Short-term Memory Impairment after Isoflurane in Mice Is Prevented by the α5 γ-Aminobutyric Acid Type A Receptor Inverse Agonist L-655,708
Short-term Memory Impairment after Isoflurane in Mice Is Prevented by the α5 γ-Aminobutyric Acid Type A Receptor Inverse Agonist L-655,708
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DOI：
10.1097/aln.0b013e3181f56228
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发表时间：
2010-11-01
期刊：
影响因子：
8.8
通讯作者：
Orser, Beverley A.
中科院分区：
文献类型：
--
作者：
Saab, Bechara J.;MacLean, Ashley J. B.;Orser, Beverley A.
背景：记忆阻滞是麻醉状态的重要组成部分。然而，麻醉后记忆缺陷是一种不良反应，且对其了解甚少。已知含有抑制性α 5亚基的γ-氨基丁酸A亚型受体（α 5GABA（A））在记忆过程中起关键作用，并且对麻醉剂的正性调节高度敏感。我们推测，在异氟醚麻醉过程中抑制α 5 GABA（A）受体的活性可以预防麻醉后早期的记忆缺陷。方法：小鼠用L-655，708，α 5 GABA（A）受体选择性反向激动剂，或车辆预处理。然后将其暴露于异氟烷1 h（1.3%，或1个最小肺泡浓度，或空气-氧气对照）。然后，无论是1或24小时后，小鼠在恐惧相关的上下文和线索学习范式条件反射。此外，还研究了L-655，708对异氟烷固定剂量的影响。运动协调，镇静，焦虑，和异氟醚在大脑中的浓度在5分钟，1小时，和24小时后isofluranes.Results：运动和感觉功能恢复在几分钟内终止异氟醚给药。相比之下，背景恐惧记忆中的一个强大的赤字持续至少24小时。α 5GABA（A）受体反向激动剂L-655，708可完全预防记忆缺陷，而不改变异氟烷的固定剂量。微量浓度的异氟烷在大脑中测定后24 h treatment.Conclusions：记忆缺陷发生后很长一段时间的镇静，镇痛，抗焦虑作用的异氟烷消退。L-655，708可预防记忆缺陷，表明异氟烷与α 5GABA（A）受体的相互作用有助于麻醉后早期的记忆障碍。
Background: Memory blockade is an essential component of the anesthetic state. However, postanesthesia memory deficits represent an undesirable and poorly understood adverse effect. Inhibitory alpha 5 subunit-containing gamma-aminobutyric acid subtype A receptors (alpha 5GABA(A)) are known to play a critical role in memory processes and are highly sensitive to positive modulation by anesthetics. We postulated that inhibiting the activity of alpha 5GABA(A) receptors during isoflurane anesthesia would prevent memory deficits in the early postanesthesia period.Methods: Mice were pretreated with L-655,708, an alpha 5GABA(A) receptor selective inverse agonist, or vehicle. They were then exposed to isoflurane for 1 h (1.3%, or 1 minimum alveolar concentration, or air-oxygen control). Then, either 1 or 24 h later, mice were conditioned in fear-associated contextual and cued learning paradigms. In addition, the effect of L-655,708 on the immobilizing dose of isoflurane was studied. Motor coordination, sedation, anxiety, and the concentration of isoflurane in the brain at 5 min, 1 h, and 24 h after isoflurane were also examined.Results: Motor and sensory function recovered within minutes after termination of isoflurane administration. In contrast, a robust deficit in contextual fear memory persisted for at least 24 h. The alpha 5GABA(A) receptor inverse agonist, L-655,708, completely prevented memory deficits without changing the immobilizing dose of isoflurane. Trace concentrations of isoflurane were measured in the brain 24 h after treatment.Conclusions: Memory deficits occurred long after the sedative, analgesic, and anxiolytic effects of isoflurane subsided. L-655,708 prevented memory deficit, suggesting that an isoflurane interaction at alpha 5GABA(A) receptors contributes to memory impairment during the early postanesthesia period.