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Comparative Pro-cognitive and Neurochemical Profiles of Glycine Modulatory Site Agonists and Glycine Reuptake Inhibitors in the Rat: Potential Relevance to Cognitive Dysfunction and Its Management.
Molecular Neurobiology ( IF 5.1 ) Pub Date : 2020-01-20 , DOI: 10.1007/s12035-020-01875-9
Kevin C F Fone 1 , David J G Watson 1 , Rodolphe I Billiras 2 , Dorothee I Sicard 2 , Anne Dekeyne 2 , Jean-Michel Rivet 2 , Alain Gobert 2 , Mark J Millan 2
Affiliation  

Frontocortical NMDA receptors are pivotal in regulating cognition and mood, are hypofunctional in schizophrenia, and may contribute to autistic spectrum disorders. Despite extensive interest in agents potentiating activity at the co-agonist glycine modulatory site, few comparative functional studies exist. This study systematically compared the actions of the glycine reuptake inhibitors, sarcosine (40-200 mg/kg) and ORG24598 (0.63-5 mg/kg), the agonists, glycine (40-800 mg/kg), and D-serine (10-160 mg/kg) and the partial agonists, S18841 (2.5 mg/kg s.c.) and D-cycloserine (2.5-40 mg/kg) that all dose-dependently prevented scopolamine disruption of social recognition in adult rats. Over similar dose ranges, they also prevented a delay-induced impairment of novel object recognition (NOR). Glycine reuptake inhibitors specifically elevated glycine but not D-serine levels in rat prefrontal cortical (PFC) microdialysates, while glycine and D-serine markedly increased levels of glycine and D-serine, respectively. D-Cycloserine slightly elevated D-serine levels. Conversely, S18841 exerted no influence on glycine, D-serine, other amino acids, monamines, or acetylcholine. Reversal of NOR deficits by systemic S18841 was prevented by the NMDA receptor antagonist, CPP (20 mg/kg), and the glycine modulatory site antagonist, L701,324 (10 mg/kg). S18841 blocked deficits in NOR following microinjection into the PFC (2.5-10 μg/side) but not the striatum. Finally, in rats socially isolated from weaning (a neurodevelopmental model of schizophrenia), S18841 (2.5 and 10 mg/kg s.c.) reversed impairment of NOR and contextual fear-motivated learning without altering isolation-induced hyperactivity. In conclusion, despite contrasting neurochemical profiles, partial glycine site agonists and glycine reuptake inhibitors exhibit comparable pro-cognitive effects in rats of potential relevance to treatment of schizophrenia and other brain disorders where cognitive performance is impaired.

中文翻译:

大鼠中甘氨酸调节位点激动剂和甘氨酸再摄取抑制剂的比较促认知和神经化学特征:与认知功能障碍及其管理的潜在相关性。

额皮质 NMDA 受体在调节认知和情绪方面起关键作用,在精神分裂症中功能低下,并可能导致自闭症谱系障碍。尽管对在共激动剂甘氨酸调节位点增强活性的药物有广泛的兴趣,但很少有比较功能研究存在。本研究系统地比较了甘氨酸再摄取抑制剂肌氨酸 (40-200 mg/kg) 和 ORG24598 (0.63-5 mg/kg)、激动剂甘氨酸 (40-800 mg/kg) 和 D-丝氨酸的作用。 10-160 mg/kg) 和部分激动剂 S18841 (2.5 mg/kg sc) 和 D-环丝氨酸 (2.5-40 mg/kg) 均剂量依赖性地阻止东莨菪碱破坏成年大鼠的社会识别。在相似的剂量范围内,它们还防止了延迟引起的新物体识别 (NOR) 损伤。甘氨酸再摄取抑制剂特异性升高大鼠前额叶皮层 (PFC) 微透析液中的甘氨酸水平,而不是 D-丝氨酸水平,而甘氨酸和 D-丝氨酸分别显着增加甘氨酸和 D-丝氨酸的水平。D-环丝氨酸略微升高 D-丝氨酸水平。相反,S18841 对甘氨酸、D-丝氨酸、其他氨基酸、单胺或乙酰胆碱没有影响。NMDA 受体拮抗剂 CPP (20 mg/kg) 和甘氨酸调节位点拮抗剂 L701,324 (10 mg/kg) 可防止全身性 S18841 逆转 NOR 缺陷。S18841 在显微注射到 PFC(2.5-10 μg/侧)后阻止 NOR 的缺陷,但不阻止纹状体。最后,在断奶后社会隔离的大鼠(精神分裂症的神经发育模型)中,S18841(2.5 和 10 mg/kg sc ) 在不改变孤立引起的多动症的情况下逆转 NOR 和情境恐惧动机学习的损害。总之,尽管神经化学特征不同,部分甘氨酸位点激动剂和甘氨酸再摄取抑制剂在与治疗精神分裂症和其他认知能力受损的脑部疾病可能相关的大鼠中表现出相当的促认知作用。
更新日期:2020-04-22
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