药学学报, 2018, 53(10): 1583-1590
引用本文:
于子茹, 杜冠华. 乙酰胆碱α4β2型受体与抑郁症[J]. 药学学报, 2018, 53(10): 1583-1590.
YU Zi-ru, DU Guan-hua. The research advance on the α4β2 acetylcholine receptor and depression[J]. Acta Pharmaceutica Sinica, 2018, 53(10): 1583-1590.

乙酰胆碱α4β2型受体与抑郁症
于子茹, 杜冠华
中国医学科学院、北京协和医学院药物研究所, 北京 100050
摘要:
抑郁症作为情感性神经疾病是目前世界上最易致残的疾病之一,且有着很高的自杀率。目前临床应用的一线药物选择性5-HT再摄取抑制剂一直具有极大的局限性。抑郁症发病机制复杂,胆碱能假说近年来受到了关注。已有大量临床及临床前研究表明,烟碱型乙酰胆碱受体的拮抗剂和部分激动剂对于抗抑郁治疗具有显著作用,可以改善患者海马功能、影响腹侧中脑和腹侧被盖区奖赏与焦虑系统并调节杏仁核应激系统,从而达到改善情绪、缓解抑郁症的作用。目前围绕着胆碱能系统与抑郁症的关系仍在进行着大量研究,该文对胆碱受体α4β2亚型与抑郁症的关系及其机制进行了综述,供抗抑郁新药研发人员参考。
关键词:    α4β2烟碱型乙酰胆碱受体      胆碱能假说      抑郁症      情感障碍     
The research advance on the α4β2 acetylcholine receptor and depression
YU Zi-ru, DU Guan-hua
Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
Abstract:
Depression is currently the most popular disease in the world with a high suicide rate. Selective 5-HT reuptake inhibitors have been used as first-line drugs in clinics, but the therapeutic effect is greatly limited. The pathogenesis of depression is complicated, meanwhile the cholinergic hypothesis has received more and more attention. A large number of clinical and preclinical studies have shown that antagonists and partial agonists acting on nicotinic acetylcholine receptors have a significant effect on antidepressant therapy, which can improve the hippocampus recognizes, influence rewards and anxiety systems controlled by the ventral midbrain and ventral tegmental area, and regulate the amygdala pressure system, thereby improving mood and relieving depression. At present, the relationship between the cholinergic system and depression is still undergoing a lot of research. In this article, the relationship between α4β2 nicotinic acetylcholine receptor (nAChRs) and depression is reviewed to provide a reference for study of new anti-depression drugs.
Key words:    α4β2 nicotinic acetylcholine receptor    cholinergic hypothesis    depression    affective disorder   
收稿日期: 2018-04-10
DOI: 10.16438/j.0513-4870.2018-0322
基金项目: 国家自然科学基金资助项目(81603100);国家重点研发计划资助项目(2016YFC1000905);中国医学科学院医学与健康科技创新工程(2017-I2M-1-010).
通讯作者: 杜冠华,Tel:86-10-63165184,E-mail:dugh@imm.ac.cn
Email: dugh@imm.ac.cn
相关功能
PDF(285KB) Free
打印本文
0
作者相关文章
于子茹  在本刊中的所有文章
杜冠华  在本刊中的所有文章

参考文献:
[1] GBD 2015 DALYs and HALE Collaborators. Global, regional, and national disability-adjusted life-years (DALYs) for 315 diseases and injuries and healthy life expectancy (HALE), 1990-2015:a systematic analysis for the Global Burden of Disease Study 2015[J]. Lancet, 2017, 388:1603-1658.
[2] Kessler RC, Berglund P, Demler O, et al. The epidemiology of major depressive disorder:results from the national comorbidity survey replication (NCS-R)[J]. JAMA, 2003, 289:3095-3105.
[3] Liu XQ, Bai ZJ. A meta-analysis of risk factors for suicide in patients with major depression disorder[J]. Chin J Clin Psychol (中国临床心理学杂志), 2014, 22:291-294.
[4] Guo JM, Zeng KB. Risk factors for suicidal behaviors in Chinese population with depression:a meta analysis[J]. J Chongqing Med Univ (重庆医科大学学报), 2013, 38:1495-1499.
[5] Khan H, Amin S, Patel S. Targeting BDNF modulation by plant glycosides as a novel therapeutic strategy in the treatment of depression[J]. Life Sci, 2018, 196:18-27.
[6] Janowsky DS, El-Yousef MK, Davis JM, et al. A cholinergic-adrenergic hypothesis of mania and depression[J]. Lancet, 1972, 2:632-635.
[7] Shytle RD, Silver AA, Lukas RJ, et al. Nicotinic acetylcholine receptors as targets for antidepressants[J]. Mol Psychiatry, 2002, 7:525-535.
[8] Unwin N. Acetylcholine receptor channel imaged in the open state[J]. Nature, 1995, 373:37-43.
[9] Wang X, Wang YH, Liu X, et al. Construction of the brain-targeting drug carrier through imprinting of nicotinic acetylcholine receptor α7[J]. Acta Pharm Sin (药学学报), 2017, 52:488-493.
[10] Tummala R, Desai D, Szamosi J, et al. Safety and tolerability of dexmecamylamine (TC-5214) adjunct to ongoing antidepressant therapy in patients with major depressive disorder and an inadequate response to antidepressant therapy:results of a long-term study[J]. J Clin Psychopharmacol, 2015, 35:77-81.
[11] Schnoll RA, Leone FT, Hitsman B. Symptoms of depression and smoking behaviors following treatment with transdermal nicotine patch[J]. J Addict Dis, 2013, 32:46-52.
[12] Rejasgutiérrez J, Bruguera E, Cedillo S. Modelling a budgetary impact analysis for funding drug-based smoking cessation therapies for patients with major depressive disorder in Spain[J]. Eur Psychiatry, 2017, 45:41-49.
[13] Rohsenow DJ, Tidey JW, Martin RA, et al. Varenicline versus nicotine patch with brief advice for smokers with substance use disorders with or without depression:effects on smoking, substance use and depressive symptoms[J]. Addiction, 2017, 112:1808-1820.
[14] Hannestad JO, Cosgrove KP, Dellagioia NF, et al. Changes in the cholinergic system between bipolar depression and euthymia as measured with[123I]5IA single photon emission computed tomography[J]. Biol Psychiatry, 2013, 74:768-776.
[15] Saricicek A, Esterlis I, Maloney KH, et al. Persistent β2*-nicotinic acetylcholinergic receptor dysfunction in major depressive disorder[J]. Am J Psychiatry, 2012, 169:851-859.
[16] Mineur YS, Obayemi A, Wigestrand MB, et al. Cholinergic signaling in the hippocampus regulates social stress resilience and anxiety-and depression-like behavior[J]. Proc Nat Acad Sci U S A, 2013, 110:3573-3578.
[17] Ma HY. Progress in clinical application of new antidepressants[J]. Pract J Med Pharm (实用医药杂志), 2013, 30:940-944.
[18] Psychiatrists RCO. Smoking and mental health[J]. Revista Medica De Chile, 2013, 131:873-880.
[19] Smith PH, Mazure CM, Mckee SA. Smoking and mental illness in the U.S. population[J]. Tob Control, 2014, 23:e147-e153.
[20] Esterlis I, Ranganathan M, Bois F, et al. In vivo evidence for β2 nicotinic acetylcholine receptor subunit upregulation in smokers as compared with nonsmokers with schizophrenia[J]. Biol Psychiatry, 2014, 76:495-502.
[21] Magara S, Holst S, Lundberg S, et al. Altered explorative strategies and reactive coping style in the FSL rat model of depression[J]. Front Behav Neurosci, 2015, 9:89.
[22] Owope TE, Ishola IO, Akinleye MO, et al. Antidepressant effect of Cnestis ferruginea Vahl ex DC (Connaraceae):involvement of cholinergic, monoaminergic and L-arginine-nitric oxide pathways[J]. Drug Res, 2016, 66:235-245.
[23] Chen L, Liu H, Chen JL, et al. Anti-depressive mechanism of Fufang Chaigui prescription based on neuroendocrine hormone and metabolomic correlation analysis[J]. China J Chin Mater Med (中国中药杂志), 2015, 40:4080-4087.
[24] Tidey JW, Pacek LR, Koopmeiners JS, et al. Effects of 6-week use of reduced-nicotine content cigarettes in smokers with and without elevated depressive symptoms[J]. Nicotine Toba Res, 2017, 19:59-67.
[25] Aboul-Fotouh. Behavioral effects of nicotinic antagonist mecamylamine in a rat model of depression:prefrontal cortex level of BDNF protein and monoaminergic neurotransmitters[J]. Psychopharmacology (Berl), 2015, 232:1095-1105.
[26] Cinciripini PM, Karam-Hage M. Study suggests varenicline safe and effective among adults with stable depression[J]. Evid Based Med, 2014, 19:92.
[27] Rabenstein RL, Caldarone BJ, Picciotto MR. The nicotinic antagonist mecamylamine has antidepressant-like effects in wild-type but not β2-or α7-nicotinic acetylcholine receptor subunit knockout mice[J]. Psychopharmacology, 2006, 189:395-401.
[28] Mineur YS, Somenzi O, Picciotto MR. Cytisine, a partial agonist of high-affinity nicotinic acetylcholine receptors, has antidepressant-like properties in male C57BL/6J mice[J]. Neuropharmacology, 2007, 52:1256-1262.
[29] Picciotto MR, Caldarone BJ, Brunzell DH, et al. Neuronal nicotinic acetylcholine receptor subunit knockout mice:physiological and behavioral phenotypes and possible clinical implications[J]. Pharmacol Ther, 2001, 92:89-108.
[30] Klink R, de Kerchove d'Exaerde A, Zoli M, et al. Molecular and physiological diversity of nicotinic acetylcholine receptors in the midbrain dopaminergic nuclei[J]. J Neurosci, 2001, 21:1452-1463.
[31] Marubio LM, del Mar Arroyo-Jimenez M, Cordero-Erausquin M, et al. Reduced antinociception in mice lacking neuronal nicotinic receptor subunits[J]. Nature, 1999, 398:805-810.
[32] Picciotto MR, Higley MJ, Mineur YS. Acetylcholine as a neuromodulator:cholinergic signaling shapes nervous system function and behavior[J]. Neuron, 2012, 76:116-129.
[33] Ren J, Qin C, Hu F, et al. Habenula "cholinergic" neurons corelease glutamate and acetylcholine and activate postsynaptic neurons via distinct transmission modes[J]. Neuron, 2011, 69:445-452.
[34] Nirogi R, Goura V, Abraham R, et al. α4β2* neuronal nicotinic receptor ligands (agonist, partial agonist and positive allosteric modulators) as therapeutic prospects for pain[J]. Eur J Pharmacol, 2013, 712:22-29.
[35] Schlicker E, Feuerstein T. Human presynaptic receptors[J]. Pharmacol Ther, 2016, 172:1-21.
[36] Gray R, Rajan AS, Radcliffe KA, et al. Hippocampal synaptic transmission enhanced by low concentrations of nicotine[J]. Nature, 1996, 383:713-716.
[37] Wang BW, Liao WN, Chang CT, et al. Facilitation of glutamate release by nicotine involves the activation of a Ca2+/calmodulin signaling pathway in rat prefrontal cortex nerve terminals[J]. Synapse, 2006, 59:491-501.
[38] Wall TR, Henderson BJ, Voren G, et al. TC299423, a novel agonist for nicotinic acetylcholine receptors[J]. Front Pharmacol, 2017, 8:641.
[39] Mineur YS, Picciotto MR. Nicotine receptors and depression:revisiting and revising the cholinergic hypothesis[J]. Trends Pharmacol Sci, 2010, 31:580-586.
[40] Schriber RA, Anbari Z, Robins RW, et al. Hippocampal volume as an amplifier of the effect of social context on adolescent depression[J]. Clin Psychol Sci, 2017, 5:632-649.
[41] Holliday ED, Nucero P, Kutlu MG, et al. Long-term effects of chronic nicotine on emotional and cognitive behaviors and hippocampus cell morphology in mice:comparisons of adult and adolescent nicotine exposure[J]. Eur J Neurosci, 2016, 44:2818-2828.
[42] Picciotto MR, Zoli M, Léna C, et al. Abnormal avoidance learning in mice lacking functional high-affinity nicotine receptor in the brain[J]. Nature, 1995, 374:65-67.
[43] Ross SA, Wong JY, Clifford JJ, et al. Phenotypic characterization of an alpha 4 neuronal nicotinic acetylcholine receptor subunit knock-out mouse[J]. J Neurosci, 2000, 20:6431-6441.
[44] Zoli M, Picciotto M R, Ferrari R, et al. Increased neurodegeneration during ageing in mice lacking high-affinity nicotine receptors[J]. EMBO J, 1999, 18:1235-1244.
[45] Fuenzalida M, Pérez MÁ, Arias HR. Role of nicotinic and muscarinic receptors on synaptic plasticity and neurological diseases[J]. Curr Pharm Des, 2016, 22:2004-2014.
[46] Dehkordi O, Rose JE, Dávilagarcía MI, et al. Neuroanatomical relationships between orexin/hypocretin-containing neurons/nerve fibers and nicotine-induced c-Fos-activated cells of the reward-addiction neurocircuitry[J]. J Alcohol Drug Depend, 2017, 5:273.
[47] Lozada AF, Wang X, Gounko NV, et al. Glutamatergic synapse formation is promoted by alpha7-containing nicotinic acetylcholine receptors[J]. J Neurosci, 2012, 32:7651-7661.
[48] Liu Z, Neff RA, Berg DK. Sequential interplay of nicotinic and GABAergic signaling guides neuronal development[J]. Science, 2006, 314:1610-1613.
[49] Role LW, Berg DK. Nicotinic receptors in the development and modulation of CNS synapses[J]. Neuron, 1996, 16:1077-1085.
[50] Norman H, D'Souza MS. Endogenous opioid system:a promising target for future smoking cessation medications[J]. Psychopharmacology, 2017, 234:1-24.
[51] Tolu S, Marti F, Morel C, et al. Nicotine enhances alcohol intake and dopaminergic responses through β2* and β4* nicotinic acetylcholine receptors[J]. Sci Rep, 2017, 7:45116.
[52] Puddifoot CA, Wu M, Sung RJ, et al. Ly6h regulates trafficking of alpha7 nicotinic acetylcholine receptors and nicotine-induced potentiation of glutamatergic signaling[J]. J Neurosci, 2015, 35:3420-3430.
[53] Navarrete M, Perea G, Maglio L, et al. Astrocyte calcium signal and gliotransmission in human brain tissue[J]. Cerebral Cortex, 2013, 23:1240-1246.
[54] Maskos U. Role of endogenous acetylcholine in the control of the dopaminergic system via nicotinic receptors[J]. J Neurochem, 2010, 114:641-646.
[55] Grady SR, Meinerz NM, Cao J, et al. Nicotinic agonists stimulate acetylcholine release from mouse interpeduncular nucleus:a function mediated by a different nAChR than dopamine release from striatum[J]. J Neurochem, 2001, 76:258-268.
[56] Maskos U, Molles BE, Pons S, et al. Nicotine reinforcement and cognition restored by targeted expression of nicotinic receptors[J]. Nature, 2005, 436:103-107.
[57] Pang X, Liu L, Ngolab J, et al. Habenula cholinergic neurons regulate anxiety during nicotine withdrawal via nicotinic acetylcholine receptors[J]. Neuropharmacology, 2016, 107:294-304.
[58] Grenhoff J, Aston-Jones G, Svensson TH. Nicotinic effects on the firing pattern of midbrain dopamine neurons[J]. Acta Physiol Scand, 1986, 128:351-358.
[59] Mameliengvall M, Evrard A, Pons S, et al. Hierarchical control of dopamine neuron-firing patterns by nicotinic receptors[J]. Neuron, 2006, 50:911-921.
[60] Saleh A, Potter GG, Mcquoid DR, et al. Effects of early life stress on depression, cognitive performance and brain morphology[J]. Psychol Med, 2017, 47:171-181.
[61] Young KD, Siegle GJ, Misaki M, et al. Altered task-based and resting-state amygdala functional connectivity following real-time fMRI amygdala neurofeedback training in major depressive disorder[J]. Neuroimage Clin, 2018, 5:691-703.
[62] Pandya AA. Desformylflustrabromine:a novel positive allosteric modulator for beta2 subunit containing nicotinic receptor sub-types[J]. Curr Pharm Des, 2016, 22:2057-2063.
[63] Fan WH, Yu F, Yao JP. Effect of Chaihu Shugan on hippocampal regulation of HPA axis in chronic stress depression model rats[J]. J Basic Chin Med (中国中医基础医学杂志), 2015, 21:50-52.
[64] Mineur YS, Fote GM, Blakeman S, et al. Multiple nicotinic acetylcholine receptor subtypes in the mouse amygdale regulate affective behaviors and response to social stress[J]. Neuropsychopharmacology, 2016, 41:1579-1587.
[65] Zhang J, Mcdonald AJ. Light and electron microscopic analysis of enkephalin-like immunoreactivity in the basolateral amygdala, including evidence for convergence of enkephalin-containing axon terminals and norepinephrine transporter-containing axon terminals onto common targets[J]. Brain Res, 2016, 1636:62-73.
[66] Femenía T, Gómezgalán M, Lindskog M, et al. Dysfunctional hippocampal activity affects emotion and cognition in mood disorders[J]. Brain Res, 2012, 1476:58-70.
[67] Xu X, Zheng C, An L, et al. Effects of dopamine and serotonin systems on modulating neural oscillations in hippocampus-prefrontal cortex pathway in rats[J]. Brain Topogr, 2016, 29:539-551.
[68] Shytle RD, Silver AA, Sheehan KH, et al. Neuronal nicotinic receptor inhibition for treating mood disorders:preliminary controlled evidence with mecamylamine[J]. Depress Anxiety, 2002, 16:89-92.
[69] Han J, Wang D, Liu S, et al. Cytisine, a partial agonist of α4β2 nicotinic acetylcholine receptors, reduced unpredictable chronic mild stress-induced depression-like behaviors[J]. Biomol Ther (Seoul), 2016, 24:291-297.
[70] Zhang HK, Eaton JB, Fedolak A, et al. Synthesis and biological evaluation of novel hybrids of highly potent and selective α4β2-nicotinic acetylcholine receptor (nAChR) partial agonists[J]. Eur J Med Chem, 2016, 124:689-697.
[71] Warnerschmidt JL, Schmidt EF, Marshall JJ, et al. Cholinergic interneurons in the nucleus accumbens regulate depression-like behavior[J]. Proc Nat Acad Sci U S A, 2012, 109:11360-11365.
[72] Mihalak KB, Carroll FI, Luetje CW. Varenicline is a partial agonist at α4β2 and a full agonist at alpha7 neuronal nicotinic receptors[J]. Mol Pharmacol, 2006, 70:801-805.