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Simultaneous activation of mGlu2 and muscarinic receptors reverses MK-801-induced cognitive decline in rodents.
Neuropharmacology ( IF 4.6 ) Pub Date : 2019-11-27 , DOI: 10.1016/j.neuropharm.2019.107866
Paulina Cieślik 1 , Helena Domin 1 , Agnieszka Chocyk 2 , Piotr Gruca 2 , Ewa Litwa 2 , Agata Płoska 3 , Adrianna Radulska 3 , Iwona Pelikant-Małecka 3 , Piotr Brański 1 , Leszek Kalinowski 3 , Joanna M Wierońska 1
Affiliation  

The activity of an allosteric agonist of muscarinic M1 receptor, VU0357017, and a positive allosteric modulator (PAM) of M5 receptor, VU0238429, were investigated alone or in combination with the mGlu2 receptor PAM, LY487379 using the following behavioural tests: prepulse inhibition (PPI), novel object recognition (NOR), and spatial delayed alternation (SDA). VU0357017 (10 and 20 mg/kg) and VU0238429 (5 and 10 mg/kg) reversed deficits in PPI while VU0238429 (2.5 and 5 mg/kg) was effective in SDA. The simultaneous administration of subeffective doses of M1 or M5 activators (5, 1, or 0.25 mg/kg) with LY487379 (0.5 mg/kg) induced the same effect as that observed for the active dose of each compound. Selective M1 or M5 receptor blockers antagonized the effect exerted by these combinations, and pharmacokinetic studies confirmed independent transport through the blood-brain barrier. The expression of both receptors (M1 and M5) was established in brain structures involved in cognition (neocortex, hippocampus, and entorhinal cortex) in both the rat and the mouse brains by immunofluorescence staining. Specifically, double neuronal staining of mGlu2-M1 and mGlu2-M5 receptors was observed in many areas of the rat brain, while the number of double-stained mGlu2-M1 receptors was moderate in the mouse brain with no mGlu2-M5 colocalization. Finally, the combined administration of subeffective doses of the compounds did not alter prolactin levels or motor coordination, in contrast to the compounds given alone at the highest dose or in combination with standard neuroleptics.

中文翻译:

mGlu2和毒蕈碱受体的同时激活可以逆转MK-801诱导的啮齿动物的认知能力下降。

毒蕈碱M1受体变构激动剂VU0357017和M5受体正变构调节剂(PAM)VU0238429的活性通过以下行为测试单独研究,或与mGlu2受体PAM LY487379组合使用:脉冲抑制(PPI) ),新颖的物体识别(NOR)和空间延迟交替(SDA)。VU0357017(10和20 mg / kg)和VU0238429(5和10 mg / kg)逆转了PPI的不足,而VU0238429(2.5和5 mg / kg)在SDA中有效。亚有效剂量的M1或M5激活剂(5、1或0.25 mg / kg)与LY487379(0.5 mg / kg)的同时给药诱导的效果与每种化合物的有效剂量相同。选择性的M1或M5受体阻滞剂拮抗了这些组合所产生的作用,药代动力学研究证实了通过血脑屏障的独立转运。两种受体(M1和M5)的表达均通过免疫荧光染色在大鼠和小鼠的大脑中参与认知的大脑结构(新皮层,海马和内嗅皮层)中建立。具体来说,在大鼠大脑的许多区域都观察到了mGlu2-M1和mGlu2-M5受体的双神经元染色,而在小鼠大脑中,双重染色的mGlu2-M1受体的数量中等,没有mGlu2-M5的共定位。最后,与单独以最高剂量或与标准抗精神病药联合使用时相比,亚有效剂量化合物的联合给药不会改变催乳素水平或运动协调。两种受体(M1和M5)的表达均通过免疫荧光染色在大鼠和小鼠的大脑中参与认知的大脑结构(新皮层,海马和内嗅皮层)中建立。具体来说,在大鼠大脑的许多区域都观察到了mGlu2-M1和mGlu2-M5受体的双神经元染色,而在小鼠大脑中,双重染色的mGlu2-M1受体的数量中等,没有mGlu2-M5的共定位。最后,与单独以最高剂量或与标准抗精神病药联合使用时相比,亚有效剂量化合物的联合给药不会改变催乳素水平或运动协调。两种受体(M1和M5)的表达均通过免疫荧光染色在大鼠和小鼠的大脑中参与认知的大脑结构(新皮层,海马和内嗅皮层)中建立。具体来说,在大鼠大脑的许多区域都观察到了mGlu2-M1和mGlu2-M5受体的双神经元染色,而在小鼠大脑中,双重染色的mGlu2-M1受体的数量中等,没有mGlu2-M5的共定位。最后,与单独以最高剂量或与标准抗精神病药联合使用时相比,亚有效剂量化合物的联合给药不会改变催乳素水平或运动协调。和内嗅皮层)通过免疫荧光染色在大鼠和小鼠的大脑中进行。具体来说,在大鼠大脑的许多区域都观察到了mGlu2-M1和mGlu2-M5受体的双神经元染色,而在小鼠大脑中,双重染色的mGlu2-M1受体的数量中等,没有mGlu2-M5的共定位。最后,与以最高剂量单独给予或与标准抗精神病药联合给予的化合物相反,亚有效剂量化合物的联合给药未改变催乳素水平或运动协调。免疫荧光染色在大鼠和小鼠大脑中的内质网和内嗅皮层)。具体来说,在大鼠大脑的许多区域都观察到了mGlu2-M1和mGlu2-M5受体的双神经元染色,而在小鼠大脑中,双重染色的mGlu2-M1受体的数量中等,没有mGlu2-M5的共定位。最后,与以最高剂量单独给予或与标准抗精神病药联合给予的化合物相反,亚有效剂量化合物的联合给药未改变催乳素水平或运动协调。
更新日期:2019-11-27
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