Positive allosteric modulators (PAMs) of α5GABA_A receptors (α5GABAARs) are emerging as potential therapeutics for a range of neuropsychiatric disorders. However, their role in memory processing of healthy animals is not sufficiently examined. We tested the effects of MP-III-022 (1 mg/kg, 2.5 mg/kg and 10 mg/kg), a PAM known to be selective for α5GABAARs and devoid of prominent side-effects, in different behavioral paradigms (Morris water maze, novel object recognition test and social novelty discrimination) and on GABRA5 expression in Wistar rats, 30 min and 24 h after intraperitoneal treatment administration. The lowest dose tested worsened short-term object memory. The same dose, administered two times in a span of 24 h, improved spatial and impaired object and, at a trend level, social memory. The highest dose had a detrimental effect on all types of long-term memory (object memory at a trend level) and short-term spatial memory, but improved short-term object and social memory. Distinct sets of expression changes were detected in both prefrontal cortex and two regions of the hippocampus, but the latter ones could be assessed as more consequential. An increase of GABRA5 mRNA in CA2 occurred in parallel with improvement of object and social, but impairment of spatial memory, while the opposite happened with a trend level change in CA1. Our study demonstrates the variability of the roles of the α5GABAAR based on its level of expression and localization, in dependence on the type and protocol of cognitive tasks, as well as the respective timing of pharmacological modulation and testing.

α5GABA _A受体 (α5GABAARs) 的正变构调节剂 (PAMs) 正在成为一系列神经精神疾病的潜在治疗剂。然而，它们在健康动物的记忆处理中的作用尚未得到充分检验。我们测试了 MP-III-022（1 mg/kg、2.5 mg/kg 和 10 mg/kg）的效果，这是一种已知对 α5GABAAR 具有选择性且没有明显副作用的 PAM，在不同的行为范式中（Morris water迷宫，新物体识别测试和社会新奇辨别）和腹腔内治疗给药后 30 分钟和 24 小时 Wistar 大鼠中 GABRA5 的表达。测试的最低剂量恶化了短期对象记忆。相同剂量，在 24 小时内给药两次，改善了空间和受损对象，并在趋势水平上改善了社会记忆。最高剂量对所有类型的长期记忆（趋势水平的对象记忆）和短期空间记忆都有不利影响，但改善了短期对象和社会记忆。在前额叶皮层和大脑的两个区域都检测到不同的表达变化。海马体，但后者可以被评估为更重要。CA2 中 GABRA5 mRNA 的增加与对象和社会的改善同时发生，但空间记忆受损，而 CA1 的趋势水平变化则相反。我们的研究证明了 α5GABAAR 作用的可变性基于其表达和定位水平，取决于认知任务的类型和协议，以及药理调节和测试的相应时间。