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Involvement of DA D3 Receptors in Structural Neuroplasticity of Selected Limbic Brain Circuits: Possible Role in Treatment-Resistant Depression

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Therapeutic Applications of Dopamine D3 Receptor Function

Part of the book series: Current Topics in Behavioral Neurosciences ((CTBN,volume 60))

Abstract

Structural neuroplasticity in the adult brain is a process involving quantitative changes of the number and size of neurons and of their dendritic arborization, axon branching, spines, and synapses. These changes can occur in specific neural circuits as adaptive response to environmental challenges, exposure to stressors, tissue damage or degeneration. Converging studies point to evidence of structural plasticity in circuits operated by glutamate, GABA, dopamine, and serotonin neurotransmitters, in concert with neurotrophic factors such as Brain Derived Neurotrophic Factor (BDNF) or Insulin Growth Factor 1 (IGF1) and a series of modulators that include circulating hormones. Intriguingly, most of these endogenous agents trigger the activation of the PI3K/Akt/mTOR and ERK1/2 intracellular pathways that, in turn, lead to the production of growth-related structural changes, enhancing protein synthesis, metabolic enzyme functions, mitogenesis for energy, and new lipid-bilayer membrane apposition. The dopamine (DA) D3 receptor has been shown to play a specific role by inducing structural plasticity of the DAergic neurons of the nigrostriatal and mesocorticolimbic circuit, where they are expressed in rodents and humans, via activation of the mTORC1 and ERK1/2 pathways. These effects are BDNF-dependent and require the recruitment of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors to allow the structural changes. Since in mood disorders, depression and anhedonia have been proposed to be associated with impaired neuroplasticity and reduced DAergic tone in brain circuits connecting prefrontal cortex, ventral striatum, amygdala, and ventral mesencephalon, activation of D3 receptors could provide a therapeutic benefit. Sustained improvements of mood and anhedonia were observed in subjects with an unsatisfactory response to serotonin uptake inhibitors (SSRI) when treated with D3-preferential D2/D3 agonists such as pramipexole and ropinirole. The recent evidence that downstream mTOR pathway activation in human mesencephalic DA neurons is also produced by ketamine, probably the most effective antidepressant currently used in subjects with treatment-resistant depression, further supports the rationale for a D3 receptor activation in mood disorders.

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References

  • Accili D, Fishburn CS, Drago J, Steiner H, Lachowicz JE, Park BH, Gauda EB, Lee EJ, Cool MH, Sibley DR, Gerfen CR, Westphal H, Fuchs S (1996) A targeted mutation of the D3 dopamine receptor gene is associated with hyperactivity in mice. Proc Natl Acad Sci U S A 93(5):1945–1949

    Article  CAS  Google Scholar 

  • Autry AE, Adachi M, Nosyreva E, Na ES, Los MF, Cheng PF et al (2011) NMDA receptor blockade at rest triggers rapid behavioral antidepressant responses. Nature 475:91–95

    Article  CAS  Google Scholar 

  • Baik JH, Picetti R, Saiardi A, Thiriet G, Dierich A, Depaulis A et al (1995) Parkinsonian-like locomotor impairment in mice lacking dopamine D2 receptors. Nature 377(6548):424–428

    Article  CAS  Google Scholar 

  • Barone P, Poewe W, Albrecht S, Debieuvre C, Massey D, Rascol O et al (2010) Pramipexole for the treatment of depressive symptoms in patients with Parkinson’s disease: a randomised, double-blind, placebo-controlled trial. Lancet Neurol 9:573–580

    Article  CAS  Google Scholar 

  • Beom SR, Cheong D, Torres G, Caron MG, Kim KM (2004) Comparative studies of molecular mechanisms of dopamine D2 and D3 receptors for the activation of extracellular signal-regulated kinase. J Biol Chem 279:28304–28314

    Article  CAS  Google Scholar 

  • Berman RM, Marcus RN, Swanink R, McQuade RD, Carson WH, Corey-Lisle PK et al (2007) The efficacy and safety of aripiprazole as adjunctive therapy in major depressive disorder: a multicenter, randomized, double-blind, placebo-controlled study. J Clin Psychiatry 68:843–853

    Article  CAS  Google Scholar 

  • Bessa JM, Ferreira D, Melo I, Marques F, Cerqueira JJ, Palha JA et al (2009) The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling. Mol Psychiatry 14:764–777

    Article  CAS  Google Scholar 

  • Bongarzone ER, Howard SG, Schonmann V, Campagnoni AT (1998) Identification of the dopamine D3 receptor in oligodendrocyte precursors: potential role in regulating differentiation and myelin formation. J Neurosci 18(14):5344–5353

    Article  CAS  Google Scholar 

  • Breuer ME, Groenink L, Oosting RS, Buerger E, Korte M, Ferger B et al (2009) Antidepressant effects of pramipexole, a dopamine D3/D2 receptor agonist, and 7-OH-DPAT, a dopamine D3 receptor agonist, in olfactory bulbectomized rats. Eur J Pharmacol 616:134–140

    Article  CAS  Google Scholar 

  • Castrén E, Monteggia LM (2021) Brain-derived neurotrophic factor signaling in depression and antidepressant action. Biol Psychiatry 90(2):128–136

    Article  Google Scholar 

  • Castrén E, Rantamäki T (2010) The role of BDNF and its receptors in depression and antidepressant drug action: reactivation of developmental plasticity. Dev Neurobiol 70:289–297

    Article  Google Scholar 

  • Cavalleri L, Merlo Pich E, Millan MJ, Chiamulera C, Kunath T, Spano PF, Collo G (2018) Ketamine enhances structural plasticity in mouse mesencephalic and human iPSC-derived dopaminergic neurons via AMPAR-driven BDNF and mTOR signaling. Mol Psychiatry 23(4):812–823

    Article  CAS  Google Scholar 

  • Chen F, Madsen TM, Wegener G, Nyengaard JR (2009) Repeated electroconvulsive seizures increase the total number of synapses in adult male rat hippocampus. Eur Neuropsychopharmacol 19:329–338

    Article  CAS  Google Scholar 

  • Christoffel DJ, Golden SA, Russo SJ (2011) Structural and synaptic plasticity in stress-related disorders. Rev Neurosci 22:535–549

    Article  CAS  Google Scholar 

  • Clarkson RL, Liptak AT, Gee SM, Sohal VS, Bender KJ (2017) D3 receptors regulate excitability in a unique class of prefrontal pyramidal cells. J Neurosci 37(24):5846–5860

    Article  CAS  Google Scholar 

  • Collo G, Zanetti S, Missale C, Spano PF (2008) Dopamine D3 receptor-preferring agonists increase dendrite arborization of mesencephalic dopaminergic neurons via extracellular signal-regulated kinase phosphorylation. Eur J Neurosci 28:1231–1240

    Article  Google Scholar 

  • Collo G, Bono F, Cavalleri L, Plebani L, Merlo Pich E, Millan MJ et al (2012) Pre-synaptic dopamine D3 receptor mediates cocaine-induced structural plasticity in mesencephalic dopaminergic neurons via ERK and Akt pathways. J Neurochem 120:765–778

    Article  CAS  Google Scholar 

  • Collo G, Cavalleri L, Bono F, Mora C, Fedele S, Invernizzi RW, Gennarelli M, Piovani G, Kunath T, Millan MJ, Merlo Pich E, Spano P (2018) Ropinirole and pramipexole promote structural plasticity in human iPSC-derived dopaminergic neurons via BDNF and mTOR signaling. Neural Plast:4196961

    Google Scholar 

  • Collo G, Merlo Pich E (2018) Ketamine enhances structural plasticity in human dopaminergic neurons: possible relevance for treatment-resistant depression. Neural Regen Res 13(4):645–646

    Article  CAS  Google Scholar 

  • Cussac D, Newman-Tancredi A, Pasteau V, Millan MJ (1999) Human dopamine D3 receptors mediate mitogen-activated proteinkinase activation via a phosphatidylinositol 3-kinase and an atypical protein kinase C-dependent mechanism. Mol Pharmacol 56:1025–1103

    Article  CAS  Google Scholar 

  • Der-Avakian A, Mazei-Robison MS, Kesby JP, Nestler EJ, Markou A (2014) Enduring deficits in brain reward function after chronic social defeat in rats: susceptibility, resilience, and antidepressant response. Biol Psychiatry 76:542–549

    Article  CAS  Google Scholar 

  • Diaz J, Pilon C, Le Foll B, Gros C, Triller A, Schwartz JC, Sokoloff P (2000) Dopamine D3 receptors expressed by all mesencephalic dopamine neurons. J Neurosci 20(23):8677–8684

    Article  CAS  Google Scholar 

  • Drevets WC, Price JL, Furey ML (2008) Brain structural and functional abnormalities in mood disorders: implications for neurocircuitry models of depression. Brain Struct Funct 213:93–118

    Article  Google Scholar 

  • Du F, Li R, Huang Y, Li X, Le W (2005) Dopamine D3 receptor-preferring agonists induce neurotrophic effects on mesencephalic dopamine neurons. Eur J Neurosci 22(10):2422–2430

    Article  Google Scholar 

  • Dukart J, Regen F, Kherif F, Colla M, Bajbouj M, Heuser I et al (2014) Electroconvulsive therapy-induced brain plasticity determines therapeutic outcome in mood disorders. Proc Natl Acad Sci U S A 111:1156–1161

    Google Scholar 

  • Duman RS, Aghajanian GK, Sanacora G, Krystal JH (2016) Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants. Nat Med 22:238–249

    Article  CAS  Google Scholar 

  • Durgam S, Earley W, Guo H, Li D, Németh G, Laszlovszky I et al (2016) Efficacy and safety of adjunctive cariprazine in inadequate responders to antidepressants: a randomized, double-blind, placebo-controlled study in adult patients with major depressive disorder. J Clin Psychiatry 77:371–378

    Article  Google Scholar 

  • Fawcett J, Rush AJ, Vukelich J, Diaz SH, Dunklee L, Romo P et al (2016) Clinical experience with high dose pramipexole in treatment resistant mood disorder patients. Am J Psychiatry 173:107–111

    Article  Google Scholar 

  • Fedele S, Collo G, Behr K, Bischofberger J, Müller S, Kunath T, Christensen K, Gündner AL, Graf M, Jagasia R, Taylor V (2017) Expansion of human midbrain floor plate progenitors from induced pluripotent stem cells increases dopaminergic neuron differentiation potential. Sci Rep 7(1):6036

    Article  Google Scholar 

  • Ford CP (2014) The role of D2-autoreceptors in regulating dopamine neuron activity and transmission. Neuroscience 282:13–22

    Article  CAS  Google Scholar 

  • Guillin O, Diaz J, Carroll P, Griffon N, Schwartz JC, Sokoloff P (2001) BDNF controls dopamine D3 receptor expression and triggers behavioural sensitization. Nature 411(6833):86–89

    Article  CAS  Google Scholar 

  • Gurevich EV, Joyce JN (1999) Distribution of dopamine D3 receptor expressing neurons in the human forebrain: comparison with D2 receptor expressing neurons. Neuropsychopharmacology 20(1):60–80

    Article  CAS  Google Scholar 

  • Jernigan CS, Goswami DB, Austin MC, Iyo AH, Chandran A, Stockmeier CA et al (2011) The mTOR signaling pathway in the prefrontal cortex is compromised in major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry 35:1774–1779

    Article  CAS  Google Scholar 

  • Jourdi H, Hsu YT, Zhou M, Qin Q, Bi X, Baudry M (2009) Positive AMPA receptor modulation rapidly stimulates BDNF release and increases dendritic mRNA translation. J Neurosci 29:8688–8697

    Article  CAS  Google Scholar 

  • Joyce JN, Woolsey C, Ryoo H, Borwege S, Hagner D (2004) Low dose pramipexole is neuroprotective in the MPTP mouse model of Parkinson's disease, and downregulates the dopamine transporter via the D3 receptor. BMC Biol 2:22

    Article  Google Scholar 

  • Kim KM, Valenzano KJ, Robinson SR, Yao WD, Barak LS, Caron MG (2001) Differential regulation of the dopamine D2 and D3 receptors by G protein-coupled receptor kinases and beta-arrestins. J Biol Chem 276(40):37409–37414

    Article  CAS  Google Scholar 

  • Koeltzow TE, Xu M, Cooper DC, Hu XT, Tonegawa S, Wolf ME, White FJ (1998) Alterations in dopamine release but not dopamine autoreceptor function in dopamine D3 receptor mutant mice. J Neurosci 18(6):2231–2238

    Article  CAS  Google Scholar 

  • Koleske AJ (2013) Molecular mechanisms of dendrite stability. Nat Rev Neurosci 14(8):536–550

    Article  CAS  Google Scholar 

  • Kriks S, Shim JW, Piao J, Ganat YM, Wakeman DR, Xie Z, Carrillo-Reid L, Auyeung G, Antonacci C, Buch A et al (2011) Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson’s disease. Nature 480(7378):547–551

    Article  CAS  Google Scholar 

  • Kumar V, Zhang MX, Swank MV, Kunz J, Wu GY (2005) Regulation of dendritic morphogenesis by Ras-PI3K-AktmTOR and Ras-MAPK signaling pathways. J Neurosci 25(49):11288–11299

    Article  CAS  Google Scholar 

  • Leggio GM, Salomone S, Bucolo C, Platania C, Micale V, Caraci F et al (2013) Dopamine D(3) receptor as a new pharmacological target for the treatment of depression. Eur J Pharmacol 719:25–33

    Article  CAS  Google Scholar 

  • Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M et al (2010) mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 329:959–964

    Article  CAS  Google Scholar 

  • Li Y, Zhu ZR, Ou BC, Wang YQ, Tan ZB, Deng CM, Gao YY et al (2015) Dopamine D2/D3 but not dopamine D1 receptors are involved in the rapid antidepressant-like effects of ketamine in the forced swim test. Behav Brain Res 279:100–105

    Article  CAS  Google Scholar 

  • Liston C, Gan WB (2011) Glucocorticoids are critical regulators of dendritic spine development and plasticity in vivo. Proc Natl Acad Sci U S A 108(38):16074–16079

    Article  CAS  Google Scholar 

  • Mattson MP, Gleichmann M, Cheng A (2008) Mitochondria in neuroplasticity and neurological disorders. Neuron 60(5):748–766

    Article  CAS  Google Scholar 

  • McGinnis MM, Siciliano CA, Jones SR (2016) Dopamine D3 autoreceptor inhibition enhances cocaine potency at the dopamine transporter. J Neurochem 138(6):821–829

    Article  CAS  Google Scholar 

  • Miller OH, Moran JT, Hall BJ (2016) Two cellular hypotheses explaining the initiation of ketamine’s antidepressant actions: direct inhibition and disinhibition. Neuropharmacology 100:17–26

    Article  CAS  Google Scholar 

  • Miyazaki I, Asanuma M, Diaz-Corrales FJ, Miyoshi K, Ogawa N (2004) Direct evidence for expression of dopamine receptors in astrocytes from basal ganglia. Brain Res 1029(1):120–123

    Article  CAS  Google Scholar 

  • Montoya A, Elgueta D, Campos J, Chovar O, Falcón P, Matus S, Alfaro I, Bono MR, Pacheco R (2019) Dopamine receptor D3 signaling in astrocytes promotes neuroinflammation. J Neuroinflammation 16(1):258

    Article  CAS  Google Scholar 

  • Mueller D, Chapman CA, Stewart J (2006) Amphetamine induces dendritic growth in ventral tegmental area dopaminergic neurons in vivo via basic fibroblast growth factor. Neuroscience 137:727–735

    Article  CAS  Google Scholar 

  • Razgado-Hernandez LF, Espadas-Alvarez AJ, Reyna-Velazquez P, Sierra-Sanchez A, Anaya-Martinez V, Jimenez-Estrada I, Bannon MJ, Martinez-Fong D, Aceves-Ruiz J (2015) The transfection of BDNF to dopamine neurons potentiates the effect of dopamine D3 receptor agonist recovering the striatal innervation, dendritic spines and motor behavior in an aged rat model of Parkinson’s disease. PLoS One 10(2):e0117391

    Article  Google Scholar 

  • Reinhart V, Bove SE, Volfson D, Lewis DA, Kleiman RJ, Lanz TA (2015) Evaluation of TrkB and BDNF transcripts in prefrontal cortex, hippocampus, and striatum from subjects with schizophrenia, bipolar disorder, and major depressive disorder. Neurobiol Dis 77:220–227

    Article  CAS  Google Scholar 

  • Rodríguez-Sánchez M, Escartín-Pérez RE, Leyva-Gómez G, Avalos-Fuentes JA, Paz-Bermúdez FJ, Loya-López SI, Aceves J, Erlij D, Cortés H, Florán B (2019) Blockade of intranigral and systemic D3 receptors stimulates motor activity in the rat promoting a reciprocal interaction among glutamate, dopamine, and GABA. Biomol Ther 9(10):511

    Google Scholar 

  • Salles MJ, Hervé D, Rivet JM, Longueville S, Millan MJ, Girault JA, Mannoury la Cour C (2013) Transient and rapid activation of Akt/GSK-3β and mTORC1 signaling by D3 dopamine receptor stimulation in dorsal striatum and nucleus accumbens. J Neurochem 125(4):532–544

    Article  CAS  Google Scholar 

  • Schwarz A, Gozzi A, Reese T, Bertani S, Crestan V, Hagan J, Heidbreder C, Bifone A (2004) Selective dopamine D3 receptor antagonist SB-277011-A potentiates phMRI response to acute amphetamine challenge in the rat brain. Synapse 54:1–10

    Article  CAS  Google Scholar 

  • Schwartz J, Murrough JW, Iosifescu DV (2016) Ketamine for treatment-resistant depression: recent developments and clinical applications. Evid Based Ment Health 19(2):35–38

    Article  Google Scholar 

  • Tundo A, Betro’ S, Iomm MI, de Filippis R (2022) Efficacy and safety of 24-week pramipexole augmentation in patients with treatment resistant depression. A retrospective cohort study. Prog Neuropsychopharmacol Biol Psychiatry 112:110425

    Article  CAS  Google Scholar 

  • Van Kampen JM, Eckman CB (2006) Dopamine D3 receptor agonist delivery to a model of Parkinson's disease restores the nigrostriatal pathway and improves locomotor behavior. J Neurosci 26:7272–7280

    Article  Google Scholar 

  • Watson DJ, Loiseau F, Ingallinesi M, Millan MJ, Marsden CA, Fone KC (2012) Selective blockade of dopamine D3 receptors enhances while D2 receptor antagonism impairs social novelty discrimination and novel object recognition in rats: a key role for the prefrontal cortex. Neuropsychopharmacology 37:770–786

    Article  CAS  Google Scholar 

  • Yang P, Perlmutter JS, Benzinger T, Morris JC, Xu J (2020) Dopamine D3 receptor: a neglected participant in Parkinson disease pathogenesis and treatment? Ageing Res Rev 57:100994. https://doi.org/10.1016/j.arr.2019.100994

    Article  CAS  Google Scholar 

  • Zanos P, Gould TD (2018) Mechanisms of ketamine action as an antidepressant. Mol Psychiatry 23(4):801–811

    Article  CAS  Google Scholar 

  • Zapata A, Shippenberg TS (2005) Lack of functional D2 receptors prevents the effects of the D3-preferring agonist (+)-PD 128907 on dialysate dopamine levels. Neuropharmacology 48(1):43–50

    Article  CAS  Google Scholar 

  • Zhang Y, Chen K, Sloan SA, Bennett ML, Scholze AR, O'Keeffe S, Phatnani HP, Guarnieri P et al (2014) An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci 34(36):11929–11947

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Research & Development, Alfasigma SpA, Bologna, Italy

    Emilio Merlo Pich & Caterina Toma

  2. Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy

    Laura Cavalleri & Ginetta Collo

Authors
  1. Emilio Merlo Pich
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  2. Laura Cavalleri
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  3. Caterina Toma
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  4. Ginetta Collo
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Correspondence to Emilio Merlo Pich .

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Editors and Affiliations

  1. Addiction Imaging Research Group, Centre for Addiction and Mental Health, Toronto, ON, Canada

    Isabelle Boileau

  2. Dept of Molecular&Translational Medicine, University of Brescia, Brescia, Italy

    Ginetta Collo

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Merlo Pich, E., Cavalleri, L., Toma, C., Collo, G. (2022). Involvement of DA D3 Receptors in Structural Neuroplasticity of Selected Limbic Brain Circuits: Possible Role in Treatment-Resistant Depression. In: Boileau, I., Collo, G. (eds) Therapeutic Applications of Dopamine D3 Receptor Function. Current Topics in Behavioral Neurosciences, vol 60. Springer, Cham. https://doi.org/10.1007/7854_2022_348

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