Institute of Neuroscience, School of Biomedical Sciences, Queen's Medical Centre, University of Nottingham Medical School, Nottingham, UK.
Psychopharmacology (Berl). 2011 Feb;213(2-3):413-30. doi: 10.1007/s00213-010-1854-3. Epub 2010 Apr 20.
In rats, 5-hydroxytryptamine(6) (5-HT(6)) receptor antagonists improve learning and memory, but the effects of agonists are poorly defined. This study investigated the effects of 5-HT(6) receptor agonists and antagonists on a rodent model of recognition memory.
Selective 5-HT(6) receptor agonists and antagonists were administered either alone, after a scopolamine-induced impairment, or combined with sub-effective doses of the acetylcholinesterase inhibitor, donepezil, or the glutamate NMDA receptor antagonist, memantine, in a novel object discrimination paradigm in adult rats.
After a 4-h inter-trial delay to induce natural forgetting, vehicle-treated rats spent an equivalent time exploring novel and familiar objects during the choice trial. The 5-HT(6) receptor agonists, E-6801 (1.25-10 mg/kg i.p.) and EMD-386088 (5-10 mg/kg i.p.), and antagonists, SB-271046 and Ro 04-6790 (5 and 10 mg/kg), along with donepezil (0.1-3 mg/kg) and memantine (5-20 mg/kg) all produced significant and mostly dose-dependent increases in novel object exploration, indicative of memory enhancement. Furthermore, sub-effective doses of E-6801 (1 mg/kg) when co-administered with either SB-271046 (3 mg/kg), donepezil (0.1 mg/kg) or memantine (5 mg/kg), and EMD-386088 (2 mg/kg) co-administered with SB-271046 (3 mg/kg) also significantly enhanced object-recognition memory. Additionally, using a 1-min inter-trial delay, E-6801 (2.5 and 5 mg/kg) was as effective as donepezil (0.3 and 1 mg/kg) in reversing a scopolamine-induced (0.5 mg/kg) impairment in object recognition.
This is the first study to demonstrate that E-6801, a potent 5-HT(6) receptor agonist, improves recognition memory by combined modulation of cholinergic and glutamatergic neurotransmission.
在大鼠中，5-羟色胺（6）（5-HT（6））受体拮抗剂可改善学习和记忆，但激动剂的作用尚不清楚。本研究旨在探讨 5-HT（6）受体激动剂和拮抗剂对识别记忆的啮齿动物模型的影响。
在成年大鼠的新物体识别范式中，单独给予选择性 5-HT（6）受体激动剂和拮抗剂，或在东莨菪碱诱导损伤后给予，或与乙酰胆碱酯酶抑制剂多奈哌齐（donepezil）或谷氨酸 NMDA 受体拮抗剂美金刚（memantine）的亚有效剂量联合给予。
在 4 小时的试验间隔延迟以诱导自然遗忘后，载体处理的大鼠在选择试验中花费相等的时间探索新的和熟悉的物体。5-HT（6）受体激动剂 E-6801（1.25-10mg/kg 腹腔注射）和 EMD-386088（5-10mg/kg 腹腔注射）以及拮抗剂 SB-271046 和 Ro 04-6790（5 和 10mg/kg）以及多奈哌齐（0.1-3mg/kg）和 memantine（5-20mg/kg）均显著且主要剂量依赖性地增加新物体探索，表明记忆增强。此外，亚有效剂量的 E-6801（1mg/kg）与 SB-271046（3mg/kg）、多奈哌齐（0.1mg/kg）或 memantine（5mg/kg）联合给予，以及 EMD-386088（2mg/kg）与 SB-271046（3mg/kg）联合给予也显著增强了物体识别记忆。此外，使用 1 分钟的试验间隔延迟，E-6801（2.5 和 5mg/kg）与多奈哌齐（0.3 和 1mg/kg）一样有效，可逆转东莨菪碱（0.5mg/kg）诱导的物体识别损伤。
这是第一项研究表明，5-HT（6）受体激动剂 E-6801 通过联合调节胆碱能和谷氨酸能神经传递来改善识别记忆。
