Povroznik Jessica M, Rudy Carolyn C, Hunsberger Holly C, Tosto David E, Reed Miranda N
aBiomedical Sciences bBehavioral Neuroscience, Department of Psychology cCenter for Neuroscience dCenter for Basic and Translational Stroke Research, West Virginia University, Morgantown, West Virginia, USA.
Behav Pharmacol. 2014 Aug;25(4):331-5. doi: 10.1097/FBP.0000000000000053.
N-methyl-D-aspartate receptors (NMDARs) are essential for several kinds of synaptic plasticity and play a critical role in learning and memory. Deficits in NMDAR functioning may be partially responsible for the learning and memory deficits associated with aging and numerous diseases. Administration of MK-801, a noncompetitive NMDAR antagonist, is commonly used as a preclinical model of NMDAR dysfunction. The objective of this study was to assess the effects of α5GABAA receptor inhibition on learning deficits in the incremental repeated acquisition (IRA) task induced by acute MK-801 administration. The IRA task, commonly used to examine factors that affect learning, begins with a single response and increments to progressively longer chains throughout a single session as behavior meets preset criteria. MK-801 (0.03-0.5 mg/kg, intraperitoneally), administered 10 min pretesting, produced a significant dose-dependent decrease in measures of IRA performance at doses greater than or equal to 0.25 mg/kg. The MK-801-induced deficit was attenuated after treatment with an α5GABAA receptor inverse agonist, L-655,708 (1 mg/kg, intraperitoneally). The present study provides the focus for, and supports the feasibility of, further in-depth definitive studies examining α5GABAA receptor inhibition as a suitable candidate for the attenuation of NMDAR-related deficits.
N-甲基-D-天冬氨酸受体（NMDARs）对于多种突触可塑性至关重要，并且在学习和记忆中发挥关键作用。NMDAR功能缺陷可能部分导致与衰老及众多疾病相关的学习和记忆缺陷。给予非竞争性NMDAR拮抗剂MK-801通常被用作NMDAR功能障碍的临床前模型。本研究的目的是评估α5GABAA受体抑制对急性给予MK-801诱导的递增重复习得（IRA）任务中学习缺陷的影响。IRA任务常用于检查影响学习的因素，从单一反应开始，随着行为达到预设标准，在单个实验过程中逐渐增加到更长的反应链。在测试前10分钟腹腔注射MK-801（0.03 - 0.5毫克/千克），当剂量大于或等于0.25毫克/千克时，IRA表现的测量值出现显著的剂量依赖性下降。在用α5GABAA受体反向激动剂L-655,708（1毫克/千克，腹腔注射）治疗后，MK-801诱导的缺陷得到减轻。本研究为进一步深入的确定性研究提供了重点，并支持将α5GABAA受体抑制作为减轻NMDAR相关缺陷的合适候选方法的可行性。
