mGluR5参与小鼠睡眠剥夺快速抗抑郁作用的机制研究
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摘要
目的:探讨代谢型谷氨酸受体5(mGluR5)在睡眠剥夺抗抑郁作用中的机制。方法:采用坐骨神经分支选择损伤(SNI)方法制备神经病理性痛小鼠伴发负性情绪的动物模型,利用旷场和高架十字实验评估小鼠的焦虑样行为,利用悬尾实验和糖水偏好实验评估小鼠的抑郁样行为,利用von-Frey方法检测小鼠的机械痛敏行为;采用温和处理的方法对有抑郁样行为小鼠进行睡眠剥夺,并评估睡眠剥夺对小鼠焦虑、抑郁样行为的影响;采用Western Blot方法检测SNI模型及睡眠剥夺后小鼠内侧前额叶皮层(mPFC)内mGluR5表达量的变化;进一步对小清蛋白(PV)阳性神经元mGluR5敲除的小鼠进行睡眠剥夺前后的行为学检测。结果:SNI模型小鼠40 d后出现焦虑样行为,60 d左右出现抑郁样行为,睡眠剥夺可明显缓解其抑郁样行为,但是对焦虑样行为和机械痛敏无影响;抑郁情绪及睡眠剥夺对mPFC内mGluR5表达水平无影响,但PV~+神经元mGluR5敲除的小鼠表现出抑郁样行为,且睡眠剥夺对其抑郁样行为无缓解作用。结论:睡眠剥夺可以明显缓解神经病理性痛伴发的抑郁样行为,PV~+神经元的mGluR5在抑郁样行为的发生和睡眠剥夺的抗抑郁效果中可能发挥着重要的作用。
Objective: To investigate the mechanism for metabolic glutamate receptor 5(mGluR5) in the rapid antidepressant effect of sleep deprivation. Methods: Animal model of neuropathic pain accompanying negative emotion was established by spared nerve injury(SNI). Anxiety-like behaviors were assessed by open field test and elevated plus maze. Depression-like behaviors were evaluated by tail suspension test and sucrose preference test. Mechanical allodynia was measured by quantifying the withdraw threshold of the hindpaw in response to Von-Frey filaments. We utilized gentle stimulus to perform sleep deprivation on depression-like mice and assessed the effects of sleep deprivation on anxiety and depression-like behaviors. The effects of SNI and sleep deprivation on the expression of mGluR5 in medial prefrontal cortex(m PFC) of mice were measured by Western Blot method. Furthermore,the behavioral changes of PVmGluR5 KO mice were detected before and after sleep deprivation. Results: Mice developed anxiety-like behaviors on40 days and depression-like behaviors on 60 days after the induction of SNI. Sleep deprivation significantly alleviated depression-like behaviors but not anxiety-like behaviors and mechanical allodynia. Depressive state and sleep deprivation had no effect on the expression of mGluR5 in m PFC. However,PV-mGluR5 KO mice showed depression-like behaviors,and sleep deprivation had no alleviatory effect on depression-like behaviors. Conclusion: Sleep deprivation significantly alleviates depressive-like behavior associated with neuropathic pain. Moreover,mGluR5 in PV+interneurons may play an important role in the occurrence of depressive-like behaviors and the antidepressant effect of sleep deprivation.
Objective: To investigate the mechanism for metabolic glutamate receptor 5(mGluR5) in the rapid antidepressant effect of sleep deprivation. Methods: Animal model of neuropathic pain accompanying negative emotion was established by spared nerve injury(SNI). Anxiety-like behaviors were assessed by open field test and elevated plus maze. Depression-like behaviors were evaluated by tail suspension test and sucrose preference test. Mechanical allodynia was measured by quantifying the withdraw threshold of the hindpaw in response to Von-Frey filaments. We utilized gentle stimulus to perform sleep deprivation on depression-like mice and assessed the effects of sleep deprivation on anxiety and depression-like behaviors. The effects of SNI and sleep deprivation on the expression of mGluR5 in medial prefrontal cortex(m PFC) of mice were measured by Western Blot method. Furthermore,the behavioral changes of PVmGluR5 KO mice were detected before and after sleep deprivation. Results: Mice developed anxiety-like behaviors on40 days and depression-like behaviors on 60 days after the induction of SNI. Sleep deprivation significantly alleviated depression-like behaviors but not anxiety-like behaviors and mechanical allodynia. Depressive state and sleep deprivation had no effect on the expression of mGluR5 in m PFC. However,PV-mGluR5 KO mice showed depression-like behaviors,and sleep deprivation had no alleviatory effect on depression-like behaviors. Conclusion: Sleep deprivation significantly alleviates depressive-like behavior associated with neuropathic pain. Moreover,mGluR5 in PV+interneurons may play an important role in the occurrence of depressive-like behaviors and the antidepressant effect of sleep deprivation.
引文
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[2]Peng GJ,Tian JS,Gao XX,et al.Research on the pathological mechanism and drug treatment mechanism of depression[J].Curr Neuropharmacol,2015,13(4):514-523.DOI:10.2174/1570159X1304150831120428.
[3]Palucha-Poniewiera A,Wieronska JM,Branski P,et al.Is the m Glu5 receptor a possible target for new antidepressant drugs?[J].Pharmacol Rep,2013,65(6):1506-1511.DOI:10.1016/S1734-1140(13)71511-1.
[4]Schulte W.Kombinierte psycho-und pharmakotherapie bei melancholikern[J].Oncology,1966:150-169.
[5]Boland EM,Rao H,Dinges DF,et al.Meta-analysis of the antidepressant effects of acute sleep deprivation[J].J Clin Psychiatry,2017,78(8):e1020-e1034.DOI:10.4088/JCP.16r11332.
[6]Abdallah CG,Sanacora G,Duman RS,et al.Ketamine and rapidacting antidepressants:a window into a new neurobiology for mood disorder therapeutics[J].Annu Rev Med,2015,66:509-523.DOI:10.1146/annurev-med-053013-062946.
[7]Deschwanden A,Karolewicz B,Feyissa AM,et al.Reduced metabotropic glutamate receptor 5 density in major depression determined by[(11)C]ABP688 PET and postmortem study[J].Am JPsychiatry,2011,168(7):727-734.DOI:10.1176/appi.ajp.2011.09111607.
[8]Lee KW,Westin L,Kim J,et al.Alteration by p11 of m GluR5 localization regulates depression-like behaviors[J].Mol Psychiatry,2015,20(12):1546-1556.DOI:10.1038/mp.2015.132.
[9]Smialowska M,Szewczyk B,Branski P,et al.Effect of chronic imipramine or electroconvulsive shock on the expression of m Glu R1a and m GluR5a immunoreactivity in rat brain hippocampus[J].Neuropharmacology,2002,42(8):1016-1023.DOI:org/10.1016/S0028-3908(02)00062-X.
[10]Hefti K,Holst SC,Sovago J,et al.Increased metabotropic glutamate receptor subtype 5 availability in human brain after one night without sleep[J].Biol Psychiatry,2013,73(2):161-168.DOI:10.1016/j.biopsych.2012.07.030.
[11]Tao LY,Huang MY,Saroj-Thapa,et al.Effects of macrophage migration inhibitory factor on cardiac reperfusion injury in mice with depression induced by constant-darkness[J].J Affect Disord,2018,229:403-409.DOI:10.1016/j.jad.2017.12.039.
[12]Marin O.Interneuron dysfunction in psychiatric disorders[J].Nat Rev Neurosci,2012,13(2):107-120.DOI:10.1038/nrn3155.
[13]Rudy B,Fishell G,Lee S,et al.Three groups of interneurons account for nearly 100%of neocortical GABAergic neurons[J].Dev Neurobiol,2011,71(1):45-61.DOI:10.1002/dneu.20853.
[14]Barnes SA,Pinto-Duarte A,Kappe A,et al.Disruption of m GluR5in parvalbumin-positive interneurons induces core features of neurodevelopmental disorders[J].Mol Psychiatry,2015,20(10):1161-1172.DOI:10.1038/mp.2015.113.
[15]Esterlis I,Della Gioia N,Pietrzak RH,et al.Ketamine-induced reduction in m Glu R5 availability is associated with an antidepressant response:an[(11)C]ABP688 and PET imaging study in depression[J].Mol Psychiatry,2018,23(4):824-832.DOI:10.1038/mp.2017.58.
[16]Shin S,Kwon O,Kang JI,et al.m Glu R5 in the nucleus accumbens is critical for promoting resilience to chronic stress[J].Nat Neurosci,2015,18(7):1017-1024.DOI:10.1038/nn.4028.
[17]Ametamey SM,Kessler LJ,Honer M,et al.Radiosynthesis and preclinical evaluation of 11C-ABP688 as a probe for imaging the metabotropic glutamate receptor subtype 5[J].J Nucl Med,2006,47(4):698-705.
[18]Patel S,Hamill TG,Connolly B,et al.Species differences in m GluR5 binding sites in mammalian central nervous system determined using in vitro binding with[18F]F-PEB[J].Nucl Med Biol,2007,34(8):1009-1017.DOI:10.1016/j.nucmedbio.2007.07.009.
[19]Esterlis I,Holmes SE,Sharma P,et al.Metabotropic glutamatergic receptor 5 and stress disorders:knowledge gained from receptor imaging studies[J].Biol Psychiatry,2018,84(2):95-105.DOI:10.1016/j.biopsych.2017.08.025.