Pharmacological blockade of serotonin 5-HT₇ receptor reverses working memory deficits in rats by normalizing cortical glutamate neurotransmission.
Pharmacological blockade of serotonin 5-HT₇ receptor reverses working memory deficits in rats by normalizing cortical glutamate neurotransmission.
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DOI：
10.1371/journal.pone.0020210
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Galici R
中科院分区：
文献类型：
--
作者：
Bonaventure P;Aluisio L;Shoblock J;Boggs JD;Fraser IC;Lord B;Lovenberg TW;Galici R
5-HT 7受体的作用已在各种情绪障碍的动物模型中得到证实;然而，其在认知中的功能在很大程度上仍然是推测性的。本研究评估了选择性5-HT 7拮抗剂SB-269970在工作记忆缺陷翻译模型中的作用，并研究了它是否调节大鼠皮质谷氨酸和/或多巴胺神经传递。在单独或与MK-801（一种非竞争性NMDA受体拮抗剂）以及在单独实验中与东莨菪碱（一种非选择性毒蕈碱拮抗剂）联合的延迟非匹配位置任务中评价SB-269970的作用。SB-269970（10 mg/kg）显著逆转MK-801（0.1 mg/kg）诱导的缺陷，但增强东莨菪碱（0.06 mg/kg）诱导的缺陷。在自由活动大鼠的前额叶皮层中，使用生物传感器技术和微透析分别评价SB-269970调节MK-801诱导的谷氨酸和多巴胺细胞外水平的能力。SB-269970使前额叶皮层中MK-801诱导的谷氨酸而非多巴胺细胞外水平正常化。MK-801的大鼠血浆和脑浓度不受SB-269970联合给药的影响，这表明存在药效学机制而非药代动力学机制。这些结果表明，5-HT 7受体拮抗剂可能通过选择性地使多巴胺能神经传递正常化来逆转与NMDA受体功能低下相关的认知缺陷。
The role of 5-HT7 receptor has been demonstrated in various animal models of mood disorders; however its function in cognition remains largely speculative. This study evaluates the effects of SB-269970, a selective 5-HT7 antagonist, in a translational model of working memory deficit and investigates whether it modulates cortical glutamate and/or dopamine neurotransmission in rats. The effect of SB-269970 was evaluated in the delayed non-matching to position task alone or in combination with MK-801, a non-competitive NMDA receptor antagonist, and, in separate experiments, with scopolamine, a non-selective muscarinic antagonist. SB-269970 (10 mg/kg) significantly reversed the deficits induced by MK-801 (0.1 mg/kg) but augmented the deficit induced by scopolamine (0.06 mg/kg). The ability of SB-269970 to modulate MK-801-induced glutamate and dopamine extracellular levels was separately evaluated using biosensor technology and microdialysis in the prefrontal cortex of freely moving rats. SB-269970 normalized MK-801 -induced glutamate but not dopamine extracellular levels in the prefrontal cortex. Rat plasma and brain concentrations of MK-801 were not affected by co-administration of SB-269970, arguing for a pharmacodynamic rather than a pharmacokinetic mechanism. These results indicate that 5-HT7 receptor antagonists might reverse cognitive deficits associated with NMDA receptor hypofunction by selectively normalizing glutamatergic neurotransmission.
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影响因子：
13.5
作者：
Leopoldo, Marcello;Lacivita, Enza;Berardi, Francesco;Perrone, Roberto;Hedlund, Peter B.
通讯作者：
Hedlund, Peter B.
影响因子：
2.7
作者：
Gasbarri, Antonella;Cifariello, Agata;Meneses, Alfredo
通讯作者：
Meneses, Alfredo
影响因子：
5.3
作者：
Adams, B;Moghaddam, B
通讯作者：
Moghaddam, B
影响因子：
1.6
作者：
Galici, Ruggero;Boggs, Jamin D.;Atack, John R.
通讯作者：
Atack, John R.
影响因子：
3.4
作者：
Krystal, JH;D'Souza, DC;Hoffman, R
通讯作者：
Hoffman, R