day 3, after withdrawal of the drug (P less than 0.008; a longer duration was not investigated). The occurrence of non-appetitively motivated exploratory behavior was inversely correlated with the scores for urination/defecation (P less than 0.003) and, therefore, most likely reflected the anxiolytic action of flumazenil. During treatment with drug or vehicle, the control and the drug groups made comparable numbers of "working memory" errors (P = 0.17). However, upon withdrawal of drug and introduction of alley gates (to confine the animal for 10 sec to the center platform, after an alley was explored), the working memory errors of the rats exposed to the drug, remained unchanged (P = 0.35), relative to the preceding three trials, while the performance of the control group was disrupted, as shown by an increase in the numbers of errors (P less than 0.004). At day seven of treatment with drug, the emergence of exploratory behavior was associated with an increased density and/or affinity of benzodiazepine receptors in cortex, hippocampus and brain stem, while three days after withdrawal of drug, when the exploratory behavior reached its peak, there was a reduction in GABA-enhanced binding of [3H]flunitrazepam in the cortex.
研究了长期给予苯二氮䓬受体拮抗剂氟马西尼（Ro 15 - 1788；以4毫克/千克/天的剂量加入饮用水中，持续14天）对成年大鼠在12臂放射状迷宫中行为表现的影响。与对照组相比，接受氟马西尼治疗的动物非食欲驱动的探索行为增加（P < 0.002），之所以这样称呼是因为这种行为在88%的情况下发生在未设诱饵的通道中，面向房间中央光照良好的“丰富环境”，而不是面向设诱饵通道及房间“昏暗”角落。这种行为在药物治疗的第5天至第7天出现，在药物治疗期间持续增加（P < 0.002），并在停药后第3天达到峰值（P < 0.008；未研究更长的时间）。非食欲驱动探索行为的发生与排尿/排便评分呈负相关（P < 0.003），因此很可能反映了氟马西尼的抗焦虑作用。在药物或赋形剂治疗期间，对照组和药物组的“工作记忆”错误数量相当（P = 0.17）。然而，停药并引入通道门（在探索一个通道后将动物限制在中央平台10秒）后，与前三次试验相比，接受药物处理的大鼠的工作记忆错误保持不变（P = 0.35），而对照组的表现受到干扰，错误数量增加（P < 0.004）。在药物治疗的第7天，探索行为的出现与皮质、海马体和脑干中苯二氮䓬受体密度和/或亲和力增加有关，而在停药三天后，当探索行为达到峰值时，皮质中GABA增强的[³H]氟硝西泮结合减少。
