Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, 88040-900, Brazil.
Neuroscience. 2011 Apr 14;179:179-87. doi: 10.1016/j.neuroscience.2011.01.057. Epub 2011 Feb 1.
Tolerance to the anxiolytic-like effect of drugs may develop because of a memory derived from prior experience in certain apparatuses such as the elevated plus-maze (EPM). Activity in basolateral amygdala was shown to be required for consolidating this knowledge. The dorsal hippocampus (DH) is also implicated in long-term memory consolidation, a process relying on new protein synthesis. It is unknown, however, whether the DH protein synthesis disruption would prevent the phenomenon rendering animals unresponsive to benzodiazepines in the EPM retest. To address this, we bilaterally infused the protein synthesis inhibitor anisomycin (ANI) into the rat DH 0, 3 or 6 h after, or 15 min before, the EPM test. DH infusion of ANI (80 μg) around the time of EPM testing preserved the anxiolysis of the midazolam (MDZ; 0.5 mg/kg, i.p.) in rats retested in the EPM 24 h later, suggesting that information consolidated by DH protein synthesis impacts on the subsequent animal's responsiveness to this drug. To examine whether impaired memory acquisition could also contribute to the prevention of MDZ tolerance seen in EPM-experienced animals infused with ANI before testing, the EPM retest was performed 3 h after testing to coincide with the temporal window in which short-term memory remains, for the reason that this process does not require protein synthesis for its formation. The pretest DH anisomycin infusion's ability to prevent the MDZ tolerance on retesting was now missing. This result confirms a specific action of the ANI on memory consolidation. We also found that rats express further avoidance to open-arms in the EPM retest. However, neither pretest nor posttest DH ANI infusion interfered with this pattern of results exhibited by EPM-experienced rats.
对药物抗焦虑样作用的耐受性可能会产生，因为在某些设备（如高架十字迷宫（EPM））中存在来自先前经验的记忆。已表明外侧杏仁核的活动对于巩固这种知识是必需的。背侧海马（DH）也与长期记忆巩固有关，这一过程依赖于新的蛋白质合成。然而，尚不清楚 DH 蛋白质合成的破坏是否会阻止这种现象，从而使动物在 EPM 再测试中对苯二氮䓬类药物无反应。为了解决这个问题，我们在 EPM 测试后 0、3 或 6 小时或 15 分钟前，将蛋白质合成抑制剂放线菌酮（ANI）双侧注入大鼠 DH。DH 内的 ANI 输注（80 μg）在 EPM 测试时间周围，保留了在 24 小时后在 EPM 中重新测试的咪达唑仑（MDZ；0.5 mg/kg，ip）的抗焦虑作用，这表明由 DH 蛋白质合成巩固的信息影响随后动物对这种药物的反应性。为了研究在测试前用 ANI 预处理的 EPM 经验动物中，受损的记忆获取是否也会导致 MDZ 耐受性的预防，EPM 再测试在测试后 3 小时进行，与短期记忆保持的时间窗口相吻合，因为这个过程不需要蛋白质合成来形成记忆。现在，预测试 DH anisomycin 输注在重新测试时预防 MDZ 耐受的能力已经消失。这一结果证实了 ANI 对记忆巩固的特定作用。我们还发现，大鼠在 EPM 再测试中对开放臂表现出进一步的回避。然而，无论是预测试还是后测试 DH ANI 输注都不会干扰 EPM 经验大鼠所表现出的这种结果模式。
