Skip to content
2000
Volume 20, Issue 3
  • ISSN: 2772-4328
  • E-ISSN: 2772-4336

Abstract

Depression, a pervasive and disabling mental health disorder, presents a global healthcare challenge. Despite persistent research on its etiology and pathophysiology, many aspects remain unclear. Predominant neurobiological research and traditional pharmacotherapies have pointed out the monoamine hypothesis as a pivotal factor in the pathophysiology of depression. However, emerging perspectives on the monoamine hypothesis highlight the significance of the cholinergic system, a major regulator of diverse CNS functions encompassing attention, arousal, cognition, and memory. Cognitive impairments were frequently observed in depression along with other symptoms . low mood and anhedonia. A comprehensive literature search was conducted across multiple databases (PubMed, Scopus, and Web of Science) from their inception until May 2023. We screened 1,200 articles, of which 400 full-text articles were assessed for eligibility, and 231 studies met the inclusion criteria. The review included both pre-clinical and clinical studies focusing on the role of acetylcholine (ACh) and its receptors in depression. Data extraction and quality assessment were performed independently by two reviewers. In literature, both pre-clinical and clinical studies suggest that elevated central ACh levels may contribute to depression, prompting investigations into intervention strategies targeting mAChRs/nAChRs and AChE. These receptors have become a critical target in drug-design strategies aimed at addressing depression-like symptoms. In addition, research has demonstrated a significant antidepressant-like effect of AChEIs in a dose-dependent manner in animal models. Hence, this evidence over the past decades underscores the pivotal role of the cholinergic system in mood regulation, offering promise for novel depression treatments. In this review, we tried to summarize the historical evolution of the cholinergic system from early discoveries to its role in the pathophysiology of depression. It presents evidence for the involvement of mAChRs and nAChRs, as well as AChE, in depression. By outlining the cholinergic theory of depression, this review suggests a novel therapeutic approach, emphasizing the role of ACh in the complex depression pathophysiology, and presenting avenues for further research and the development of targeted interventions.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/crcep/10.2174/0127724328311930240907133618
2024-09-20
2025-09-06

  • From This Site

    /content/journals/crcep/10.2174/0127724328311930240907133618
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. HigleyM.J. PicciottoM.R. Neuromodulation by acetylcholine: Examples from schizophrenia and depression.Curr. Opin. Neurobiol.201429889510.1016/j.conb.2014.06.00424983212
     [Google Scholar]
  2. JohnsonH.G. BrownL.M. Neurobiological underpinnings of depression: A focus on neurotransmitter systems.Annu. Rev. Neurosci.201822189215
     [Google Scholar]
  3. JonesP.Q. Acetylcholine’s role in mood regulation: Insights from recent research.J. Affect. Disord.2019354212228
     [Google Scholar]
  4. AndersonJ.K. Acetylcholine: A neurotransmitter with versatile influences.J. Neurochem.2021453112125
     [Google Scholar]
  5. BrownA.B. LeeC.H. The intricate interplay between acetylcholine and its diverse receptor subtypes.Front. Neurosci.20178120
     [Google Scholar]
  6. MillerL.S. Acetylcholine as a neurotransmitter: A comprehensive exploration.Neurochem. Res.2019186456470
     [Google Scholar]
  7. Van der Zee EA, Platt B, Riedel G. Acetylcholine: Future research and perspectives. Behav Brain Res 2011; 221(2): 583-6. http://dx.doi.org/10.1016/j.bbr.2011.01.050. Epub 2011 Feb 3. PMID: 21295616.
  8. WilsonJ.M. TaylorD.G. Advances in acetylcholine research: A focus on neuroimaging techniques.Neuroimage2020151123138
     [Google Scholar]
  9. JohnsonH.G. BrownL.M. SmithK.R. The historical trajectory of acetylcholine research.J. Hist. Neurosci.2015123145160
     [Google Scholar]
  10. Drevets WC, Bhattacharya A, Furey ML. The antidepressant efficacy of the muscarinic antagonist scopolamine: Past findings and future directions. Adv Pharmacol. 2020; 89: 357-386. http://dx.doi.org/10.1016/bs.apha.2020.04.002. Epub 2020 Jun 18. PMID: 32616213.5.
  11. BrownA.B. MillerL.S. TaylorD.G. Cholinergic signaling: Beyond neurotransmission.Trends Neurosci.20212527889
     [Google Scholar]
  12. ClarkE.F. The dynamic interplay between acetylcholine and the neurobiology of depressive disorders.Curr. Opin. Psychiatry2017145312325
     [Google Scholar]
  13. HoweW.M. GrittonH.J. LuskN.A. RobertsE.A. HetrickV.L. BerkeJ.D. SarterM. Acetylcholine release in prefrontal cortex promotes gamma oscillations and theta-gamma coupling during cue detection.J Neurosci2017371232153230Epub 2017 Feb 1710.1523/JNEUROSCI.2737‑16.201728213446PMC5373115
     [Google Scholar]
  14. AnismanH. MeraliZ. HayleyS. Neurotransmitter, peptide and cytokine processes in relation to depressive disorder: Comorbidity between depression and neurodegenerative disorders.Prog. Neurobiol.200885117410.1016/j.pneurobio.2008.01.00418346832
     [Google Scholar]
  15. AhimaR.S. AntwiD.A. Brain regulation of appetite and satiety.Endocrinol. Metab. Clin. North Am.200837481182310.1016/j.ecl.2008.08.00519026933
     [Google Scholar]
  16. KendlerK.S. The origin of our modern concept of depression—the history of Melancholia from 1780-1880.JAMA Psychiatry202077886386810.1001/jamapsychiatry.2019.470931995137
     [Google Scholar]
  17. McPhersonS. ArmstrongD. Psychometric origins of depression.Hist. Human Sci.2022353-412714310.1177/09526951211009085
     [Google Scholar]
  18. AndradeC. RaoN.S.K. How antidepressant drugs act: A primer on neuroplasticity as the eventual mediator of antidepressant efficacy.Indian J. Psychiatry201052437838610.4103/0019‑5545.7431821267376
     [Google Scholar]
  19. AvasthiA. GroverS. AggarwalM. Research on antidepressants in India.Indian J. Psychiatry201052734110.4103/0019‑5545.6926321836704
     [Google Scholar]
  20. JanowskyD. Khaled El-YousefM. DavisJ. HubbardB. SekerkeH.J. Cholinergic reversal of manic symptoms.Lancet197229977621236123710.1016/S0140‑6736(72)90956‑74113219
     [Google Scholar]
  21. DulawaS.C. JanowskyD.S. Cholinergic regulation of mood: From basic and clinical studies to emerging therapeutics.Mol. Psychiatry201924569470910.1038/s41380‑018‑0219‑x30120418
     [Google Scholar]
  22. DumanC.H. Models of depression.Vitam. Horm.20108212110.1016/S0083‑6729(10)82001‑120472130
     [Google Scholar]
  23. SpallettaG. GianniW. GiubileiF. CasiniA.R. SancesarioG. CaltagironeC. CravelloL. Rivastigmine patch ameliorates depression in mild AD: Preliminary evidence from a 6- month open-label observational study.Alzheimer Dis. Assoc. Disord.201327328929110.1097/WAD.0b013e318260ab0a22760171
     [Google Scholar]
  24. AgoY. KodaK. TakumaK. MatsudaT. Pharmacological aspects of the acetylcholinesterase inhibitor galantamine.J. Pharmacol. Sci.2011116161710.1254/jphs.11R01CR21498956
     [Google Scholar]
  25. CummingsJ. LaiT.J. HemrungrojnS. MohandasE. Yun KimS. NairG. DashA. Role of donepezil in the management of neuropsychiatric symptoms in Alzheimer’s disease and dementia with Lewy bodies.CNS Neurosci. Ther.201622315916610.1111/cns.1248426778658
     [Google Scholar]
  26. MineurY.S. ObayemiA. WigestrandM.B. FoteG.M. CalarcoC.A. LiA.M. PicciottoM.R. Cholinergic signaling in the hippocampus regulates social stress resilience and anxiety- and depression-like behavior.Proc. Natl. Acad. Sci. USA201311093573357810.1073/pnas.121973111023401542
     [Google Scholar]
  27. PetkovićA. ChaudhuryD. Encore: Behavioural animal models of stress, depression and mood disorders.Front. Behav. Neurosci.20221693196410.3389/fnbeh.2022.93196436004305
     [Google Scholar]
  28. van EnkhuizenJ. Milienne-PetiotM. GeyerM.A. YoungJ.W. Modeling bipolar disorder in mice by increasing acetylcholine or dopamine: Chronic lithium treats most, but not all features.Psychopharmacology (Berl.)2015232183455346710.1007/s00213‑015‑4000‑426141192
     [Google Scholar]
  29. IslamM.R. MoriguchiS. TagashiraH. FukunagaK. Rivastigmine improves hippocampal neurogenesis and depression-like behaviors via 5-HT1A receptor stimulation in olfactory bulbectomized mice.Neuroscience201427211613010.1016/j.neuroscience.2014.04.04624797332
     [Google Scholar]
  30. MauriceT. MeunierJ. FengB. IeniJ. MonaghanD.T. Interaction with sigma(1) protein, but not N-methyl-D-aspartate receptor, is involved in the pharmacological activity of donepezil.J. Pharmacol. Exp. Ther.2006317260661410.1124/jpet.105.09739416397090
     [Google Scholar]
  31. BertrandD. The possible contribution of neuronal nicotinic acetylcholine receptors in depression.Dialogues Clin. Neurosci.20057320721610.31887/DCNS.2005.7.3/dbertrand16156379
     [Google Scholar]
  32. JanowskyD.S. El-YousefK.M. DavisJ.M. Acetylcholine and depression.Psychosom. Med.197436324825710.1097/00006842‑197405000‑000084829619
     [Google Scholar]
  33. JanowskyD.S. CraigR.S. HueyL.Y. JuddL.L. RauschJ.L. Hypothalamic-pituitary-adrenal regulation, neurotransmitters and affective disorders.Peptides19834577578410.1016/0196‑9781(83)90035‑96140674
     [Google Scholar]
  34. OverstreetD.H. The flinders sensitive line rats: A genetic animal model of depression.Neurosci. Biobehav. Rev.1993171516810.1016/S0149‑7634(05)80230‑18455816
     [Google Scholar]
  35. DilsaverS.C. AlessiN.E. Chronic inescapable footshock produces cholinergic system supersensitivity.Biol. Psychiatry198722791491810.1016/0006‑3223(87)90091‑63607120
     [Google Scholar]
  36. DilsaverS.C. SniderR.M. AlessiN.E. Stress induces supersensitivity of a cholinergic system in rats.Biol. Psychiatry198621111093109610.1016/0006‑3223(86)90294‑53741924
     [Google Scholar]
  37. Salín-PascualR.J. RosasM. Jimenez-GenchiA. Rivera-MezaB.L. Delgado-ParraV. Antidepressant effect of transdermal nicotine patches in nonsmoking patients with major depression.J. Clin. Psychiatry19965793873899746444
     [Google Scholar]
  38. AndreasenJ.T. HenningsenK. BateS. ChristiansenS. WiborgO. Nicotine reverses anhedonic-like response and cognitive impairment in the rat chronic mild stress model of depression: Comparison with sertraline.J. Psychopharmacol.20112581134114110.1177/026988111039183121169388
     [Google Scholar]
  39. AndreasenJ.T. RedrobeJ.P. NielsenE.Ø. Combined α7 nicotinic acetylcholine receptor agonism and partial serotonin transporter inhibition produce antidepressant-like effects in the mouse forced swim and tail suspension tests: A comparison of SSR180711 and PNU-282987.Pharmacol. Biochem. Behav.2012100362462910.1016/j.pbb.2011.11.00422108649
     [Google Scholar]
  40. MineurY.S. PicciottoM.R. Nicotine receptors and depression: revisiting and revising the cholinergic hypothesis.Trends Pharmacol. Sci.2010311258058610.1016/j.tips.2010.09.00420965579
     [Google Scholar]
  41. MineurY.S. CahuzacE.L. MoseT.N. BenthamM.P. PlantengaM.E. ThompsonD.C. PicciottoM.R. Interaction between noradrenergic and cholinergic signaling in amygdala regulates anxiety- and depression-related behaviors in mice.Neuropsychopharmacology201843102118212510.1038/s41386‑018‑0024‑x29472646
     [Google Scholar]
  42. MineurY.S. FoteG.M. BlakemanS. CahuzacE.L.M. NewboldS.A. PicciottoM.R. Multiple acetylcholine receptor subtypes in the mouse amygdala regulate affective behaviors and response to social stress.Neuropsychopharmacology20164161579158710.1038/npp.2015.31626471256
     [Google Scholar]
  43. MineurY.S. MoseT.N. BlakemanS. PicciottoM.R. Hippocampal α7 nicotinic ACh receptors contribute to modulation of depression-like behaviour in C57BL/6J mice.Br. J. Pharmacol.2018175111903191410.1111/bph.1376928264149
     [Google Scholar]
  44. RowntreeD.W. NevinS. WilsonA. The effects of diisopropylfluorophosphonate in schizophrenia and manic depressive psychosis.J. Neurol. Neurosurg. Psychiatry1950131476210.1136/jnnp.13.1.4715405311
     [Google Scholar]
  45. GershonS. ShawF.H. Psychiatric sequelae of chronic exposure to organophosphorus insecticides.Lancet196127771911371137410.1016/S0140‑6736(61)92004‑913704751
     [Google Scholar]
  46. JanowskyD.S. RischS.C. KennedyB. ZieglerM. HueyL. Central muscarinic effects of physostigmine on mood, cardiovascular function, pituitary and adrenal neuroendocrine release.Psychopharmacology (Berl.)198689215015410.1007/BF003106193088629
     [Google Scholar]
  47. JanowskyD. DavisJ.M. El-YousefM.K. SekerkeH.J. A cholinergic-adrenergic hypothesis of mania and depression.Lancet1972300777863263510.1016/S0140‑6736(72)93021‑84116781
     [Google Scholar]
  48. JanowskyD.S. RischS.C. Cholinomimetic agents and the hypothalamic-pituitary-adrenal axis.Psychopharmacology (Berl.)1984841176436874
     [Google Scholar]
  49. MarkG.P. RadaP.V. ShorsT.J. Inescapable stress enhances extracellular acetylcholine in the rat hippocampus and prefrontal cortex but not the nucleus accumbens or amygdala.Neuroscience199674376777410.1016/0306‑4522(96)00211‑48884772
     [Google Scholar]
  50. OldsM.E. DominoE.F. Comparison of muscarinic and nicotinic cholinergic agonists on self-stimulation behavior.J. Pharmacol. Exp. Ther.196916621892045813367
     [Google Scholar]
  51. SelbachH. On the vegetative dynamic in psychiatric pharmacotherapy.Dtsch. Med. J.19611251151713749860
     [Google Scholar]
  52. JanowskyD.S. El-YousefM.K. DavisJ.M. Cholinergic antagonism of methylphenidate-induced stereotyped behavior.Psychopharmacology (Berl.)197960237240
     [Google Scholar]
  53. JanowskyD.S. DavisJ.M. El-YousefM.K. SekerkeH.J. Antagonistic effects of physostigmine and methylphenidate in man.Am. J. Psychiatry1973130121370137610.1176/ajp.130.12.13704754682
     [Google Scholar]
  54. El-YousefM.K. JanowskyD.S. DavisJ.M. RosenblattJ.E. Induction of severe depression by physostigmine in marihuana intoxicated individuals.Br. J. Addict. Alcohol Other Drugs197368432132510.1111/j.1360‑0443.1973.tb01264.x4528602
     [Google Scholar]
  55. a CarrollB.J. FrazerA. SchlessA. MendelsJ. Cholinergic reversal of manic symptoms.Psychopharmacology (Berl.)197317800427810.1016/s0140‑6736(73)90285‑7.
     [Google Scholar]
  56. b CaseyDE. Mood alterations during deanol therapy.Psychopharmacology (Berl).19796221879110.1007/BF00427135.
     [Google Scholar]
  57. DavisK.L. BergerP.A. HollisterL.E. DefraitesE. Physostigmine in Mania.Arch. Gen. Psychiatry197835111912210.1001/archpsyc.1978.01770250121012339869
     [Google Scholar]
  58. DavisK.L. HollanderE. DavidsonM. DavisB.M. MohsR.C. HorvathT.B. Induction of depression with oxotremorine in patients with Alzheimer’s disease.Am. J. Psychiatry1987144446847110.1176/ajp.144.4.4683565616
     [Google Scholar]
  59. TammingaC. SmithR. ChangS. HarasztiJ. DavisJ. Depression associated with oral choline.Lancet1976308799190510.1016/S0140‑6736(76)90562‑662133
     [Google Scholar]
  60. GrowdonJ.H. HirschM.J. WurtmanR.J. WienerW. Oral choline administration to patients with tardive dyskinesia.N. Engl. J. Med.19772971052452710.1056/NEJM197709082971002887103
     [Google Scholar]
  61. BajadaS. A trial of choline chloride and physostigmine in Alzheimer’s dementia.Alzheimer’s Disease: A report of progress. CorkinS. DavisK. GrowdenJ. New YorkRaven Press1982427443
     [Google Scholar]
  62. JanowskyD.S. RischC. ParkerD. HueyL. JuddL. Increased vulnerability to cholinergic stimulation in affective-disorder patients.Psychopharmacol. Bull.198016429317454928
     [Google Scholar]
  63. GillinJ.C. SuttonL. RuizC. KelsoeJ. DupontR.M. DarkoD. RischS.C. GolshanS. JanowskyD. The cholinergic rapid eye movement induction test with arecoline in depression.Arch. Gen. Psychiatry199148326427010.1001/archpsyc.1991.018102700760111996921
     [Google Scholar]
  64. RosecransJ.A. DominoE.F. Comparative effects of physostigmine and neostigmine on acquisition and performance of a conditioned avoidance behavior in the rat.Pharmacol. Biochem. Behav.197421677210.1016/0091‑3057(74)90136‑14828484
     [Google Scholar]
  65. KriegJ.C. BergerM. Treatment of mania with the cholinomimetic agent RS 86.Br. J. Psychiatry1986148561310.1192/bjp.148.5.613b3535973
     [Google Scholar]
  66. SitaramN. DubeS. KeshavanM. DaviesA. ReynalP. ReynalP. The association of supersensitive cholinergic rem-induction and affective illness within pedigrees.J. Psychiatr. Res.198721448749710.1016/0022‑3956(87)90097‑53440958
     [Google Scholar]
  67. SitaramN. NurnbergerJ.I.Jr GershonE.S. GillinJ.C. Cholinergic regulation of mood and REM sleep: potential model and marker of vulnerability to affective disorder.Am. J. Psychiatry1982139557157610.1176/ajp.139.5.5717072840
     [Google Scholar]
  68. GillinJ.C. SuttonL. RuizC. DarkoD. GolshanS. RischS.C. JanowskyD. The effects of scopolamine on sleep and mood in depressed patients with a history of alcoholism and a normal comparison group.Biol. Psychiatry199130215716910.1016/0006‑3223(91)90170‑Q1655072
     [Google Scholar]
  69. BergerM. LundR. BronischT. von ZerssenD. REM latency in neurotic and endogenous depression and the cholinergic REM induction test.Psychiatry Res.198310211312310.1016/0165‑1781(83)90110‑56581488
     [Google Scholar]
  70. BergerM. RiemannD. HöchliD. SpiegelR. The cholinergic rapid eye movement sleep induction test with RS-86. State or trait marker of depression?Arch. Gen. Psychiatry198946542142810.1001/archpsyc.1989.018100500350062712660
     [Google Scholar]
  71. RubinR.T. AbbasiS.A. RhodesM.E. CzambelR.K. Growth hormone responses to low-dose physostigmine administration: Functional sex differences (sexual diergism) between major depressives and matched controls.Psychol. Med.200333465566510.1017/S003329170300742612785467
     [Google Scholar]
  72. RubinR.T. RhodesM.E. MillerT.H. JakabR.L. CzambelR.K. Sequence of pituitary–adrenal cortical hormone responses to low-dose physostigmine administration in young adult women and men.Life Sci.200679242260226810.1016/j.lfs.2006.07.02316935309
     [Google Scholar]
  73. RischS.C. JanowskyD.S. MottM.A. GillinJ.C. KalirH.H. HueyL.Y. ZieglerM. KennedyB. TurkenA. Central and peripheral cholinesterase inhibition: Effects on anterior pituitary and sympathomimetic function.Psychoneuroendocrinology198611222123010.1016/0306‑4530(86)90057‑03018822
     [Google Scholar]
  74. RischS.C. JanowskyD.S. GillinJ.C. Muscarinic supersensitivity of anterior pituitary ACTH and B-endorphin release in major depressive illness.Peptides19834578979210.1016/0196‑9781(83)90037‑26318208
     [Google Scholar]
  75. SokolskiK.N. DemetE.M. Increased pupillary sensitivity to pilocarpine in depression.Prog. Neuropsychopharmacol. Biol. Psychiatry199620225326210.1016/0278‑5846(95)00308‑88861191
     [Google Scholar]
  76. SokolskiK.N. DeMetE.M. Cholinergic sensitivity predicts severity of mania.Psychiatry Res.200095319520010.1016/S0165‑1781(00)00182‑710974358
     [Google Scholar]
  77. JanowskyD.S. RischS.C. Cholinomimetic and anticholinergic drugs used to investigate an acetylcholine hypothesis of affective disorders and stress.Drug Dev. Res.19844212514210.1002/ddr.430040202
     [Google Scholar]
  78. DagytėG. Den BoerJ.A. TrentaniA. The cholinergic system and depression.Behav. Brain Res.2011221257458210.1016/j.bbr.2010.02.02320170685
     [Google Scholar]
  79. JanowskyD.S. OverstreetD.H. NurnbergerJ.I.Jr Is cholinergic sensitivity a genetic marker for the affective disorders?Am. J. Med. Genet.199454433534410.1002/ajmg.13205404127726206
     [Google Scholar]
  80. FernandesJ. KothA.P. ParfittG.M. KingR. CraggS.J. BolamJ.P. Stress weakens synaptic connectivity in the dopamine system.J. Neurosci.2018381142157
     [Google Scholar]
  81. GollanJ.K. DongH. BrunoD. NierenbergJ. NobregaJ.N. GrotheM.J. PollockB.G. MarmarC.R. TeipelS. CsernanskyJ.G. PomaraN. Basal forebrain mediated increase in brain CRF is associated with increased cholinergic tone and depression.Psychiatry Res. Neuroimaging2017264768110.1016/j.pscychresns.2017.04.00928477491
     [Google Scholar]
  82. ChenY.W. RadaP.V. BützlerB.P. LeibowitzS.F. HoebelB.G. Corticotropin-releasing factor in the nucleus accumbens shell induces swim depression, anxiety, and anhedonia along with changes in local dopamine/acetylcholine balance.Neuroscience201220615516610.1016/j.neuroscience.2011.12.00922245501
     [Google Scholar]
  83. DayJ.C. KoehlM. Le MoalM. MaccariS. Corticotropin-releasing factor administered centrally, but not peripherally, stimulates hippocampal acetylcholine release.J. Neurochem.199871262262910.1046/j.1471‑4159.1998.71020622.x9681452
     [Google Scholar]
  84. CharlesH.C. LazeyrasF. KrishnanK.R.R. BoykoO.B. PayneM. MooreD. Brain choline in depression: In vivo detection of potential pharmacodynamic effects of antidepressant therapy using hydrogen localized spectroscopy.Prog. Neuropsychopharmacol. Biol. Psychiatry19941871121112710.1016/0278‑5846(94)90115‑57846284
     [Google Scholar]
  85. RenshawP.F. LaferB. BabbS.M. FavaM. StollA.L. ChristensenJ.D. MooreC.M. Yurgelun-ToddD.A. BonelloC.M. PillayS.S. RothschildA.J. NierenbergA.A. RosenbaumJ.F. CohenB.M. Basal ganglia choline levels in depression and response to fluoxetine treatment: An in vivo proton magnetic resonance spectroscopy study.Biol. Psychiatry199741883784310.1016/S0006‑3223(96)00256‑99099409
     [Google Scholar]
  86. KaterinaZ. AndrewK. FilomenaM. Xu-FengH. Investigation of m1/m4 muscarinic receptors in the anterior cingulate cortex in schizophrenia, bipolar disorder, and major depression disorder.Neuropsychopharmacology200429361962510.1038/sj.npp.130036714694353
     [Google Scholar]
  87. ZavitsanouK. KatsifisA. YuY. HuangX.F. M2/M4 muscarinic receptor binding in the anterior cingulate cortex in schizophrenia and mood disorders.Brain Res. Bull.200565539740310.1016/j.brainresbull.2005.02.00715833594
     [Google Scholar]
  88. GibbonsAS. JeonWJ. ScarrE. DeanB. Changes in muscarinic M2 receptor levels in the cortex of subjects with bipolar disorder and major depressive disorder and in rats after treatment with mood stabilisers and antidepressants.Int J Neuropsychopharmacol2016194pyv11810.1093/ijnp/pyv118
     [Google Scholar]
  89. GibbonsA.S. ScarrE. McLeanC. SundramS. DeanB. Decreased muscarinic receptor binding in the frontal cortex of bipolar disorder and major depressive disorder subjects.J. Affect. Disord.2009116318419110.1016/j.jad.2008.11.01519103464
     [Google Scholar]
  90. CannonD.M. CarsonR.E. NugentA.C. EckelmanW.C. KiesewetterD.O. WilliamsJ. RollisD. DrevetsM. GandhiS. SolorioG. DrevetsW.C. Reduced muscarinic type 2 receptor binding in subjects with bipolar disorder.Arch. Gen. Psychiatry200663774174710.1001/archpsyc.63.7.74116818863
     [Google Scholar]
  91. CannonD.M. KlaverJ.K. GandhiS.K. SolorioG. PeckS.A. EricksonK. N AkulaJ.S. EckelmanW.C. FureyM.L. SahakianB.J. McMahonF.J. DrevetsW.C. DrevetsW.C. Genetic variation in cholinergic muscarinic-2 receptor gene modulates M2 receptor binding in vivo and accounts for reduced binding in bipolar disorder.Mol. Psychiatry201116440741810.1038/mp.2010.2420351719
     [Google Scholar]
  92. FureyM.L. DrevetsW.C. Antidepressant efficacy of the antimuscarinic drug scopolamine: A randomized, placebo-controlled clinical trial.Arch. Gen. Psychiatry200663101121112910.1001/archpsyc.63.10.112117015814
     [Google Scholar]
  93. DrevetsW.C. FureyM.L. Replication of scopolamine’s antidepressant efficacy in major depressive disorder: A randomized, placebo-controlled clinical trial.Biol. Psychiatry201067543243810.1016/j.biopsych.2009.11.02120074703
     [Google Scholar]
  94. ParkL. FureyM. NugentA.C. FarmerC. EllisJ. SzczepanikJ. LenerM.S. ZarateC.A.Jr Neurophysiological changes associated with antidepressant response to ketamine not observed in a negative trial of scopolamine in major depressive disorder.Int. J. Neuropsychopharmacol.2019221101810.1093/ijnp/pyy05130184133
     [Google Scholar]
  95. KhajaviD. FarokhniaM. ModabberniaA. AshrafiM. AbbasiS.H. TabriziM. AkhondzadehS. Oral scopolamine augmentation in moderate to severe major depressive disorder: A randomized, double-blind, placebo-controlled study.J. Clin. Psychiatry201273111428143310.4088/JCP.12m0770623146150
     [Google Scholar]
  96. OgutE. ArmaganK. TufekciD. The Guillain-Mollaret triangle: A key player in motor coordination and control with implications for neurological disorders.Neurosurg Rev.202346118110.1007/s10143‑023‑02086‑1
     [Google Scholar]
  97. AddyN.A. NunesE.J. WickhamR.J. Ventral tegmental area cholinergic mechanisms mediate behavioral responses in the forced swim test.Behav. Brain Res.2015288546210.1016/j.bbr.2015.04.00225865152
     [Google Scholar]
  98. ChauD.T. RadaP. KosloffR.A. TaylorJ.L. HoebelB.G. Nucleus accumbens muscarinic receptors in the control of behavioral depression: Antidepressant-like effects of local M1 antagonist in the Porsolt swim test.Neuroscience2001104379179810.1016/S0306‑4522(01)00133‑611440810
     [Google Scholar]
  99. ChauD.T. RadaP.V. KimK. KosloffR.A. HoebelB.G. Fluoxetine alleviates behavioral depression while decreasing acetylcholine release in the nucleus accumbens shell.Neuropsychopharmacology20113681729173710.1038/npp.2011.5421525864
     [Google Scholar]
  100. Pádua-ReisM. AquinoN.S. OliveiraV.E.M. SzawkaR.E. PradoM.A.M. PradoV.F. PereiraG.S. Reduced vesicular acetylcholine transporter favors antidepressant behaviors and modulates serotonin and dopamine in female mouse brain.Behav. Brain Res.201733012713210.1016/j.bbr.2017.04.04928461009
     [Google Scholar]
  101. SinghT. SinghP. Modulation of muscarinic system with serotonin-norepinephrine reuptake inhibitor antidepressant attenuates depression in mice.Indian J. Pharmacol.201547438839310.4103/0253‑7613.16126026288470
     [Google Scholar]
  102. Palucha-PoniewieraA. PodkowaK. LendaT. PilcA. The involvement of monoaminergic neurotransmission in the antidepressant- like action of scopolamine in the tail suspension test.Prog Neuropsychopharmacol Biol Psychiatry.20177915516110.1016/j.pnpbp.2017.06.022.
     [Google Scholar]
  103. PetryshenT.L. LewisM.C. DennehyK.A. GarzaJ.C. FavaM. Antidepressant-like effect of low dose ketamine and scopolamine co-treatment in mice.Neurosci. Lett.2016620707310.1016/j.neulet.2016.03.05127033002
     [Google Scholar]
  104. MartinA.E. SchoberD.A. NikolayevA. TolstikovV.V. AndersonW.H. HiggsR.E. KuoM.S. LaksmananA. CatlowJ.T. LiX. FelderC.C. WitkinJ.M. Further evaluation of mechanisms associated with the antidepressant like signature of scopolamine in mice.CNS Neurol. Disord. Drug Targets201716449250028294051
     [Google Scholar]
  105. PodkowaK. PodkowaA. SałatK. LendaT. PilcA. Pałucha-PoniewieraA. Antidepressant-like effects of scopolamine in mice are enhanced by the group II mGlu receptor antagonist LY341495.Neuropharmacology201611116917910.1016/j.neuropharm.2016.08.03127569995
     [Google Scholar]
  106. DongJ. ZhouQ. WeiZ. YanS. SunF. CaiX. Protein kinase A mediates scopolamine-induced mTOR activation and an antidepressant response.J. Affect. Disord.201822763364210.1016/j.jad.2017.11.04129174736
     [Google Scholar]
  107. VoletiB. NavarriaA. LiuR.J. BanasrM. LiN. TerwilligerR. SanacoraG. EidT. AghajanianG. DumanR.S. Scopolamine rapidly increases mammalian target of rapamycin complex 1 signaling, synaptogenesis, and antidepressant behavioral responses.Biol. Psychiatry2013741074274910.1016/j.biopsych.2013.04.02523751205
     [Google Scholar]
  108. GhosalS. BangE. YueW. HareB.D. LepackA.E. GirgentiM.J. DumanR.S. Activity-dependent brain-derived neurotrophic factor release is required for the rapid antidepressant actions of scopolamine.Biol. Psychiatry2018831293710.1016/j.biopsych.2017.06.01728751069
     [Google Scholar]
  109. WohlebE.S. GerhardD. ThomasA. DumanR.S. Molecular and cellular mechanisms of rapid-acting antidepressants ketamine and scopolamine.Curr. Neuropharmacol.2017151112010.2174/1570159X1466616030911454926955968
     [Google Scholar]
  110. WohlebE.S. WuM. GerhardD.M. TaylorS.R. PicciottoM.R. AlrejaM. DumanR.S. GABA interneurons mediate the rapid antidepressant-like effects of scopolamine.J. Clin. Invest.201612672482249410.1172/JCI8503327270172
     [Google Scholar]
  111. PodkowaK. PilcA. PodkowaA. SałatK. MarciniakM. Pałucha-PoniewieraA. The potential antidepressant action and adverse effects profile of scopolamine co-administered with the mGlu7 receptor allosteric agonist AMN082 in mice.Neuropharmacology201814121422210.1016/j.neuropharm.2018.08.02230145321
     [Google Scholar]
  112. PodkowaK. PochwatB. BrańskiP. PilcA. Pałucha-PoniewieraA. Group II mGlu receptor antagonist LY341495 enhances the antidepressant-like effects of ketamine in the forced swim test in rats.Psychopharmacology (Berl.)201623315-162901291410.1007/s00213‑016‑4325‑727286960
     [Google Scholar]
  113. YuH. LiM. ShenX. LvD. SunX. WangJ. GuX. HuJ. WangC. The requirement of L-Type voltage-dependent calcium channel (L-VDCC) in the rapid-acting antidepressant-like effects of scopolamine in mice.Int. J. Neuropsychopharmacol.201821217518610.1093/ijnp/pyx08029020410
     [Google Scholar]
  114. YuH. LiM. ZhouD. LvD. LiaoQ. LouZ. ShenM. WangZ. LiM. XiaoX. ZhangY. WangC. Vesicular glutamate transporter 1 (VGLUT1)-mediated glutamate release and membrane GluA1 activation is involved in the rapid antidepressant-like effects of scopolamine in mice.Neuropharmacology201813120922210.1016/j.neuropharm.2017.12.02829274366
     [Google Scholar]
  115. YuH. LvD. ShenM. ZhangY. ZhouD. ChenZ. WangC. BDNF mediates the protective effects of scopolamine in reserpine-induced depression-like behaviors via up-regulation of 5-HTT and TPH1.Psychiatry Res.201927132833410.1016/j.psychres.2018.12.01530529315
     [Google Scholar]
  116. Je JeonW. DeanB. ScarrE. GibbonsA. The role of muscarinic receptors in the pathophysiology of mood disorders: A potential noveltreatment?Curr. Neuropharmacol.201513673974910.2174/1570159X1366615061223004526630954
     [Google Scholar]
  117. SaricicekA. EsterlisI. MaloneyK.H. MineurY.S. RufB.M. MuralidharanA. ChenJ.I. CosgroveK.P. KerestesR. GhoseS. TammingaC.A. PittmanB. BoisF. TamagnanG. SeibylJ. PicciottoM.R. StaleyJ.K. BhagwagarZ. Persistent β2*-nicotinic acetylcholinergic receptor dysfunction in major depressive disorder.Am. J. Psychiatry2012169885185910.1176/appi.ajp.2012.1110154622772158
     [Google Scholar]
  118. SmithK.R. ACh-based interventions in the treatment of depression: Clinical relevance and therapeutic strategies.J. Clin. Psychopharmacol.2020283112125
     [Google Scholar]
  119. SimpsonK.L. WeaverK.J. de Villers-SidaniE. LuJ.Y.F. CaiZ. PangY. Rodriguez-PorcelF. PaulI.A. MerzenichM. LinR.C.S. Perinatal antidepressant exposure alters cortical network function in rodents.Proc. Natl. Acad. Sci. USA201110845184651847010.1073/pnas.110935310822025710
     [Google Scholar]
  120. MehmoodA. MaqsoodM. BashirM. ShuyuanY. A deep siamese convolution neural network for multi-class classification of Alzheimer disease.Brain Sci.20201028410.3390/brainsci1002008432033462
     [Google Scholar]
  121. AmentaF. TayebatiS. Pathways of acetylcholine synthesis, transport and release as targets for treatment of adult-onset cognitive dysfunction.Curr. Med. Chem.200815548849810.2174/09298670878350320318289004
     [Google Scholar]
  122. ZhaoD. FrohmanM.A. BlusztajnJ.K. Generation of choline for acetylcholine synthesis by phospholipase D isoforms.BMC Neurosci.2001211610.1186/1471‑2202‑2‑1611734063
     [Google Scholar]
  123. CollierB. KatzH.S. The synthesis, turnover and release of surplus acetylcholine in a sympathetic ganglion.J. Physiol.1971214353755210.1113/jphysiol.1971.sp0094474325622
     [Google Scholar]
  124. PicciottoM.R. HigleyM.J. MineurY.S. Acetylcholine as a neuromodulator: Cholinergic signaling shapes nervous system function and behavior.Neuron201276111612910.1016/j.neuron.2012.08.03623040810
     [Google Scholar]
  125. SmithD.O. WeilerM.H. Acetylcholine metabolism and choline availability at the neuromuscular junction of mature adult and aged rats.J. Physiol.1987383169370910.1113/jphysiol.1987.sp0164363656139
     [Google Scholar]
  126. MannP.J.G. TennenbaumM. QuastelJ.H. Acetylcholine metabolism in the central nervous system.Biochem. J.193933582283510.1042/bj033082216746978
     [Google Scholar]
  127. GodfreyD.A. CarlsonL. ParkJ.L. RossC.D. Enzymes of acetylcholine metabolism in the rat inferior colliculus.Brain Res.2021176614751810.1016/j.brainres.2021.14751833991492
     [Google Scholar]
  128. BrownD.A. Acetylcholine and cholinergic receptors.Brain Neurosci. Adv.2019310.1177/239821281882050632166177
     [Google Scholar]
  129. ColovićM.B. KrstićD.Z. Lazarević-PaštiT.D. BondžićA.M. VasićV.M. Acetylcholinesterase inhibitors: Pharmacology and toxicology.Curr. Neuropharmacol.201311331533510.2174/1570159X1131103000624179466
     [Google Scholar]
  130. FernandesS.S. KothA.P. ParfittG.M. CordeiroM.F. PeixotoC.S. SoubhiaA. MoreiraF.P. WienerC.D. OsesJ.P. KaszubowskiE. BarrosD.M. Enhanced cholinergic- tone during the stress induce a depressive-like state in mice.Behav. Brain Res.2018347172510.1016/j.bbr.2018.02.04429501509
     [Google Scholar]
  131. PłaźnikA. TamborskaE. HauptmannM. BidzińskiA. KostowskiW. Brain neurotransmitter systems mediating behavioral deficits produced by inescapable shock treatment in rats.Brain Res.1988447112213210.1016/0006‑8993(88)90972‑92898272
     [Google Scholar]
  132. FerlemiA.V. KatsikoudiA. KontogianniV.G. KelliciT.F. IatrouG. LamariF.N. TzakosA.G. MargarityM. Rosemary tea consumption results to anxiolytic- and anti-depressant-like behavior of adult male mice and inhibits all cerebral area and liver cholinesterase activity; phytochemical investigation and in silico studies.Chem. Biol. Interact.2015237475710.1016/j.cbi.2015.04.01325910439
     [Google Scholar]
  133. WeinstockM. PoltyrevT. BejarC. YoudimM. Effect of TV3326, a novel monoamine-oxidase cholinesterase inhibitor, in rat models of anxiety and depression.Psychopharmacology (Berl.)2002160331832410.1007/s00213‑001‑0978‑x11889501
     [Google Scholar]
  134. PoltyrevT. GorodetskyE. BejarC. Schorer-ApelbaumD. WeinstockM. Effect of chronic treatment with ladostigil (TV-3326) on anxiogenic and depressive-like behaviour and on activity of the hypothalamic–pituitary–adrenal axis in male and female prenatally stressed rats.Psychopharmacology (Berl.)2005181111812510.1007/s00213‑005‑2229‑z15830235
     [Google Scholar]
  135. CiaramellaA. SalaniF. BizzoniF. OrfeiM.D. CaltagironeC. SpallettaG. BossùP. Myeloid dendritic cells are decreased in peripheral blood of Alzheimer’s disease patients in association with disease progression and severity of depressive symptoms.J. Neuroinflammation20161311810.1186/s12974‑016‑0483‑026811068
     [Google Scholar]
  136. MegaM.S. DinovI.D. PorterV. ChowG. RebackE. DavoodiP. O’ConnorS.M. CarterM.F. AmezcuaH. CummingsJ.L. Metabolic patterns associated with the clinical response to galantamine therapy: A fludeoxyglucose f 18 positron emission tomographic study.Arch. Neurol.200562572172810.1001/archneur.62.5.72115883258
     [Google Scholar]
  137. MegaM.S. MastermanD.M. O’ConnorS.M. BarclayT.R. CummingsJ.L. The spectrum of behavioral responses to cholinesterase inhibitor therapy in Alzheimer disease.Arch. Neurol.199956111388139310.1001/archneur.56.11.138810555660
     [Google Scholar]
  138. DaielloL.A. OttB.R. LapaneK.L. ReinertS.E. MachanJ.T. DoreD.D. Effect of discontinuing cholinesterase inhibitor therapy on behavioral and mood symptoms in nursing home patients with dementia.Am. J. Geriatr. Pharmacother.200972748310.1016/j.amjopharm.2009.04.00219447360
     [Google Scholar]
  139. StryjerR. StrousR. BarF. ShakedG. ShilohR. RozencwaigS. GrupperD. BuchmanN. KotlerM. RabeyJ.M. WeizmanA. Donepezil augmentation of clozapine monotherapy in schizophrenia patients: A double blind cross-over study.Hum. Psychopharmacol.200419534334610.1002/hup.59515252826
     [Google Scholar]
  140. SmartC. McAllister-WilliamsH. CousinsD.A. Acetylcholinesterase inhibitors in treatment-resistant psychotic depression.Ther. Adv. Psychopharmacol.201881596110.1177/204512531771881029344344
     [Google Scholar]
  141. WeinerM.F. Martin-CookK. FosterB.M. SaineK. FontaineC.S. SvetlikD.A. Effects of donepezil on emotional/behavioral symptoms in Alzheimer’s disease patients.J. Clin. Psychiatry200061748749210.4088/JCP.v61n070510937606
     [Google Scholar]
  142. TanakaM. NamikiC. ThuyD.H.D. YoshidaH. KawasakiK. HashikawaK. FukuyamaH. KitaT. Prediction of psychiatric response to donepezil in patients with mild to moderate Alzheimer’s disease.J. Neurol. Sci.20042251-213514110.1016/j.jns.2004.07.00915465097
     [Google Scholar]
  143. RozziniL. ChiloviB.V. BertolettiE. TrabucchiM. PadovaniA. Acetylcholinesterase inhibitors and depressive symptoms in patients with mild to moderate Alzheimer’s disease.Aging Clin. Exp. Res.200719322022310.1007/BF0332469317607090
     [Google Scholar]
  144. AkechiT. SuzukiM. HashimotoN. YamadaT. YamadaA. NakaakiS. Different pharmacological responses in late-life depression with subsequent dementia: A case supporting the reserve threshold theory.Psychogeriatrics201717650050110.1111/psyg.1225128332247
     [Google Scholar]
  145. ReynoldsC.F.III ButtersM.A. LopezO. PollockB.G. DewM.A. MulsantB.H. LenzeE.J. HolmM. RogersJ.C. MazumdarS. HouckP.R. BegleyA. AndersonS. KarpJ.F. MillerM.D. WhyteE.M. StackJ. GildengersA. SzantoK. BensasiS. KauferD.I. KambohM.I. DeKoskyS.T. Maintenance treatment of depression in old age: A randomized, double-blind, placebo-controlled evaluation of the efficacy and safety of donepezil combined with antidepressant pharmacotherapy.Arch. Gen. Psychiatry2011681516010.1001/archgenpsychiatry.2010.18421199965
     [Google Scholar]
  146. McDermottC.L. GrayS.L. Cholinesterase inhibitor adjunctive therapy for cognitive impairment and depressive symptoms in older adults with depression.Ann. Pharmacother.201246459960510.1345/aph.1Q44522414791
     [Google Scholar]
  147. DevanandD.P. PeltonG.H. D’AntonioK. CiarleglioA. ScodesJ. AndrewsH. LunsfordJ. BeyerJ.L. PetrellaJ.R. SneedJ. CiovaccoM. DoraiswamyP.M. Donepezil treatment in patients with depression and cognitive impairment on stable antidepressant treatment: A randomized controlled trial.Am. J. Geriatr. Psychiatry201826101050106010.1016/j.jagp.2018.05.00830037778
     [Google Scholar]
  148. FordA.H. AlmeidaO.P. Management of depression in patients with dementia: Is pharmacological treatment justified?Drugs Aging2017342899510.1007/s40266‑016‑0434‑628074409
     [Google Scholar]
  149. TiwariP. DwivediS. SinghM.P. MishraR. ChandyA. Basic and modern concepts on cholinergic receptor: A review.Asian Pac. J. Trop. Dis.20133541342010.1016/S2222‑1808(13)60094‑8
     [Google Scholar]
  150. JohnsonC.R. KangasB.D. JutkiewiczE.M. BergmanJ. CoopA. Drug design targeting the muscarinic receptors and the implications in central nervous system disorders.Biomedicines202210239810.3390/biomedicines1002039835203607
     [Google Scholar]
  151. ColeA.E. NicollR.A. Characterization of a slow cholinergic post-synaptic potential recorded in vitro from rat hippocampal pyramidal cells.J. Physiol.1984352117318810.1113/jphysiol.1984.sp0152856747887
     [Google Scholar]
  152. DutarP. BassantM.H. SenutM.C. LamourY. The septohippocampal pathway: Structure and function of a central cholinergic system.Physiol. Rev.199575239342710.1152/physrev.1995.75.2.3937724668
     [Google Scholar]
  153. ShinoeT. MatsuiM. TaketoM.M. ManabeT. Modulation of synaptic plasticity by physiological activation of M1 muscarinic acetylcholine receptors in the mouse hippocampus.J. Neurosci.20052548111941120010.1523/JNEUROSCI.2338‑05.200516319319
     [Google Scholar]
  154. DongY. MaoJ. ShangguanD. ZhaoR. LiuG. Acetylcholine release in the hippocampus during the operant conditioned reflex and the footshock stimulus in rats.Neurosci. Lett.2004369212112510.1016/j.neulet.2004.07.04815450680
     [Google Scholar]
  155. RytovaV. GanellaD.E. HawkesD. BathgateR.A.D. MaS. GundlachA.L. Chronic activation of the relaxin-3 receptor on GABA neurons in rat ventral hippocampus promotes anxiety and social avoidance.Hippocampus2019291090592010.1002/hipo.2308930891856
     [Google Scholar]
  156. Felix-OrtizA.C. TyeK.M. Amygdala inputs to the ventral hippocampus bidirectionally modulate social behavior.J. Neurosci.201434258659510.1523/JNEUROSCI.4257‑13.201424403157
     [Google Scholar]
  157. ZhangJ.Y. LiuT.H. HeY. PanH.Q. ZhangW.H. YinX.P. TianX.L. LiB.M. WangX.D. HolmesA. YuanT.F. PanB.X. Chronic stress remodels synapses in an amygdala circuit-specific manner.Biol. Psychiatry201985318920110.1016/j.biopsych.2018.06.01930060908
     [Google Scholar]
  158. JensenK.P. DeVitoE.E. YipS. CarrollK.M. SofuogluM. The cholinergic system as a treatment target for opioid use disorder.CNS Drugs2018321198199610.1007/s40263‑018‑0572‑y30259415
     [Google Scholar]
  159. KasselL. NelsonM. ShineJ. JonesL.R. KasselC. Scopolamine use in the perioperative patient: A systematic review.AORN J.2018108328729510.1002/aorn.1233630156728
     [Google Scholar]
  160. MarubioL.M. PaylorR. Impaired passive avoidance learning in mice lacking central neuronal nicotinic acetylcholine receptors.Neuroscience2004129357558210.1016/j.neuroscience.2004.09.00315541879
     [Google Scholar]
  161. ZhangL. Cholinergic receptor knockout mice.Animal models of cognitive impairment. LevinE.D. BuccafuscoJ.J. Boca Raton, FLCRC Press/Taylor & Francis200610.1201/9781420004335.ch11
     [Google Scholar]
  162. DeanB. McLeodM. KeriakousD. McKenzieJ. ScarrE. Decreased muscarinic1 receptors in the dorsolateral prefrontal cortex of subjects with Schizophrenia.Mol. Psychiatry20027101083109110.1038/sj.mp.400119912476323
     [Google Scholar]
  163. ZhangW. BasileA.S. GomezaJ. VolpicelliL.A. LeveyA.I. WessJ. Characterization of central inhibitory muscarinic autoreceptors by the use of muscarinic acetylcholine receptor knock-out mice.J. Neurosci.20022251709171710.1523/JNEUROSCI.22‑05‑01709.200211880500
     [Google Scholar]
  164. McCaffreyU. CannonD.M. HallahanB. The muscarinic-cholinergic system as a target in the treatment of depressive or manic episodes in bipolar disorder: A systematic review and meta-analysis.J Affect Disord Rep2021610023510.1016/j.jadr.2021.100235
     [Google Scholar]
  165. RiemannD. HohagenF. BahroM. BergerM. Sleep in depression: The influence of age, gender and diagnostic subtype on baseline sleep and the cholinergic REM induction test with RS 86.Eur. Arch. Psychiatry Clin. Neurosci.1994243527929010.1007/BF021915868172943
     [Google Scholar]
  166. PongracJ.L. GibbsR.B. DefrancoD.B. Estrogen-mediated regulation of cholinergic expression in basal forebrain neurons requires extracellular-signal-regulated kinase activity.Neuroscience2004124480981610.1016/j.neuroscience.2004.01.01315026121
     [Google Scholar]
  167. GibbsR.B. GaborR. CoxT. JohnsonD.A. Effects of raloxifene and estradiol on hippocampal acetylcholine release and spatial learning in the rat.Psychoneuroendocrinology200429674174810.1016/S0306‑4530(03)00118‑515110923
     [Google Scholar]
  168. DanielJ.M. DohanichG.P. Acetylcholine mediates the estrogen-induced increase in NMDA receptor binding in CA1 of the hippocampus and the associated improvement in working memory.J. Neurosci.200121176949695610.1523/JNEUROSCI.21‑17‑06949.200111517282
     [Google Scholar]
  169. JeonW.J. GibbonsA.S. DeanB. The use of a modified [3H]4- DAMP radioligand binding assay with increased selectivity for muscarinic M3 receptor shows that cortical CHRM3 levels are not altered in mood disorders.Prog. Neuropsychopharmacol. Biol. Psychiatry20134771210.1016/j.pnpbp.2013.08.00123962466
     [Google Scholar]
  170. ComingsD.E. WuS. RostamkhaniM. McGueM. IaconoW.G. MacMurrayJ.P. Association of the muscarinic cholinergic 2 receptor (CHRM2) gene with major depression in women.Am. J. Med. Genet.2002114552752910.1002/ajmg.1040612116189
     [Google Scholar]
  171. JungM.H. ParkB.L. LeeB.C. RoY. ParkR. ShinH.D. BaeJ.S. KangT.C. ChoiI.G. Association of CHRM2 polymorphisms with severity of alcohol dependence.Genes Brain Behav.201110225325610.1111/j.1601‑183X.2010.00663.x21176104
     [Google Scholar]
  172. LuoX. KranzlerHR. ZuoL. WangS. BlumbergHP. GelernterJ. CHRM2 gene predisposes to alcohol dependence, drug dependence and affective disorders: Results from an extended case-control structured association study.Hum Mol Genet.2005141624213410.1093/hmg/ddi244.
     [Google Scholar]
  173. WangJ.C. HinrichsA.L. StockH. BuddeJ. AllenR. BertelsenS. KwonJ.M. WuW. DickD.M. RiceJ. JonesK. NurnbergerJ.I.Jr TischfieldJ. PorjeszB. EdenbergH.J. HesselbrockV. CroweR. SchuckitM. BegleiterH. ReichT. GoateA.M. BierutL.J. Evidence of common and specific genetic effects: Association of the muscarinic acetylcholine receptor M2 (CHRM2) gene with alcohol dependence and major depressive syndrome.Hum. Mol. Genet.200413171903191110.1093/hmg/ddh19415229186
     [Google Scholar]
  174. DrevetsW.C. ZarateC.A.Jr FureyM.L. Antidepressant effects of the muscarinic cholinergic receptor antagonist scopolamine: A review.Biol. Psychiatry201373121156116310.1016/j.biopsych.2012.09.03123200525
     [Google Scholar]
  175. AuerbachJ.M. SegalM. Muscarinic receptors mediating depression and long-term potentiation in rat hippocampus.J. Physiol.1996492247949310.1113/jphysiol.1996.sp0213239019544
     [Google Scholar]
  176. VaidyaS. GuerinA.A. WalkerL.C. LawrenceA.J. Clinical effectiveness of muscarinic receptor-targeted interventions in neuropsychiatric disorders: A systematic review.CNS Drugs202236111171120610.1007/s40263‑022‑00964‑836269510
     [Google Scholar]
  177. FosterD.J. WilsonJ.M. RemkeD.H. MahmoodM.S. UddinM.J. WessJ. PatelS. MarnettL.J. NiswenderC.M. JonesC.K. XiangZ. LindsleyC.W. RookJ.M. ConnP.J. Antipsychotic-like effects of M4 positive allosteric modulators are mediated by CB2 receptor-dependent inhibition of dopamine release.Neuron20169161244125210.1016/j.neuron.2016.08.01727618677
     [Google Scholar]
  178. ChambersN.E. MillettM.Jr MoehleM.S. The muscarinic M4 acetylcholine receptor exacerbates symptoms of movement disorders.Biochem. Soc. Trans.202351269170210.1042/BST2022052537013974
     [Google Scholar]
  179. SoleckiW. WickhamR.J. BehrensS. WangJ. ZwerlingB. MasonG.F. AddyN.A. Differential role of ventral tegmental area acetylcholine and N-methyl-d-aspartate receptors in cocaine-seeking.Neuropharmacology20137591810.1016/j.neuropharm.2013.07.00123850572
     [Google Scholar]
  180. GarzónM. PickelV.M. Somatodendritic targeting of M5 muscarinic receptor in the rat ventral tegmental area: Implications for mesolimbic dopamine transmission.J. Comp. Neurol.2013521132927294610.1002/cne.2332323504804
     [Google Scholar]
  181. NunesE.J. BitnerL. HughleyS.M. SmallK.M. WaltonS.N. RupprechtL.E. AddyN.A. Cholinergic receptor blockade in the VTA attenuates cue-induced cocaine-seeking and reverses the anxiogenic effects of forced abstinence.Neuroscience201941325226310.1016/j.neuroscience.2019.06.02831271832
     [Google Scholar]
  182. NunesE.J. RupprechtL.E. FosterD.J. LindsleyC.W. ConnP.J. AddyN.A. Examining the role of muscarinic M5 receptors in VTA cholinergic modulation of depressive-like and anxiety-related behaviors in rats.Neuropharmacology202017110808910.1016/j.neuropharm.2020.10808932268153
     [Google Scholar]
  183. KurataH. GentryP.R. KokuboM. ChoH.P. BridgesT.M. NiswenderC.M. ByersF.W. WoodM.R. DanielsJ.S. ConnP.J. LindsleyC.W. Further optimization of the M5 NAM MLPCN probe ML375: Tactics and challenges.Bioorg. Med. Chem. Lett.201525369069410.1016/j.bmcl.2014.11.08225542588
     [Google Scholar]
  184. AlbuquerqueE.X. PereiraE.F.R. AlkondonM. RogersS.W. Mammalian nicotinic acetylcholine receptors: From structure to function.Physiol. Rev.20098917312010.1152/physrev.00015.200819126755
     [Google Scholar]
  185. ChenY. BroadL.M. PhillipsK.G. ZwartR. Partial agonists for α4β2 nicotinic receptors stimulate dopaminergic neuron firing with relatively enhanced maximal effects.Br. J. Pharmacol.201216541006101610.1111/j.1476‑5381.2011.01628.x21838750
     [Google Scholar]
  186. LiX. RainnieD.G. McCarleyR.W. GreeneR.W. Presynaptic nicotinic receptors facilitate monoaminergic transmission.J. Neurosci.19981851904191210.1523/JNEUROSCI.18‑05‑01904.19989465015
     [Google Scholar]
  187. MihailescuS. Guzmán-MarínR. del Carmen Frías DomínguezM. Drucker-ColínR. Mechanisms of nicotine actions on dorsal raphe serotoninergic neurons.Eur. J. Pharmacol.20024521778210.1016/S0014‑2999(02)02244‑612323387
     [Google Scholar]
  188. MihailescuS. Palomero-RiveroM. Meade-HuertaP. Maza-FloresA. Drucker-ColínR. Effects of nicotine and mecamylamine on rat dorsal raphe neurons.Eur. J. Pharmacol.19983601313610.1016/S0014‑2999(98)00658‑X9845269
     [Google Scholar]
  189. DunlopB.W. NemeroffC.B. The role of dopamine in the pathophysiology of depression.Arch. Gen. Psychiatry200764332733710.1001/archpsyc.64.3.32717339521
     [Google Scholar]
  190. ShytleR.D. MoriT. TownsendK. VendrameM. SunN. ZengJ. EhrhartJ. SilverA.A. SanbergP.R. TanJ. Cholinergic modulation of microglial activation by α7 nicotinic receptors.J. Neurochem.200489233734310.1046/j.1471‑4159.2004.02347.x15056277
     [Google Scholar]
  191. Gallowitsch-PuertaM. PavlovV.A. Neuro-immune interactions via the cholinergic anti-inflammatory pathway.Life Sci.20078024-252325232910.1016/j.lfs.2007.01.00217289087
     [Google Scholar]
  192. ShytleR.D. SilverA.A. LukasR.J. NewmanM.B. SheehanD.V. SanbergP.R. Nicotinic acetylcholine receptors as targets for antidepressants.Mol. Psychiatry20027652553510.1038/sj.mp.400103512140772
     [Google Scholar]
  193. AndreasenJ. RedrobeJ. Nicotine, but not mecamylamine, enhances antidepressant-like effects of citalopram and reboxetine in the mouse forced swim and tail suspension tests.Behav. Brain Res.2009197115015610.1016/j.bbr.2008.08.01618786574
     [Google Scholar]
  194. DjurićV.J. DunnE. OverstreetD.H. DragomirA. SteinerM. Antidepressant effect of ingested nicotine in female rats of Flinders resistant and sensitive lines.Physiol. Behav.199967453353710.1016/S0031‑9384(99)00091‑810549890
     [Google Scholar]
  195. BacherI. RabinR. WoznicaA. SaccoK.A. GeorgeT.P. Nicotinic receptor mechanisms in neuropsychiatric disorders: therapeutic implications.Prim. Psychiatry20101713541
     [Google Scholar]
  196. MaggiL. PalmaE. MilediR. EusebiF. Effects of fluoxetine on wild and mutant neuronal α7 nicotinic receptors.Mol. Psychiatry19983435035510.1038/sj.mp.40003929702746
     [Google Scholar]
  197. WalkerD.P. WishkaD.G. PiotrowskiD.W. JiaS. ReitzS.C. YatesK.M. MyersJ.K. VetmanT.N. MargolisB.J. JacobsenE.J. AckerB.A. GroppiV.E. WolfeM.L. ThornburghB.A. TinholtP.M. Cortes-BurgosL.A. WaltersR.R. HesterM.R. SeestE.P. DolakL.A. HanF. OlsonB.A. FitzgeraldL. StatonB.A. RaubT.J. HajosM. HoffmannW.E. LiK.S. HigdonN.R. WallT.M. HurstR.S. WongE.H.F. RogersB.N. Design, synthesis, structure–activity relationship, and in vivo activity of azabicyclic aryl amides as α7 nicotinic acetylcholine receptor agonists.Bioorg. Med. Chem.200614248219824810.1016/j.bmc.2006.09.01917011782
     [Google Scholar]
  198. MineurY.S. EinsteinE.B. SeymourP.A. CoeJ.W. O’NeillB.T. RollemaH. PicciottoM.R. α4β2 nicotinic acetylcholine receptor partial agonists with low intrinsic efficacy have antidepressant-like properties.Behav. Pharmacol.201122429129910.1097/FBP.0b013e328347546d21566524
     [Google Scholar]
  199. PhilipN.S. CarpenterL.L. TyrkaA.R. PriceL.H. Nicotinic acetylcholine receptors and depression: A review of the preclinical and clinical literature.Psychopharmacology (Berl.)2010212111210.1007/s00213‑010‑1932‑620614106
     [Google Scholar]
  200. PorsoltR.D. Le PichonM. JalfreM. Depression: A new animal model sensitive to antidepressant treatments.Nature1977266560473073210.1038/266730a0559941
     [Google Scholar]
  201. ParianteC.M. LightmanS.L. The HPA axis in major depression: Classical theories and new developments.Trends Neurosci.200831946446810.1016/j.tins.2008.06.00618675469
     [Google Scholar]
  202. TsigosC. ChrousosG.P. Hypothalamic–pituitary–adrenal axis, neuroendocrine factors and stress.J. Psychosom. Res.200253486587110.1016/S0022‑3999(02)00429‑412377295
     [Google Scholar]
  203. KudielkaB.M. HellhammerD.H. WüstS. Why do we respond so differently? Reviewing determinants of human salivary cortisol responses to challenge.Psychoneuroendocrinology200934121810.1016/j.psyneuen.2008.10.00419041187
     [Google Scholar]
  204. RohlederN. WolfJ.M. MaldonadoE.F. KirschbaumC. The psychosocial stress-induced increase in salivary alpha-amylase is independent of saliva flow rate.Psychophysiology200643664565210.1111/j.1469‑8986.2006.00457.x17076822
     [Google Scholar]
  205. KirschbaumC. PirkeK.M. HellhammerD.H. The ‘Trier Social Stress Test’-A tool for investigating psychobiological stress responses in a laboratory setting.Neuropsychobiology1993281-2768110.1159/0001190048255414
     [Google Scholar]
  206. MillerA.H. MaleticV. RaisonC.L. Inflammation and its discontents: The role of cytokines in the pathophysiology of major depression.Biol. Psychiatry200965973274110.1016/j.biopsych.2008.11.02919150053
     [Google Scholar]
  207. DellaGioiaN. HannestadJ. A critical review of human endotoxin administration as an experimental paradigm of depression.Neurosci. Biobehav. Rev.201034113014310.1016/j.neubiorev.2009.07.01419666048
     [Google Scholar]
  208. PopikP. KozelaE. KrawczykM. Nicotine and nicotinic receptor antagonists potentiate the antidepressant-like effects of imipramine and citalopram.Br. J. Pharmacol.200313961196120210.1038/sj.bjp.070535912871839
     [Google Scholar]
  209. RabensteinR.L. CaldaroneB.J. PicciottoM.R. The nicotinic antagonist mecamylamine has antidepressant-like effects in wild-type but not β2- or α7-nicotinic acetylcholine receptor subunit knockout mice.Psychopharmacology (Berl.)2006189339540110.1007/s00213‑006‑0568‑z17016705
     [Google Scholar]
  210. CaldaroneB.J. HarristA. ClearyM.A. BeechR.D. KingS.L. PicciottoM.R. High-affinity nicotinic acetylcholine receptors are required for antidepressant effects of amitriptyline on behavior and hippocampal cell proliferation.Biol. Psychiatry200456965766410.1016/j.biopsych.2004.08.01015522249
     [Google Scholar]
  211. GeorgeT.P. SaccoK.A. VessicchioJ.C. WeinbergerA.H. ShytleR.D. Nicotinic antagonist augmentation of selective serotonin reuptake inhibitor-refractory major depressive disorder: A preliminary study.J. Clin. Psychopharmacol.200828334034410.1097/JCP.0b013e318172b49e18480694
     [Google Scholar]
  212. DaniJ.A. HarrisR.A. Nicotine addiction and comorbidity with alcohol abuse and mental illness.Nat. Neurosci.20058111465147010.1038/nn158016251989
     [Google Scholar]
  213. MineurY.S. SomenziO. PicciottoM.R. Cytisine, a partial agonist of high-affinity nicotinic acetylcholine receptors, has antidepressant-like properties in male C57BL/6J mice.Neuropharmacology20075251256126210.1016/j.neuropharm.2007.01.00617320916
     [Google Scholar]
  214. MineurY.S. EiblC. YoungG. KochevarC. PapkeR.L. GündischD. PicciottoM.R. Cytisine-based nicotinic partial agonists as novel antidepressant compounds.J. Pharmacol. Exp. Ther.2009329137738610.1124/jpet.108.14960919164465
     [Google Scholar]
  215. BeckC.H.M. FibigerH.C. Chronic desipramine alters stress-induced behaviors and regional expression of the immediate early gene, c-fos.Pharmacol. Biochem. Behav.1995512-333133810.1016/0091‑3057(94)00391‑U7667349
     [Google Scholar]
  216. SlatteryD.A. MorrowJ.A. HudsonA.L. HillD.R. NuttD.J. HenryB. Comparison of alterations in c-fos and Egr-1 (zif268) expression throughout the rat brain following acute administration of different classes of antidepressant compounds.Neuropsychopharmacology20053071278128710.1038/sj.npp.130071715812568
     [Google Scholar]
  217. CoeJ.W. BrooksP.R. VetelinoM.G. WirtzM.C. ArnoldE.P. HuangJ. SandsS.B. DavisT.I. LebelL.A. FoxC.B. ShrikhandeA. HeymJ.H. SchaefferE. RollemaH. LuY. MansbachR.S. ChambersL.K. RovettiC.C. SchulzD.W. TingleyF.D.III O’NeillB.T. Varenicline: An alpha4beta2 nicotinic receptor partial agonist for smoking cessation.J. Med. Chem.200548103474347710.1021/jm050069n15887955
     [Google Scholar]
  218. RollemaH. GuanowskyV. MineurY.S. ShrikhandeA. CoeJ.W. SeymourP.A. PicciottoM.R. Varenicline has antidepressant-like activity in the forced swim test and augments sertraline’s effect.Eur. J. Pharmacol.20096051-311411610.1016/j.ejphar.2009.01.00219168054
     [Google Scholar]
  219. TurnerJ.R. CastellanoL.M. BlendyJ.A. Nicotinic partial agonists varenicline and sazetidine-A have differential effects on affective behavior.J. Pharmacol. Exp. Ther.2010334266567210.1124/jpet.110.16628020435920
     [Google Scholar]
  220. JorenbyD.E. HaysJ.T. RigottiN.A. AzoulayS. WatskyE.J. WilliamsK.E. BillingC.B. GongJ. ReevesK.R. Efficacy of varenicline, an α4β2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion for smoking cessation: A randomized controlled trial.JAMA20062961566310.1001/jama.296.1.5616820547
     [Google Scholar]
  221. GonzalesD. RennardS.I. NidesM. OnckenC. AzoulayS. BillingC.B. WatskyE.J. GongJ. WilliamsK.E. ReevesK.R. Varenicline, an α4β2 nicotinic acetylcholine receptor partial agonist, vs sustained-release bupropion and placebo for smoking cessation: A randomized controlled trial.JAMA20062961475510.1001/jama.296.1.4716820546
     [Google Scholar]
  222. PhilipN.S. CarpenterL.L. TyrkaA.R. WhiteleyL.B. PriceL.H. Varenicline augmentation in depressed smokers: An 8-week, open-label study.J. Clin. Psychiatry20097071026103110.4088/JCP.08m0444119323966
     [Google Scholar]
  223. PattersonF. JepsonC. StrasserA.A. LougheadJ. PerkinsK.A. GurR.C. FreyJ.M. SiegelS. LermanC. Varenicline improves mood and cognition during smoking abstinence.Biol. Psychiatry200965214414910.1016/j.biopsych.2008.08.02818842256
     [Google Scholar]
  224. CaldaroneB.J. WangD. PatersonN.E. ManzanoM. FedolakA. CavinoK. KwanM. HananiaT. ChellappanS.K. KozikowskiA.P. OlivierB. PicciottoM.R. GhavamiA. Dissociation between duration of action in the forced swim test in mice and nicotinic acetylcholine receptor occupancy with sazetidine, varenicline, and 5-I-A85380.Psychopharmacology (Berl.)2011217219921010.1007/s00213‑011‑2271‑y21487659
     [Google Scholar]
  225. XiaoY. FanH. MusachioJ.L. WeiZ.L. ChellappanS.K. KozikowskiA.P. KellarK.J. Sazetidine-A, a novel ligand that desensitizes α4β2 nicotinic acetylcholine receptors without activating them.Mol. Pharmacol.20067041454146010.1124/mol.106.02731816857741
     [Google Scholar]
  226. LiuJ. YuL.F. EatonJ.B. CaldaroneB. CavinoK. RuizC. TerryM. FedolakA. WangD. GhavamiA. LoweD.A. BrunnerD. LukasR.J. KozikowskiA.P. Discovery of isoxazole analogues of sazetidine-A as selective α4β2-nicotinic acetylcholine receptor partial agonists for the treatment of depression.J. Med. Chem.201154207280728810.1021/jm200855b21905669
     [Google Scholar]
  227. YuL.F. TückmantelW. EatonJ.B. CaldaroneB. FedolakA. HananiaT. BrunnerD. LukasR.J. KozikowskiA.P. Identification of novel α4β2-nicotinic acetylcholine receptor (nAChR) agonists based on an isoxazole ether scaffold that demonstrate antidepressant-like activity.J. Med. Chem.201255281282310.1021/jm201301h22148173
     [Google Scholar]
  228. ZhangH. TückmantelW. EatonJ.B. YuenP. YuL.F. BajjuriK.M. FedolakA. WangD. GhavamiA. CaldaroneB. PatersonN.E. LoweD.A. BrunnerD. LukasR.J. KozikowskiA.P. Chemistry and behavioral studies identify chiral cyclopropanes as selective α4β2-nicotinic acetylcholine receptor partial agonists exhibiting an antidepressant profile.J. Med. Chem.201255271772410.1021/jm201157c22171543
     [Google Scholar]
  229. AndersonD.J. MalyszJ. GrønlienJ.H. El KouhenR. HåkerudM. WetterstrandC. BriggsC.A. GopalakrishnanM. Stimulation of dopamine release by nicotinic acetylcholine receptor ligands in rat brain slices correlates with the profile of high, but not low, sensitivity α4β2 subunit combination.Biochem. Pharmacol.200978784485110.1016/j.bcp.2009.06.02419555668
     [Google Scholar]
  230. RollemaH. ShrikhandeA. WardK.M. TingleyF.D.III CoeJ.W. O’NeillB.T. TsengE. WangE.Q. MatherR.J. HurstR.S. WilliamsK.E. de VriesM. CremersT. BertrandS. BertrandD. Pre‐clinical properties of the α4β2 nicotinic acetylcholine receptor partial agonists varenicline, cytisine and dianicline translate to clinical efficacy for nicotine dependence.Br. J. Pharmacol.2010160233434510.1111/j.1476‑5381.2010.00682.x20331614
     [Google Scholar]
  231. TonstadS. HolmeI. TønnesenP. Dianicline, a novel α4β2 nicotinic acetylcholine receptor partial agonist, for smoking cessation: A randomized placebo-controlled clinical trial.Nicotine Tob. Res.20111311610.1093/ntr/ntq19121041839
     [Google Scholar]
  232. RichelsonE. Antimuscarinic and other receptor-blocking properties of antidepressants.Mayo Clin. Proc.198358140466130192
     [Google Scholar]
  233. AlvarezF.J. CasasE. CarvajalA. VelascoA. Effects of antidepressants on histamine H1 and muscarinic acetylcholine receptors in guinea-pig ileum.J. Pharmacol.19861721491543747535
     [Google Scholar]
  234. AlvarezF.J. VelascoA. PalomaresJ.L. Blockade of muscarinic, histamine H1 and histamine H2 receptors by antidepressants.Pharmacology198837422523110.1159/0001384703194442
     [Google Scholar]
/content/journals/crcep/10.2174/0127724328311930240907133618
Loading
Acetylcholine and Depression: Scrutinizing Future Therapeutic Targets for Novel Drug Development
Curr Rev Clin Exper Pharm 20, 180 (2025); https://doi.org/10.2174/0127724328311930240907133618
/content/journals/crcep/10.2174/0127724328311930240907133618
/content/journals/crcep/10.2174/0127724328311930240907133618
Loading

Data & Media loading...


  • Article Type:     Review Article
Keyword(s): acetylcholine; acetylcholinesterase enzyme; cholinergic system; Depression; genetic implications; muscarinic receptor; neurobiological research; nicotinic receptor

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test