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2000
Volume 24, Issue 5
  • ISSN: 1871-5273
  • E-ISSN: 1996-3181

Abstract

Depression is a serious mental health disorder that impacts more than 350 million individuals globally. While the roles of serotonin and norepinephrine in depression have been extensively studied, the importance of dopaminergic pathways—essential for mood, cognition, motor control, and endocrine function—often gets overlooked. This review focuses on four major dopamine (DA) circuits: the mesolimbic (MLP), mesocortical (MCP), nigrostriatal (NSP), and thalamic-tuberoinfundibular pathways (TTFP), and their roles in depression. The MLP, which is key to reward processing, is linked to anhedonia, a primary depression symptom. The MCP, projecting to the prefrontal cortex, affects cognitive issues like impaired attention and decision-making. The NSP, mainly responsible for motor control, is related to psychomotor retardation in depression, while the TTFP manages neuroendocrine responses, which are often disrupted in stress-related depressive conditions. Current antidepressant treatments mainly target serotonin and norepinephrine systems but tend to be less effective for patients with DArgic dysfunction, leading to treatment resistance. This review underscores emerging evidence that suggests targeting DArgic pathways could improve treatment outcomes, especially for symptoms like anhedonia and cognitive deficits that conventional therapies often fail to address. Future research should aim to combine advancements in neuroimaging, optogenetics, and genetic studies to better map DArgic pathways and create personalized treatment plans. This review highlights the potential for new therapies that focus on DA systems, which could pave the way for more effective and tailored approaches to treating depression.

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References

  1. Depression and other common mental disorders: Global health estimates. Geneva: World Health Organization2017
     [Google Scholar]
  2. MizunoY. AshokA.H. BhatB.B. JauharS. HowesO.D. Dopamine in major depressive disorder: A systematic review and meta-analysis of in vivo imaging studies.J. Psychopharmacol.202337111058106910.1177/02698811231200881 37811803
     [Google Scholar]
  3. MalhiG.S. MannJ.J. Depression.Lancet2018392101612299231210.1016/S0140‑6736(18)31948‑2 30396512
     [Google Scholar]
  4. ZhaoF. ChengZ. PiaoJ. CuiR. LiB. Dopamine receptors: Is it possible to become a therapeutic target for depression?Front. Pharmacol.20221394778510.3389/fphar.2022.947785 36059987
     [Google Scholar]
  5. AshokA.H. MizunoY. VolkowN.D. HowesO.D. Association of stimulant use with DArgic alterations in users of cocaine, amphetamine, or methamphetamine: A systematic review and meta-analysis.JAMA Psychiatry201774551151910.1001/jamapsychiatry.2017.0135 28297025
     [Google Scholar]
  6. ÁrgyelánM. SzabóZ. KanyóB. Dopamine transporter availability in medication free and in bupropion treated depression: A 99mTc-TRODAT-1 SPECT study.J. Affect. Disord.2005891-311512310.1016/j.jad.2005.08.016 16213028
     [Google Scholar]
  7. AmsterdamJ.D. NewbergA.B. SoellerI. ShultsJ. Greater striatal dopamine transporter density may be associated with major depressive episode.J. Affect. Disord.20121412-342543110.1016/j.jad.2012.03.007 22482744
     [Google Scholar]
  8. LuoS.X. HuangE.J. Dopaminergic neurons and brain reward pathways: From neurogenesis to circuit assembly.Am. J. Pathol.2016186347848810.1016/j.ajpath.2015.09.023 26724386
     [Google Scholar]
  9. NestlerE.J. CarlezonW.A.Jr The mesolimbic dopamine reward circuit in depression.Biol. Psychiatry200659121151115910.1016/j.biopsych.2005.09.018 16566899
     [Google Scholar]
  10. NevueA.A. FelixR.A.II PortforsC.V. Dopaminergic projections of the subparafascicular thalamic nucleus to the auditory brainstem.Hear. Res.201634120220910.1016/j.heares.2016.09.001 27620513
     [Google Scholar]
  11. DelvaN.C. StanwoodG.D. Dysregulation of brain dopamine systems in major depressive disorder.Exp. Biol. Med.202124691084109310.1177/1535370221991830 33593109
     [Google Scholar]
  12. PannuA. K Goyal R. Serotonin and depression: Scrutiny of new targets for future anti-depressant drug development.Curr. Drug Targets2023241081683710.2174/1389450124666230425233727 37170981
     [Google Scholar]
  13. ChandleyM.J. OrdwayG.A. Noradrenergic dysfunction in depression and suicide. DwivediY. The neurobiological basis of suicide.Boca Raton, FLCRC Press/Taylor & Francis2012557410.1201/b12215‑4
     [Google Scholar]
  14. MillanM.J. Multi-target strategies for the improved treatment of depressive states: Conceptual foundations and neuronal substrates, drug discovery and therapeutic application.Pharmacol. Ther.2006110213537010.1016/j.pharmthera.2005.11.006 16522330
     [Google Scholar]
  15. GraceA.A. Dysregulation of the dopamine system in the pathophysiology of schizophrenia and depression.Nat. Rev. Neurosci.201617852453210.1038/nrn.2016.57 27256556
     [Google Scholar]
  16. DunlopB.W. NemeroffC.B. The role of dopamine in the pathophysiology of depression.Arch. Gen. Psychiatry200764332733710.1001/archpsyc.64.3.327 17339521
     [Google Scholar]
  17. TaylorS.F. LiberzonI. Neural correlates of emotion regulation in psychopathology.Trends Cogn. Sci.2007111041341810.1016/j.tics.2007.08.006 17928261
     [Google Scholar]
  18. VoonV. DalleyJ.W. Translatable and back-translatable measurement of motivation and apathy: The neurobiology of the nigrostriatal dopamine pathway.Neurosci. Biobehav. Rev.2011355901911
     [Google Scholar]
  19. KoobG.F. VolkowN.D. Neurocircuitry of addiction.Neuropsychopharmacology201035121723810.1038/npp.2009.110 19710631
     [Google Scholar]
  20. PizzagalliD.A. Depression, stress, and anhedonia: Toward a synthesis and integrated model.Annu. Rev. Clin. Psychol.201410139342310.1146/annurev‑clinpsy‑050212‑185606 24471371
     [Google Scholar]
  21. Der-AvakianA. MarkouA. The neurobiology of anhedonia and other reward-related deficits.Trends Neurosci.2012351687710.1016/j.tins.2011.11.005 22177980
     [Google Scholar]
  22. HymanS.E. MalenkaR.C. NestlerE.J. Neural mechanisms of addiction: The role of reward-related learning and memory.Annu. Rev. Neurosci.200629156559810.1146/annurev.neuro.29.051605.113009 16776597
     [Google Scholar]
  23. ArnstenA.F.T. Stress weakens prefrontal networks: Molecular insults to higher cognition.Nat. Neurosci.201518101376138510.1038/nn.4087 26404712
     [Google Scholar]
  24. RobinsonO.J. VytalK. CornwellB.R. GrillonC. The impact of anxiety upon cognition: Perspectives from human threat of shock studies.Front. Hum. Neurosci.2013720310.3389/fnhum.2013.00203 23730279
     [Google Scholar]
  25. HolmesA. WellmanC.L. Stress-induced prefrontal reorganization and executive dysfunction in rodents.Neurosci. Biobehav. Rev.200933677378310.1016/j.neubiorev.2008.11.005 19111570
     [Google Scholar]
  26. ParianteC.M. LightmanS.L. The HPA axis in major depression: Classical theories and new developments.Trends Neurosci.200831946446810.1016/j.tins.2008.06.006 18675469
     [Google Scholar]
  27. AnismanH. MathesonK. Stress, depression, and anhedonia: Caveats concerning animal models.Neurosci. Biobehav. Rev.2005294-552554610.1016/j.neubiorev.2005.03.007 15925696
     [Google Scholar]
  28. ElgellaieA. LarkinT. KaelleJ. MillsJ. ThomasS. Plasma prolactin is higher in major depressive disorder and females, and associated with anxiety, hostility, somatization, psychotic symptoms and heart rate.Compr Psychoneuroendocrinol2021610004910.1016/j.cpnec.2021.100049 35757357
     [Google Scholar]
  29. FitzgeraldP. DinanT.G. Prolactin and dopamine: What is the connection? A review article.J. Psychopharmacol.2008222Suppl.121910.1177/0269216307087148 18477617
     [Google Scholar]
  30. KirschP. KunadiaJ. ShahS. AgrawalN. Metabolic effects of prolactin and the role of dopamine agonists: A review.Front. Endocrinol.202213100232010.3389/fendo.2022.1002320 36246929
     [Google Scholar]
  31. BarkerD.J. RootD.H. ZhangS. MoralesM. Multiplexed neurochemical signaling by neurons of the ventral tegmental area.J. Chem. Neuroanat.201673334210.1016/j.jchemneu.2015.12.016 26763116
     [Google Scholar]
  32. GasbarriA. VerneyC. InnocenziR. CampanaE. PacittiC. Mesolimbic dopaminergic neurons innervating the hippocampal formation in the rat: A combined retrograde tracing and immunohistochemical study.Brain Res.19946681-2717910.1016/0006‑8993(94)90512‑6 7704620
     [Google Scholar]
  33. BouarabC. ThompsonB. PolterA.M. VTA GABA neurons at the interface of stress and reward.Front. Neural Circuits2019137810.3389/fncir.2019.00078 31866835
     [Google Scholar]
  34. van ZessenR. PhillipsJ.L. BudyginE.A. StuberG.D. Activation of VTA GABA neurons disrupts reward consumption.Neuron20127361184119410.1016/j.neuron.2012.02.016 22445345
     [Google Scholar]
  35. YamaguchiT. SheenW. MoralesM. Glutamatergic neurons are present in the rat ventral tegmental area.Eur. J. Neurosci.200725110611810.1111/j.1460‑9568.2006.05263.x 17241272
     [Google Scholar]
  36. PapathanouM. CreedM. DorstM.C. Targeting VGLUT2 in mature dopamine neurons decreases mesoaccumbal glutamatergic transmission and identifies a role for glutamate co-release in synaptic plasticity by increasing baseline AMPA/NMDA ratio.Front. Neural Circuits2018126410.3389/fncir.2018.00064 30210305
     [Google Scholar]
  37. HasbiA. PerreaultM.L. ShenM.Y.F. Activation of dopamine D1-D2 receptor complex attenuates cocaine reward and reinstatement of cocaine-seeking through inhibition of DARPP-32, ERK, and ΔFosB.Front. Pharmacol.2018892410.3389/fphar.2017.00924 29354053
     [Google Scholar]
  38. ZhangH. ChaudhuryD. NectowA.R. α1- and β3-adrenergic receptor-mediated mesolimbic homeostatic plasticity confers resilience to social stress in susceptible mice.Biol. Psychiatry201985322623610.1016/j.biopsych.2018.08.020 30336931
     [Google Scholar]
  39. SuM. LiL. WangJ. Kv7.4 channel contributes to projection-specific auto-inhibition of dopamine neurons in the ventral tegmental area.Front. Cell. Neurosci.20191355710.3389/fncel.2019.00557 31920557
     [Google Scholar]
  40. Soares-CunhaC. de VasconcelosN.A.P. CoimbraB. Nucleus accumbens medium spiny neurons subtypes signal both reward and aversion.Mol. Psychiatry202025123241325510.1038/s41380‑019‑0484‑3 31462765
     [Google Scholar]
  41. SesackS.R. GraceA.A. Cortico-Basal Ganglia reward network: Microcircuitry.Neuropsychopharmacology2010351274710.1038/npp.2009.93 19675534
     [Google Scholar]
  42. FrancisT.C. YanoH. DemarestT.G. ShenH. BonciA. High-frequency activation of nucleus accumbens D1-MSNs drives excitatory potentiation on D2-MSNs.Neuron20191033432444.e310.1016/j.neuron.2019.05.031 31221559
     [Google Scholar]
  43. PerreaultM.L. HasbiA. AlijaniaramM. The dopamine D1-D2 receptor heteromer localizes in dynorphin/enkephalin neurons: Increased high affinity state following amphetamine and in schizophrenia.J. Biol. Chem.201028547366253663410.1074/jbc.M110.159954 20864528
     [Google Scholar]
  44. Soares-CunhaC. CoimbraB. SousaN. RodriguesA.J. Reappraising striatal D1 and D2-neurons in reward and aversion.Neurosci. Biobehav. Rev.20166837038610.1016/j.neubiorev.2016.05.021 27235078
     [Google Scholar]
  45. KooJ.W. ChaudhuryD. HanM.H. NestlerE.J. Role of mesolimbic brain-derived neurotrophic factor in depression.Biol. Psychiatry2019861073874810.1016/j.biopsych.2019.05.020 31327473
     [Google Scholar]
  46. MarmotM.G. Status Syndrome.JAMA2006295111304130710.1001/jama.295.11.1304 16537740
     [Google Scholar]
  47. GodoyL.D. TareckiR.L. MeissnerK. DayP. ShaikhM.K. McKinneyA.M. Mindfulness training and stress reactivity in depression: Results from a controlled trial.Psychosom. Med.201880214114810.1097/PSY.0000000000000548 29389736
     [Google Scholar]
  48. KesslerR.C. BerglundP. DemlerO. JinR. MerikangasK.R. WaltersE.E. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication.Arch. Gen. Psychiatry200562659360210.1001/archpsyc.62.6.593 15939837
     [Google Scholar]
  49. HeimC. BinderE.B. Current research trends in early life stress and depression: Review of human studies on sensitive periods, gene–environment interactions, and epigenetics.Exp. Neurol.2012233110211110.1016/j.expneurol.2011.10.032 22101006
     [Google Scholar]
  50. FatimaM. AhmadM.H. SrivastavS. RizviM.A. MondalA.C. A selective D2 dopamine receptor agonist alleviates depression through up-regulation of tyrosine hydroxylase and increased neurogenesis in hippocampus of the prenatally stressed rats.Neurochem. Int.202013610473010.1016/j.neuint.2020.104730 32201282
     [Google Scholar]
  51. SantanaN. MengodG. ArtigasF. Quantitative analysis of the expression of dopamine D1 and D2 receptors in pyramidal and GABAergic neurons of the rat prefrontal cortex.Cereb. Cortex200919484986010.1093/cercor/bhn134 18689859
     [Google Scholar]
  52. Trantham-DavidsonH. NeelyL.C. LavinA. SeamansJ.K. Mechanisms underlying differential D1 versus D2 dopamine receptor regulation of inhibition in prefrontal cortex.J. Neurosci.20042447106521065910.1523/JNEUROSCI.3179‑04.2004 15564581
     [Google Scholar]
  53. McCarthyC.I. Chou-FreedC. RodríguezS.S. YaneffA. DavioC. RaingoJ. Constitutive activity of dopamine receptor type 1 (D1R) increases CaV2.2 currents in PFC neurons.J. Gen. Physiol.20201525e20191249210.1085/jgp.201912492 32259196
     [Google Scholar]
  54. ScornaienckiR. CantrupR. RushlowW.J. RajakumarN. Prefrontal cortical D1 dopamine receptors modulate subcortical D2 dopamine receptor-mediated stress responsiveness.Int. J. Neuropsychopharmacol.20091291195120810.1017/S1461145709000121 19275776
     [Google Scholar]
  55. BeaulieuJ.M. GainetdinovR.R. The physiology, signaling, and pharmacology of dopamine receptors.Pharmacol. Rev.201163118221710.1124/pr.110.002642 21303898
     [Google Scholar]
  56. ZhangB. GuoF. MaY. Activation of D1R/PKA/mTOR signaling cascade in medial prefrontal cortex underlying the antidepressant effects of l-SPD.Sci. Rep.201771380910.1038/s41598‑017‑03680‑2 28630404
     [Google Scholar]
  57. WohlebE.S. GerhardD. ThomasA. DumanR.S. Molecular and cellular mechanisms of rapid-acting antidepressants ketamine and scopolamine.Curr. Neuropharmacol.2017151112010.2174/1570159X14666160309114549 26955968
     [Google Scholar]
  58. HareB.D. ShinoharaR. LiuR.J. PothulaS. DiLeoneR.J. DumanR.S. Optogenetic stimulation of medial prefrontal cortex Drd1 neurons produces rapid and long-lasting antidepressant effects.Nat. Commun.201910122310.1038/s41467‑018‑08168‑9 30644390
     [Google Scholar]
  59. ShinoharaR. TaniguchiM. EhrlichA.T. Dopamine D1 receptor subtype mediates acute stress-induced dendritic growth in excitatory neurons of the medial prefrontal cortex and contributes to suppression of stress susceptibility in mice.Mol. Psychiatry20182381717173010.1038/mp.2017.177 28924188
     [Google Scholar]
  60. GeeS. EllwoodI. PatelT. LuongoF. DeisserothK. SohalV.S. Synaptic activity unmasks dopamine D2 receptor modulation of a specific class of layer V pyramidal neurons in prefrontal cortex.J. Neurosci.201232144959497110.1523/JNEUROSCI.5835‑11.2012 22492051
     [Google Scholar]
  61. PappM. GrucaP. LasonM. NiemczykM. WillnerP. The role of prefrontal cortex dopamine D2 and D3 receptors in the mechanism of action of venlafaxine and deep brain stimulation in animal models of treatment-responsive and treatment-resistant depression.J. Psychopharmacol.201933674875610.1177/0269881119827889 30789286
     [Google Scholar]
  62. WangJ. JiaY. LiG. The dopamine receptor D3 regulates lipopolysaccharide-induced depressive-like behavior in mice.Int. J. Neuropsychopharmacol.201821544846010.1093/ijnp/pyy005 29390063
     [Google Scholar]
  63. LiuW. GeT. LengY. The role of neural plasticity in depression: From hippocampus to prefrontal cortex.Neural Plast.2017201711110.1155/2017/6871089 28246558
     [Google Scholar]
  64. Palacios-FilardoJ. MellorJ.R. Neuromodulation of hippocampal long-term synaptic plasticity.Curr. Opin. Neurobiol.201954374310.1016/j.conb.2018.08.009 30212713
     [Google Scholar]
  65. KimJ.J. DiamondD.M. The stressed hippocampus, synaptic plasticity and lost memories.Nat. Rev. Neurosci.20023645346210.1038/nrn849 12042880
     [Google Scholar]
  66. WiescholleckV. Manahan-VaughanD. Antagonism of D1/D5 receptors prevents long-term depression (LTD) and learning-facilitated LTD at the perforant path-dentate gyrus synapse in freely behaving rats.Hippocampus201424121615162210.1002/hipo.22340 25112177
     [Google Scholar]
  67. LieberknechtV. CunhaM.P. JunqueiraS.C. Antidepressant-like effect of pramipexole in an inflammatory model of depression.Behav. Brain Res.201732036537310.1016/j.bbr.2016.11.007 27825895
     [Google Scholar]
  68. BagotR.C. PariseE.M. PeñaC.J. Ventral hippocampal afferents to the nucleus accumbens regulate susceptibility to depression.Nat. Commun.201561706210.1038/ncomms8062 25952660
     [Google Scholar]
  69. YangY. WangH. HuJ. HuH. Lateral habenula in the pathophysiology of depression.Curr. Opin. Neurobiol.201848909610.1016/j.conb.2017.10.024 29175713
     [Google Scholar]
  70. CerniauskasI. WintererJ. de JongJ.W. Chronic stress induces activity, synaptic, and transcriptional remodeling of the lateral habenula associated with deficits in motivated behaviors.Neuron20191045899915.e810.1016/j.neuron.2019.09.005 31672263
     [Google Scholar]
  71. SeoJ-S. ZhongP. LiuA. YanZ. GreengardP. Elevation of p11 in lateral habenula mediates depression-like behavior.Mol. Psychiatry20182351113111910.1038/mp.2017.96 28507317
     [Google Scholar]
  72. LiK. ZhouT. LiaoL. βCaMKII in lateral habenula mediates core symptoms of depression.Science201334161491016102010.1126/science.1240729 23990563
     [Google Scholar]
  73. MatsumotoM. HikosakaO. Lateral habenula as a source of negative reward signals in dopamine neurons.Nature200744771481111111510.1038/nature05860 17522629
     [Google Scholar]
  74. ChanJ. NiY. ZhangP. ZhangJ. ChenY. D1-like dopamine receptor dysfunction in the lateral habenula nucleus increased anxiety-like behavior in rat.Neuroscience201734054255010.1016/j.neuroscience.2016.11.005 27865867
     [Google Scholar]
  75. ProulxC.D. HikosakaO. MalinowR. Reward processing by the lateral habenula in normal and depressive behaviors.Nat. Neurosci.20141791146115210.1038/nn.3779 25157511
     [Google Scholar]
  76. HuiY. DuC. XuT. ZhangQ. TanH. LiuJ. Dopamine D4 receptors in the lateral habenula regulate depression-related behaviors via a pre-synaptic mechanism in experimental Parkinson’s disease.Neurochem. Int.202014010484410.1016/j.neuint.2020.104844 32891683
     [Google Scholar]
  77. RootD.H. MelendezR.I. ZaborszkyL. NapierT.C. The ventral pallidum: Subregion-specific functional anatomy and roles in motivated behaviors.Prog. Neurobiol.2015130297010.1016/j.pneurobio.2015.03.005 25857550
     [Google Scholar]
  78. SmithK.S. TindellA.J. AldridgeJ.W. BerridgeK.C. Ventral pallidum roles in reward and motivation.Behav. Brain Res.2009196215516710.1016/j.bbr.2008.09.038 18955088
     [Google Scholar]
  79. TooleyJ. MarconiL. AlipioJ.B. Glutamatergic ventral pallidal neurons modulate activity of the habenula-tegmental circuitry and constrain reward seeking.Biol. Psychiatry201883121012102310.1016/j.biopsych.2018.01.003 29452828
     [Google Scholar]
  80. FagetL. ZellV. SouterE. Opponent control of behavioral reinforcement by inhibitory and excitatory projections from the ventral pallidum.Nat. Commun.20189184910.1038/s41467‑018‑03125‑y 29487284
     [Google Scholar]
  81. WenglerK. AshinoffB.K. PueraroE. CassidyC.M. HorgaG. RutherfordB.R. Association between neuromelanin-sensitive MRI signal and psychomotor slowing in late-life depression.Neuropsychopharmacology20214671233123910.1038/s41386‑020‑00860‑z
     [Google Scholar]
  82. WiseT. RaduaJ. ViaE. Common and distinct patterns of grey-matter volume alteration in major depression and bipolar disorder: Evidence from voxel-based meta-analysis.Mol. Psychiatry201722101455146310.1038/mp.2016.72 27217146
     [Google Scholar]
  83. BrandlF. WeiseB. Mulej BratecS. Common and specific large-scale brain changes in major depressive disorder, anxiety disorders, and chronic pain: A transdiagnostic multimodal meta-analysis of structural and functional MRI studies.Neuropsychopharmacology20224751071108010.1038/s41386‑022‑01271‑y
     [Google Scholar]
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The Potential Role of Dopamine Pathways in the Pathophysiology of Depression: Current Advances and Future Aspects
CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) 24, 340 (2025); https://doi.org/10.2174/0118715273357909241126064951
/content/journals/cnsnddt/10.2174/0118715273357909241126064951
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  • Article Type:     Review Article
Keyword(s): Depression; dopamine pathways; mesocortical pathway; mesolimbic pathway; nigrostriatal pathway; thalamic-tuberoinfundibular pathway

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