Filarowska-Jurko Joanna, Grochecki Pawel, Gibuła-Tarlowska Ewa, Listos Joanna, Kedzierska Ewa, Socha Justyna, Smaga Irena, Slowik Tymoteusz, Filip Małgorzata, Kotlinska Jolanta H
Department of Pharmacology and Pharmacodynamics, Medical University of Lublin, Chodzki 4a, 20-093 Lublin, Poland.
Department of Drug Addiction Pharmacology, Maj Institute of Pharmacology Polish Academy of Sciences, Smetna 12, 31-343 Krakow, Poland.
Molecules. 2024 Dec 20;29(24):6017. doi: 10.3390/molecules29246017.
The N-methyl-D-aspartate (NMDA) glutamate receptor is a major target of ethanol, and it is implicated in learning and memory formation, and other cognitive functions. Glycine acts as a co-agonist for this receptor. We examined whether Org24598, a selective inhibitor of glycine transporter1 (GlyT1), affects ethanol withdrawal-induced deficits in recognition memory (Novel Object Recognition (NOR) task) and spatial memory (Barnes Maze (BM) task) in rats, and whether the NMDA receptor glycine site participates in this phenomenon. Male Wistar rats were habituated to NOR or BM tasks, and then received binge-like intragastric ethanol administration (5 days, 5 g/kg). After ethanol withdrawal, Org24598 (0.1, 0.3, and 0.6 mg/kg) was administered 30 min before NOR (day 10 of withdrawal) or the reversal learning phase of BM (day 11-13 of withdrawal) task. The expression of GluN1 and GluN2B subunits of NMDA receptors were measured in the perirhinal cortex (PRC) and hippocampus (HIP) after termination of NOR. In the BM task, a glycine antagonist, L-701,324 (5 mg/kg), was administered 30 min before Org24598 to confirm the involvement of the NMDA receptor glycine site in the effects of Org24598. Our study showed that binge-like ethanol administration induced recognition and spatial memory impairments after withdrawal in rats. Additionally, an up-regulation of GluN1 and GluN2B subunits of the NMDA receptor was observed in the HIP and PRC on day 11 of abstinence. Org24598 ameliorated memory loss and normalized the expression of these subunits. L-701,324 reversed the effect of Org24598. Thus, NMDA receptor glycine sites are important in ethanol withdrawal-induced memory impairments.
N-甲基-D-天冬氨酸（NMDA）谷氨酸受体是乙醇的主要作用靶点，它与学习、记忆形成及其他认知功能有关。甘氨酸作为该受体的协同激动剂。我们研究了甘氨酸转运体1（GlyT1）的选择性抑制剂Org24598是否会影响乙醇戒断诱导的大鼠认知记忆（新物体识别（NOR）任务）和空间记忆（巴恩斯迷宫（BM）任务）缺陷，以及NMDA受体甘氨酸位点是否参与这一现象。雄性Wistar大鼠先适应NOR或BM任务，然后接受类似暴饮的胃内乙醇给药（5天，5克/千克）。乙醇戒断后，在NOR（戒断第10天）或BM（戒断第11 - 13天）任务的逆向学习阶段前30分钟给予Org24598（0.1、0.3和0.6毫克/千克）。NOR任务结束后，在嗅周皮质（PRC）和海马体（HIP）中检测NMDA受体GluN1和GluN2B亚基的表达。在BM任务中，在给予Org24598前30分钟给予甘氨酸拮抗剂L-701,324（5毫克/千克），以确认NMDA受体甘氨酸位点参与Org24598的作用。我们的研究表明，类似暴饮的乙醇给药会导致大鼠戒断后出现认知和空间记忆障碍。此外，在戒断第11天，在HIP和PRC中观察到NMDA受体GluN1和GluN2B亚基上调。Org24598改善了记忆丧失并使这些亚基的表达恢复正常。L-701,324逆转了Org24598的作用。因此，NMDA受体甘氨酸位点在乙醇戒断诱导的记忆障碍中起重要作用。
