Memory Dysfunction Correlates with the Dysregulated Dopaminergic System in the Ventral Tegmental Area in Alzheimer’s Disease



Alzheimer’s disease (AD) is one of the neurodegenerative diseases associated with neuroinflammation. Tau neurofibrillary tangles and amyloid beta (Aβ) plaques can activate microglia and then elevate the levels of neuroinflammatory mediators in AD models. The elevation of cytokines levels can lead to increased Aβ production, which is one of the causes of the pathogenesis of AD. Although it is noteworthy that AD is associated with deficit in cholinergic system, it also demonstrated that AD is associated with dopaminergic neurodegeneration in the ventral tegmental area (VTA). The VTA sends dopaminergic inputs into the hippocampus and regulates the memory and learning functions. The depletion of dopaminergic neurons in the VTA in AD models might lead to memory impairments and cognition deficit. We suggest here that that neurodegeneration in the dopamine neurons is involved in the development of dysregulated behaviors in AD animal models. In this chapter, we illustrate the role of AD-associated neuroinflammation in dopaminergic neurodegeneration in the VTA.


Alzheimer’s disease Neuroinflammation Memory dysfunction Ventral tegmental area Dopaminergic neurodegeneration 



The book chapter was written during the period of fund supported by the International Scientific Partnership Program (ISPP-146) from the Deanship of Scientific Research, King Saud University.

Conflict of Interest

The authors declare no conflict of interest.


  1. 1.
    Hebert LE, Weuve J, Scherr PA, Evans DA (2013) Alzheimer disease in the United States (2010–2050) estimated using the 2010 census. Neurology 80:1778–1783PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Duckett L (2001) Alzheimer’s dementia: morbidity and mortality. J Insurance Med (New York, NY) 33:227–234Google Scholar
  3. 3.
    Todd S, Barr S, Passmore AP (2013) Cause of death in Alzheimer’s disease: a cohort study. QJM Int J Med 106:747–753CrossRefGoogle Scholar
  4. 4.
    Hebert LE, Scherr PA, Bienias JL, Bennett DA, Evans DA (2003) Alzheimer disease in the US population: prevalence estimates using the 2000 census. Arch Neurol 60:1119–1122PubMedCrossRefPubMedCentralGoogle Scholar
  5. 5.
    Weuve J, Hebert LE, Scherr PA, Evans DA (2014) Deaths in the United States among persons with Alzheimer’s disease (2010–2050). Alzheimer’s Dement 10:e40–e46CrossRefGoogle Scholar
  6. 6.
    Arriagada PV, Growdon JH, Hedley-Whyte ET, Hyman BT (1992) Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer’s disease. Neurology 42:631–631PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Bancher C, Brunner C, Lassmann H, Budka H, Jellinger K, Wiche G, Seitelberger F, Grundke-Iqbal I, Iqbal K, Wisniewski HM (1989) Accumulation of abnormally phosphorylated τ precedes the formation of neurofibrillary tangles in Alzheimer’s disease. Brain Res 477:90–99PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Brion J-P (1998) Neurofibrillary tangles and Alzheimer’s disease. Eur Neurol 40:130–140PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Metaxas A, Kempf SJ (2016) Neurofibrillary tangles in Alzheimer’s disease: elucidation of the molecular mechanism by immunohistochemistry and tau protein phospho-proteomics. Neural Regener Res 11:1579CrossRefGoogle Scholar
  10. 10.
    Beharry C, Cohen LS, Di J, Ibrahim K, Briffa-Mirabella S, Alonso Adel C (2014) Tau-induced neurodegeneration: mechanisms and targets. Neurosci Bull 30:346–358PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Iqbal K, Liu F, Gong CX, Alonso Adel C, Grundke-Iqbal I (2009) Mechanisms of tau-induced neurodegeneration. Acta Neuropathol 118:53–69PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Cacabelos R, Barquero M, Garcia P, Alvarez XA, de Seijas Varela E (1991) Cerebrospinal fluid interleukin-1 beta (IL-1 beta) in Alzheimer’s disease and neurological disorders. Methods Find Exp Clin Pharmacol 13:455–458PubMedGoogle Scholar
  13. 13.
    Griffin WS, Stanley LC, Ling CHEN, White L, MacLeod V, Perrot LJ, White CL 3rd, Araoz C (1989) Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease. Proc Natl Acad Sci 86:7611–7615PubMedCrossRefGoogle Scholar
  14. 14.
    Ng A, Tam WW, Zhang MW, Ho CS, Husain SF, McIntyre RS, Ho RC (2018) IL-1β, IL-6, TNF-α and CRP in elderly patients with depression or Alzheimer’s disease: systematic review and meta-analysis. Sci Rep 8:12050PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Belkhelfa M, Rafa H, Medjeber O, Arroul-Lammali A, Behairi N, Abada-Bendib M, Makrelouf M, Belarbi S, Masmoudi AN, Tazir M (2014) IFN-γ and TNF-α are involved during Alzheimer disease progression and correlate with nitric oxide production: a study in Algerian patients. J Interferon Cytokine Res 34:839–847PubMedCrossRefGoogle Scholar
  16. 16.
    Fillit H, Ding W, Buee L, Kalman J, Altstiel L, Lawlor B, Wolf-Klein G (1991) Elevated circulating tumor necrosis factor levels in Alzheimer’s disease. Neurosci Lett 129:318–320PubMedCrossRefGoogle Scholar
  17. 17.
    Komurcu HF, Kilic N, Demirbilek ME, Akin KO (2016) Plasma levels of vitamin B12, epidermal growth factor and tumor necrosis factor alpha in patients with Alzheimer dementia. Int J Res Med Sci 4:734–738CrossRefGoogle Scholar
  18. 18.
    Swardfager W, Lanctôt K, Rothenburg L, Wong A, Cappell J, Herrmann N (2010) A meta-analysis of cytokines in Alzheimer’s disease. Biol Psychiatry 68:930–941PubMedCrossRefGoogle Scholar
  19. 19.
    Alasmari F, Alshammari MA, Alasmari AF, Alanazi WA, Alhazzani K (2018a) Neuroinflammatory cytokines induce amyloid beta neurotoxicity through modulating amyloid precursor protein levels/metabolism. Biomed Res Int 2018:3087475PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Alasmari F, Ashby CR Jr, Hall FS, Sari Y, Tiwari AK (2018b) Modulation of the ATP-binding Cassette B1 transporter by neuro-inflammatory cytokines: role in the pathogenesis of Alzheimer’s disease. Front Pharmacol 9:658PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Shoghi-Jadid K, Small GW, Agdeppa ED, Kepe V, Ercoli LM, Siddarth P, Read S, Satyamurthy N, Petric A, Huang SC, Barrio JR (2002) Localization of neurofibrillary tangles and beta-amyloid plaques in the brains of living patients with Alzheimer disease. Am J Geriatr Psychiatry 10:24–35PubMedCrossRefGoogle Scholar
  22. 22.
    Forloni G, Demicheli F, Giorgi S, Bendotti C, Angeretti N (1992) Expression of amyloid precursor protein mRNAs in endothelial, neuronal and glial cells: modulation by interleukin-1. Mol Brain Res 16:128–134PubMedCrossRefGoogle Scholar
  23. 23.
    Walther W, Kobelt D, Bauer L, Aumann J, Stein U (2015) Chemosensitization by diverging modulation by short-term and long-term TNF-alpha action on ABCB1 expression and NF-kappaB signaling in colon cancer. Int J Oncol 47:2276–2285PubMedCrossRefGoogle Scholar
  24. 24.
    Alberdi E, Sánchez-Gómez MV, Cavaliere F, Pérez-Samartín A, Zugaza JL, Trullas R, Domercq M, Matute C (2010) Amyloid β oligomers induce Ca2+ dysregulation and neuronal death through activation of ionotropic glutamate receptors. Cell Calcium 47:264–272PubMedCrossRefGoogle Scholar
  25. 25.
    Nobili A, Latagliata EC, Viscomi MT, Cavallucci V, Cutuli D, Giacovazzo G, Krashia P, Rizzo FR, Marino R, Federici M (2017) Dopamine neuronal loss contributes to memory and reward dysfunction in a model of Alzheimer’s disease. Nat Commun 8:14727PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Holtzman-Assif O, Laurent V, Westbrook RF (2010) Blockade of dopamine activity in the nucleus accumbens impairs learning extinction of conditioned fear. Learn Mem 17:71–75PubMedCrossRefGoogle Scholar
  27. 27.
    Russo SJ, Nestler EJ (2013) The brain reward circuitry in mood disorders. Nat Rev Neurosci 14:609–625PubMedCrossRefGoogle Scholar
  28. 28.
    Tizabi Y, Bai L, Copeland RL Jr, Taylor RE (2007) Combined effects of systemic alcohol and nicotine on dopamine release in the nucleus accumbens shell. Alcohol Alcohol 42:413–416PubMedCrossRefGoogle Scholar
  29. 29.
    Tizabi Y, Copeland RL Jr, Louis VA, Taylor RE (2002) Effects of combined systemic alcohol and central nicotine administration into ventral tegmental area on dopamine release in the nucleus accumbens. Alcohol Clin Exp Res 26:394–399PubMedCrossRefGoogle Scholar
  30. 30.
    Di Chiara G (1998) A motivational learning hypothesis of the role of mesolimbic dopamine in compulsive drug use. J Psychopharmacol 12:54–67PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Lisman JE, Grace AA (2005) The hippocampal-VTA loop: controlling the entry of information into long-term memory. Neuron 46:703–713PubMedCrossRefGoogle Scholar
  32. 32.
    Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, Jacobs AH, Wyss-Coray T, Vitorica J, Ransohoff RM (2015) Neuroinflammation in Alzheimer’s disease. Lancet Neurol 14:388–405PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Yan SD, Chen X, Fu J, Chen M, Zhu H, Roher A, Slattery T, Zhao L, Nagashima M, Morser J, Migheli A, Nawroth P, Stern D, Schmidt AM (1996) RAGE and amyloid-beta peptide neurotoxicity in Alzheimer’s disease. Nature 382:685–691PubMedCrossRefGoogle Scholar
  34. 34.
    Chen WW, Zhang X, Huang WJ (2016) Role of neuroinflammation in neurodegenerative diseases (Review). Mol Med Rep 13:3391–3396PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Crews L, Masliah E (2010) Molecular mechanisms of neurodegeneration in Alzheimer’s disease. Hum Mol Genet 19:R12–R20PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Toledo EM, Inestrosa NC (2010) Activation of Wnt signaling by lithium and rosiglitazone reduced spatial memory impairment and neurodegeneration in brains of an APPswe/PSEN1DeltaE9 mouse model of Alzheimer’s disease. Mol Psychiatry 15(272–285):28Google Scholar
  37. 37.
    Tu S, Okamoto S, Lipton SA, Xu H (2014) Oligomeric Abeta-induced synaptic dysfunction in Alzheimer’s disease. Mol Neurodegener 9:48PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Patel NS, Paris D, Mathura V, Quadros AN, Crawford FC, Mullan MJ (2005) Inflammatory cytokine levels correlate with amyloid load in transgenic mouse models of Alzheimer’s disease. J Neuroinflammation 2:9PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Sivanesan S, Tan A, Rajadas J (2013) Pathogenesis of Abeta oligomers in synaptic failure. Curr Alzheimer Res 10:316–323PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Dani M, Wood M, Mizoguchi R, Fan Z, Walker Z, Morgan R, Hinz R, Biju M, Kuruvilla T, Brooks DJ (2018) Microglial activation correlates in vivo with both tau and amyloid in Alzheimer’s disease. Brain 141:2740–2754PubMedGoogle Scholar
  41. 41.
    Giovannini MG, Scali C, Prosperi C, Bellucci A, Vannucchi MG, Rosi S, Pepeu G, Casamenti F (2002) β-Amyloid-induced inflammation and cholinergic hypofunction in the rat brain in vivo: involvement of the p38MAPK pathway. Neurobiol Dis 11:257–274PubMedCrossRefGoogle Scholar
  42. 42.
    Yates SL, Burgess LH, Kocsis-Angle J, Antal JM, Dority MD, Embury PB, Piotrkowski AM, Brunden KR (2000) Amyloid β and amylin fibrils induce increases in proinflammatory cytokine and chemokine production by THP-1 cells and murine microglia. J Neurochem 74:1017–1025PubMedCrossRefGoogle Scholar
  43. 43.
    Perluigi M, Barone E, Di Domenico F, Butterfield DA (2016) Aberrant protein phosphorylation in Alzheimer disease brain disturbs pro-survival and cell death pathways. Biochimica et Biophysica Acta (BBA) Mol Basis Dis 1862:1871–1882CrossRefGoogle Scholar
  44. 44.
    Robertson LA, Moya KL, Breen KC (2004) The potential role of tau protein O-glycosylation in Alzheimer’s disease. J Alzheimer’s Dis 6:489–495CrossRefGoogle Scholar
  45. 45.
    Takahashi M, Tsujioka Y, Yamada T, Tsuboi Y, Okada H, Yamamoto T, Liposits Z (1999) Glycosylation of microtubule-associated protein tau in Alzheimer’s disease brain. Acta Neuropathol 97:635–641PubMedCrossRefGoogle Scholar
  46. 46.
    Grundke-Iqbal I, Iqbal K, Tung Y-C, Quinlan M, Wisniewski HM, Binder LI (1986) Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci 83:4913–4917PubMedCrossRefGoogle Scholar
  47. 47.
    Inoue H, Hiradate Y, Shirakata Y, Kanai K, Kosaka K, Gotoh A, Fukuda Y, Nakai Y, Uchida T, Sato E (2014) Site-specific phosphorylation of Tau protein is associated with deacetylation of microtubules in mouse spermatogenic cells during meiosis. FEBS Lett 588:2003–2008PubMedCrossRefGoogle Scholar
  48. 48.
    Bharadwaj PR, Dubey AK, Masters CL, Martins RN, Macreadie IG (2009) Aβ aggregation and possible implications in Alzheimer’s disease pathogenesis. J Cell Mol Med 13:412–421PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Blasko I, Apochal A, Boeck G, Hartmann T, Grubeck-Loebenstein B, Ransmayr G (2001) Ibuprofen decreases cytokine-induced amyloid beta production in neuronal cells. Neurobiol Dis 8:1094–1101PubMedCrossRefGoogle Scholar
  50. 50.
    Yamamoto M, Kiyota T, Horiba M, Buescher JL, Walsh SM, Gendelman HE, Ikezu T (2007) Interferon-γ and tumor necrosis factor-α regulate amyloid-β plaque deposition and β-secretase expression in Swedish mutant APP transgenic mice. Am J Pathol 170:680–692PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Caruso G, Fresta CG, Musso N, Giambirtone M, Grasso M, Spampinato SF, Merlo S, Drago F, Lazzarino G, Sortino MA (2019) Carnosine prevents Aβ-induced oxidative stress and inflammation in microglial cells: a key role of TGF-β1. Cells 8:64PubMedCentralCrossRefPubMedGoogle Scholar
  52. 52.
    Morales I, Guzmán-Martínez L, Cerda-Troncoso C, Farías GA, Maccioni RB (2014) Neuroinflammation in the pathogenesis of Alzheimer’s disease. A rational framework for the search of novel therapeutic approaches. Fron Cell Neurosci 8:112Google Scholar
  53. 53.
    Lee JW, Lee YK, Yuk DY, Choi DY, Ban SB, Ki Wan O, Hong JT (2008) Neuro-inflammation induced by lipopolysaccharide causes cognitive impairment through enhancement of beta-amyloid generation. J Neuroinflammation 5:37PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Sutinen EM, Pirttilä T, Anderson G, Salminen A, Ojala JO (2012) Pro-inflammatory interleukin-18 increases Alzheimer’s disease-associated amyloid-β production in human neuron-like cells. J Neuroinflamm 9:199CrossRefGoogle Scholar
  55. 55.
    Wang Z, Jackson RJ, Hong W, Taylor WM, Corbett GT, Moreno A, Liu W, Li S, Frosch MP, Slutsky I, Young-Pearse TL, Spires-Jones TL, Walsh DM (2017) Human brain-derived Abeta oligomers bind to synapses and disrupt synaptic activity in a manner that requires APP. J Neurosci 37:11947–11966PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Koffie RM, Meyer-Luehmann M, Hashimoto T, Adams KW, Mielke ML, Garcia-Alloza M, Micheva KD, Smith SJ, Kim ML, Lee VM, Hyman BT, Spires-Jones TL (2009) Oligomeric amyloid beta associates with postsynaptic densities and correlates with excitatory synapse loss near senile plaques. Proc Natl Acad Sci U S A 106:4012–4017PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Jurgensen S, Antonio LL, Mussi GE, Brito-Moreira J, Bomfim TR, De Felice FG, Garrido-Sanabria ER, Cavalheiro EA, Ferreira ST (2011) Activation of D1/D5 dopamine receptors protects neurons from synapse dysfunction induced by amyloid-beta oligomers. J Biol Chem 286:3270–3276PubMedCrossRefGoogle Scholar
  58. 58.
    Rapoport M, Dawson HN, Binder LI, Vitek MP, Ferreira A (2002) Tau is essential to beta -amyloid-induced neurotoxicity. Proc Natl Acad Sci U S A 99:6364–6369PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Iqbal K, Fei L, Gong C-X, Grundke-Iqbal I (2010) Tau in Alzheimer disease and related tauopathies. Curr Alzheimer Res 7:656–664PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Morales I, Jiménez JM, Mancilla M, Maccioni RB (2013) Tau oligomers and fibrils induce activation of microglial cells. J Alzheimer’s Dis 37:849–856CrossRefGoogle Scholar
  61. 61.
    Rohn TT, Head E, Joseph HS, Anderson AJ, Bahr BA, Cotman CW, Cribbs DH (2001) Correlation between caspase activation and neurofibrillary tangle formation in Alzheimer’s disease. Am J Pathol 158:189–198PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Kobayashi K, Nakano H, Hayashi M, Shimazaki M, Fukutani Y, Sasaki K, Sugimori K, Koshino Y (2003) Association of phosphorylation site of tau protein with neuronal apoptosis in Alzheimer’s disease. J Neurol Sci 208:17–24PubMedCrossRefGoogle Scholar
  63. 63.
    Wang J-Z, Grundke-Iqbal I, Iqbal K (2007) Kinases and phosphatases and tau sites involved in Alzheimer neurofibrillary degeneration. Eur J Neurosci 25:59–68PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Croft CL, Kurbatskaya K, Hanger DP, Noble W (2017) Inhibition of glycogen synthase kinase-3 by BTA-EG 4 reduces tau abnormalities in an organotypic brain slice culture model of Alzheimer’s disease. Sci Rep 7:7434PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Oka M, Fujisaki N, Maruko-Otake A, Ohtake Y, Shimizu S, Saito T, Hisanaga S-I, Iijima KM, Ando K (2017) Ca2+/calmodulin-dependent protein kinase II promotes neurodegeneration caused by tau phosphorylated at Ser262/356 in a transgenic Drosophila model of tauopathy. J Biochem 162:335–342PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Futch HS, Croft CL, Truong VQ, Krause EG, Golde TE (2017) Targeting psychologic stress signaling pathways in Alzheimer’s disease. Mol Neurodegener 12:49PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Vyas S, Rodrigues AJ, Silva JM, Tronche F, Almeida OFX, Sousa N, Sotiropoulos I (2016) Chronic stress and glucocorticoids: from neuronal plasticity to neurodegeneration. Neural Plastic 2016Google Scholar
  68. 68.
    Bachis A, Cruz MI, Nosheny RL, Mocchetti I (2008) Chronic unpredictable stress promotes neuronal apoptosis in the cerebral cortex. Neurosci Lett 442:104–108PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Carroll JC, Iba M, Bangasser DA, Valentino RJ, James MJ, Brunden KR, Lee VM-Y, Trojanowski JQ (2011) Chronic stress exacerbates tau pathology, neurodegeneration, and cognitive performance through a corticotropin-releasing factor receptor-dependent mechanism in a transgenic mouse model of tauopathy. J Neurosci 31:14436–14449PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Ennis GE, Yang A, Resnick SM, Ferrucci L, O’brien RJ, Moffat SD (2017) Long-term cortisol measures predict Alzheimer disease risk. Neurology 88:371–378PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Echouffo-Tcheugui JB, Conner SC, Himali JJ, Maillard P, DeCarli CS, Beiser AS, Vasan RS, Seshadri S (2018) Circulating cortisol and cognitive and structural brain measures: the Framingham Heart Study. Neurology 91:e1961–e1e70PubMedCrossRefPubMedCentralGoogle Scholar
  72. 72.
    Yagami T, Kohma H, Yamamoto Y (2012) L-type voltage-dependent calcium channels as therapeutic targets for neurodegenerative diseases. Curr Med Chem 19:4816–4827PubMedCrossRefPubMedCentralGoogle Scholar
  73. 73.
    Limbrick DD Jr, Churn SB, Sombati S, DeLorenzo RJ (1995) Inability to restore resting intracellular calcium levels as an early indicator of delayed neuronal cell death. Brain Res 690:145–156PubMedCrossRefPubMedCentralGoogle Scholar
  74. 74.
    Hynd MR, Scott HL, Dodd PR (2004) Glutamate-mediated excitotoxicity and neurodegeneration in Alzheimer’s disease. Neurochem Int 45:583–595PubMedCrossRefPubMedCentralGoogle Scholar
  75. 75.
    Wildburger NC, Lin-Ye A, Baird MA, Lei D, Bao J (2009) Neuroprotective effects of blockers for T-type calcium channels. Mol Neurodegener 4:44PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Marder K (2004) Memantine approved to treat moderate to severe Alzheimer’s disease. Curr Neurol Neurosci Rep 4:349–350PubMedCrossRefGoogle Scholar
  77. 77.
    Ferreira IL, Ferreiro E, Schmidt J, Cardoso JM, Pereira CMF, Carvalho AL, Oliveira CR, Rego AC (2015) Aβ and NMDAR activation cause mitochondrial dysfunction involving ER calcium release. Neurobiol Age 36:680–692CrossRefGoogle Scholar
  78. 78.
    He Y, Cui J, Lee JCM, Ding S, Chalimoniuk M, Simonyi A, Sun AY, Gu Z, Weisman GA, Wood WG (2011) Prolonged exposure of cortical neurons to oligomeric amyloid-β impairs NMDA receptor function via NADPH oxidase-mediated ROS production: protective effect of green tea (-)-epigallocatechin-3-gallate. ASN Neuro 3:AN20100025CrossRefGoogle Scholar
  79. 79.
    Butzlaff M, Ponimaskin E (2016) The role of serotonin receptors in Alzheimer’s disease. In: Opera Medica et PhysiologicaGoogle Scholar
  80. 80.
    Li Y, Sun H, Chen Z, Xu H, Guojun B, Zheng H (2016) Implications of GABAergic neurotransmission in Alzheimer’s disease. Fron Age Neurosci 8:31Google Scholar
  81. 81.
    Stuber GD, Britt JP, Bonci A (2012) Optogenetic modulation of neural circuits that underlie reward seeking. Biol Psychiatry 71:1061–1067PubMedCrossRefGoogle Scholar
  82. 82.
    Guzmán-Ramos K, Moreno-Castilla P, Castro-Cruz M, McGaugh JL, Martínez-Coria H, LaFerla FM, Bermúdez-Rattoni F (2012) Restoration of dopamine release deficits during object recognition memory acquisition attenuates cognitive impairment in a triple transgenic mice model of Alzheimer’s disease. Learn Mem 19:453–460PubMedCrossRefGoogle Scholar
  83. 83.
    De Marco M, Venneri A (2018) Volume and connectivity of the ventral tegmental area are linked to neurocognitive signatures of Alzheimer’s disease in humans. J Alzheimers Dis 63:167–180PubMedCrossRefGoogle Scholar
  84. 84.
    Hall H, Reyes S, Landeck N, Bye C, Leanza G, Double K, Thompson L, Halliday G, Kirik D (2014) Hippocampal Lewy pathology and cholinergic dysfunction are associated with dementia in Parkinson’s disease. Brain 137:2493–2508PubMedCrossRefGoogle Scholar
  85. 85.
    Lammel S, Lim BK, Ran C, Huang KW, Betley MJ, Tye KM, Deisseroth K, Malenka RC (2012) Input-specific control of reward and aversion in the ventral tegmental area. Nature 491:212–217PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Leemburg S, Canonica T, Luft A (2018) Motor skill learning and reward consumption differentially affect VTA activation. Sci Rep 8:687PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Rincón-Cortés M, Grace AA (2017) Sex-dependent effects of stress on immobility behavior and VTA dopamine neuron activity: modulation by ketamine. Int J Neuropsychopharmacol 20:823–832PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Ambrée O, Richter H, Sachser N, Lewejohann L, Dere E, de Souza Silva MA, Herring A, Keyvani K, Paulus W, Schäbitz W-R (2009) Levodopa ameliorates learning and memory deficits in a murine model of Alzheimer’s disease. Neurobiol Aging 30:1192–1204PubMedCrossRefGoogle Scholar
  89. 89.
    Koch G, Di Lorenzo F, Bonnì S, Giacobbe V, Bozzali M, Caltagirone C, Martorana A (2014) Dopaminergic modulation of cortical plasticity in Alzheimer’s disease patients. Neuropsychopharmacology 39:2654PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Martorana A, Di Lorenzo F, Esposito Z, Giudice TL, Bernardi G, Caltagirone C, Koch G (2013) Dopamine D2-agonist Rotigotine effects on cortical excitability and central cholinergic transmission in Alzheimer’s disease patients. Neuropharmacology 64:108–113PubMedCrossRefGoogle Scholar
  91. 91.
    Martorana A, Mori F, Esposito Z, Kusayanagi H, Monteleone F, Codeca C, Sancesario G, Bernardi G, Koch G (2009) Dopamine modulates cholinergic cortical excitability in Alzheimer’s disease patients. Neuropsychopharmacology 34:2323PubMedCrossRefGoogle Scholar
  92. 92.
    Di Lazzaro V, Oliviero A, Pilato F, Saturno E, Dileone M, Marra C, Daniele A, Ghirlanda S, Gainotti G, Tonali PA (2004) Motor cortex hyperexcitability to transcranial magnetic stimulation in Alzheimer’s disease. J Neurol Neurosurg Psychiatry 75:555–559PubMedCrossRefGoogle Scholar
  93. 93.
    Nardone R, Bergmann J, Kronbichler M, Kunz A, Klein S, Caleri F, Tezzon F, Ladurner G, Golaszewski S (2008) Abnormal short latency afferent inhibition in early Alzheimer’s disease: a transcranial magnetic demonstration. J Neural Transm 115:1557–1562PubMedCrossRefGoogle Scholar
  94. 94.
    Appiah-Kubi LS, Chaudhuri KR (2002) Sustained dopamine agonism with cabergoline in Parkinson’s disease. In: Mapping the progress of Alzheimer’s and Parkinson’s disease. Springer, BostonGoogle Scholar
  95. 95.
    Juarez B, Han M-H (2016) Diversity of dopaminergic neural circuits in response to drug exposure. Neuropsychopharmacology 41:2424PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Margolis EB, Lock H, Chefer VI, Shippenberg TS, Hjelmstad GO, Fields HL (2006) κ opioids selectively control dopaminergic neurons projecting to the prefrontal cortex. Proc Natl Acad Sci 103:2938–2942PubMedCrossRefGoogle Scholar

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© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  1. 1.Department of Pharmacology and Toxicology, College of PharmacyKing Saud UniversityRiyadhKingdom of Saudi Arabia
  2. 2.Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical SciencesUniversity of ToledoToledoUSA

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