Belozertseva I V, Kos T, Popik P, Danysz W, Bespalov A Y
Institute of Pharmacology, Pavlov Medical University, St Petersburg, Russia.
Eur Neuropsychopharmacol. 2007 Feb;17(3):172-9. doi: 10.1016/j.euroneuro.2006.03.002. Epub 2006 Apr 21.
Drugs that act to reduce glutamatergic neurotransmission such as NMDA receptor antagonists exert antidepressant-like effects in a variety of experimental paradigms, but their therapeutic application is limited by undesired side effects. In contrast, agents that reduce glutamatergic tone by blocking type I metabotropic glutamate receptors have been suggested to have more a favorable side-effect profile. The present study aimed to compare the effects of mGluR1 antagonist (EMQMCM; JNJ16567083, 3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanone methanesulfonate, 0.156-10 mg/kg) and mGluR5 antagonist (MTEP, [(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine, 1.25-10 mg/kg) in two behavioral screening assays commonly used to assess antidepressant-like activity. In the modified forced swim test in rats, imipramine (used as a positive control) decreased immobility (MED 40 mg/kg) and increased the duration of escape-oriented (climbing and diving; MED 20 mg/kg) behaviors. Both EMQMCM and MTEP decreased the floating duration (MED 1.25 and 2.5 mg/kg) and increased the duration of mobile behaviors (paddling and swimming; MED 2.5 and 5 mg/kg). EMQMCM but not MTEP increased the duration of escape behaviors (climbing and diving; MED 1.25 mg/kg). In the mouse tail suspension test, EMQMCM (5 but not 2.5, 10 and 25 mg/kg), 2-methyl-6-(phenylethynyl)-pyridine (MPEP, 10 but not 1 mg/kg) and MTEP (MED 25 mg/kg) decreased immobility scores. For EMQMCM, the dose-effect relationship was biphasic. With the exception of EMQMCM (10 mg/kg), locomotor activity in mice was not affected by treatments. The present study therefore suggests that acute blockade of mGluR5 and also of mGluR1 exerts antidepressant-like effects in behavioral despair tests in rats and mice.
作用于减少谷氨酸能神经传递的药物，如NMDA受体拮抗剂，在多种实验范式中发挥出类抗抑郁作用，但其治疗应用受到不良副作用的限制。相比之下，通过阻断I型代谢型谷氨酸受体来降低谷氨酸能张力的药物被认为具有更有利的副作用谱。本研究旨在比较mGluR1拮抗剂（EMQMCM；JNJ16567083，3-乙基-2-甲基喹啉-6-基）-（4-甲氧基环己基）-甲酮甲磺酸盐，0.156 - 10 mg/kg）和mGluR5拮抗剂（MTEP，[(2-甲基-1,3-噻唑-4-基)乙炔基]吡啶，1.25 - 10 mg/kg）在两种常用于评估类抗抑郁活性的行为筛选试验中的效果。在大鼠改良强迫游泳试验中，丙咪嗪（用作阳性对照）减少不动时间（半数有效剂量40 mg/kg）并增加逃避导向行为（攀爬和潜水；半数有效剂量20 mg/kg）的持续时间。EMQMCM和MTEP均减少漂浮持续时间（半数有效剂量1.25和2.5 mg/kg）并增加活动行为（划水和游泳；半数有效剂量2.5和5 mg/kg）的持续时间。EMQMCM而非MTEP增加逃避行为（攀爬和潜水；半数有效剂量1.25 mg/kg）的持续时间。在小鼠悬尾试验中，EMQMCM（5 mg/kg，但2.5、10和25 mg/kg无效）、2-甲基-6-（苯乙炔基）吡啶（MPEP，10 mg/kg，但1 mg/kg无效）和MTEP（半数有效剂量25 mg/kg）降低不动评分。对于EMQMCM，剂量-效应关系呈双相性。除EMQMCM（10 mg/kg）外，小鼠的运动活动不受治疗影响。因此，本研究表明，急性阻断mGluR5以及mGluR1在大鼠和小鼠的行为绝望试验中发挥出类抗抑郁作用。
