Functional interaction of metabotropic glutamate receptor 5 and NMDA-receptor by a metabotropic glutamate receptor 5 positive allosteric modulator

被引：56
|
作者：
Rosenbrock, Holger [1 ]
Kramer, Gert [1 ]
Hobson, Scott [1 ]
Koros, Eliza [1 ]
Grundl, Marc [2 ]
Grauert, Matthias [2 ]
Reymann, Klaus G. [3 ]
Schroeder, Ulrich H. [3 ]
机构：
[1] Boehringer Ingelheim Pharma GmbH & Co KG, Dept CNS Dis Res, D-88397 Biberach, Germany
[2] Boehringer Ingelheim Pharma GmbH & Co KG, Dept Chem Res, D-88397 Biberach, Germany
[3] Leibniz Inst Neurobiol, D-30118 Magdeburg, Germany
来源：
EUROPEAN JOURNAL OF PHARMACOLOGY | 2010年 / 639卷 / 1-3期
关键词：
NMDA(N-methyl-D-aspartate)-receptor mGlu(5) receptor; Metabotropic glutamate receptor 5; Positive allosteric modulator; ADX-47273; Long-term potentiation; LONG-TERM DEPRESSION; HIPPOCAMPAL CA1 REGION; SYNAPTIC-TRANSMISSION; IN-VITRO; AREA CA1; MGLUR5; POTENTIATION; GLUTAMATE-RECEPTOR-5; ACTIVATION; SLICES;
D O I：
10.1016/j.ejphar.2010.02.057
中图分类号：
R9 [药学];
学科分类号：
1007 ;
摘要：
The NMDA (N-methyl-D-aspartate)-receptor is fundamentally involved in cognitive functions. Recent studies demonstrated a functional interaction between the metabotropic glutamate receptor 5 (mG1u5 receptor) and the NMDA-receptor in neurons. In rat hippocampal slices, it was shown that activation of mGlu(5) receptor by a positive modulator in the presence of a subthreshold agonist concentration potentiated NMDA-receptor mediated currents and phosphorylation of intracellular signalling proteins. In the present study, we investigated the functional interaction of mGlu(5) receptor and NMDA-receptor by the selective mGlu(5) receptor positive modulator ADX-47273 in-vitro and in-vivo. In rat primary neurons, this compound potentiated Ca(2+) mobilization in the presence of a subthreshold concentration of the mGluR(1/5) agonist DHPG (0.3 mu M) with an EC(50) of 0.28h0.05 pM. NMDA-induced Ca(2+)-mobilization in primary neurons could be potentiated when neurons were pre-stimulated with 1 mu M ADX-47273 in the presence of 0.3 mu M DHPG. The specific mGlu(5) receptor antagonist MPEP and the Src-family kinase inhibitor PP2 blocked this potentiation demonstrating the functional interaction of the NMDA-receptor and mGlu(5) receptor in neurons. Furthermore, ADX-47273 elicited an enhancement of NMDA-receptor dependent long-term potentiation in rat hippocampal slices that could be reversed by MPEP. After intraperitoneal administration to rats. ADX-47273 showed a dose-dependent reduction of NMDA-receptor antagonist (ketamine) induced hyperlocomotion, supporting the mechanistic interaction of the NMDA-receptor and mGlu(5) receptor in-vivo. In conclusion, these findings further support the idea of a functional interaction between the mGlu(5) receptor and NMDA-receptor, which may provide a pharmacological strategy for addressing CNS diseases with cognitive impairments linked to NMDA-receptor hypofunction. (C) 2010 Elsevier B.V. All rights reserved.
引用
收藏
页码：40 / 46
页数：7
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