An International Publications House

Albert Science International Organization

Connecting People With Pioneering Thought

Albert Science International Organization (ASIO) is international , peer-reviewed , open access , cum print version & online journals.
JOURNALS || ASIO Journal of Experimental Pharmacology & Clinical Research (ASIO-JEPCR) [ISSN: 2455-7080]

Author Names : Prashant Gupta
Page No. : 01-10  volume 2 issue 1
Article Overview


Prashant Gupta, Pratap Singh Jadon, Rishi Raj Shrivastava and Manoj Sharma, The Role of Serotonergic System and Future Needs for The Treatment of Alzheimer’s Disease, ASIO Journal of Experimental Pharmacology & Clinical Research (ASIO-JEPCR), 2016, 2(1): 01-10.


dids no.: 03.2016-35559215 

dids Link:


Alzheimer’s disease is progressive neurodegenerative disease characterized by loss of cholinergic neurons in brain amygdala followed by loss of memory. The main pathological features of Alzheimer disease are senile plaques (mainly containing β-amyloid peptide derived from amyloid precursor protein) and neurofibrillary tangles (containing hyper phosphorylated tau protein), along with neuronal loss. The present review aims at the study of role of serotonin and the effect of expression of various serotonergic receptors on memory function. Serotonin receptor sub-types that occur in brain regions and are capable of playing a role in learning and memory include the 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT6, and 5­-HT7 class of receptors but the effect is varying depending upon the different receptors. Expression of serotonergic function through 5-HT1A and 5-HT1D receptors have facilitatory effect on memory, while through 5-HT-1B receptors affects the memory adversely. Similarly 5-HT2 and 5-HT3 have impairing effect on memory while 5-HT4, 5-HT6 and 5-HT7 enhance memory. Further the roles of some oxidative parameters are also discussed. Antioxidants used at the early stage may prove beneficial in the management of Alzheimer’s disease.

Key Words: Alzheimer’s disease, Serotonin, 5-HT, Memory and Serotonin, Oxidative Damage

  1. Bozon B, Davis S, Laroche S: A requirement for the immediate early gene zif268 in reconsolidation of recognition memory after retrieval. Neuron, 2003, 40, 695-701.
  2. McGeer P.L, Harada N, Kimura H, McGeer E.G, Schulzer M: Prevalence of dementia amongst elderly Japanese with leprosy: apparent effect of chronic drug therapy. Dementia, 1992, 3, 146-149.
  3. L. Ciranna: Serotonin as a Modulator of Glutamate- and GABA-Mediated Neurotrans-mission: Implications in Physiological Functions and in Pathology. Current Neuropharmacol, 2006, 4, 101-114.
  4. Sharp T, Boothman L, Raley J, Queree P:  Important messages in the ‘post’: recent discoveries in 5-HT neurone feedback control. Trends Pharmacol Sci, 2007, 28, 629–636.
  5. Kelly A.B, William P.C, Kathryn A.C, Umberto S: Fine-tuning Serotonin2C Receptor Function in the Brain: Molecular and Functional Implications. Neuropharmacol, 2008, 55, 969–976.
  6. Wisden W, Parker E.M, Mahle C.D: 1993. Cloning and characterization of the rat 5-HT5B receptor: evidence that the 5-HT5B receptor couples to a G-protein in mammalian cell mem-branes. 1993, 333, 25 – 31.
  7. Kawas, Claudia H: Early Alzheimer’s disease. N Engl J Med, 2003, 349, 1056-1063.
  8. Keller J.N, Schmitt F.A, Scheff S.W, Ding Q, Chen Q, Butterfield D.A, Markesbery W.R: Evidence of increased oxidative damage in subjects with mild cognitive impairment. Neurol, 2005, 64, 1152–1156.
  9. McGaugh J.L: Memory− a century of consolidation. Science, 2000, 287, 248-251.
  10. Korolev Lgor O.: Alzheimer’s disease a clinical and basic science review. MSRJ, 2014,(04), 24-33.
  11. Upadhyay S.N.: Serotonin receptor agonist and antagonist. IJNM, 2003, 18,1-11.
  12. Phillips R.G, LeDoux J.E: Lesions of the dorsal hippocampal formation interfere with background but not foreground contextual fear conditioning. Learn. Mem, 1994, 1, 34–44.
  13. Mayeux R: Epidemiology of neurodegeneration. Annu Rev Neurosci, 2003, 26, 81-104.
  14. Petersen R.C, Doody R, Kurz A, Mohs R.C, Morris J.C, Rabins P.V, Ritchie K, Rossor M, Thal L,Winblad B: Current concepts in mild cognitive impairment. Arch Neurol, 2001, 58, 1985–1992.
  15. Plassat J.L, Boschert U, Amlaiky N: The mouse 5-HT5 receptor reveals a remarkable heterogeneity within the5-HT1D receptor family. EMBO J, 1992, 11, 4779 – 4786.
  16. Harvey J.A: Role of 5-HT2A receptor in learning. Learn. Mem, 2003, 10, 355-362.
  17. Gupta A., Sharma P.K.: Role of serotonin in seasonal affective disorder. European review for medical and pharmacological sciences, 2013,17,49-55.
  18. Shen Y, Monsma  F.J, Metcalf  M.A : Molecular cloning and expression of a 5-hydroxytryptamine7 serotonin re-ceptor subtype. J. Biol. Chem, 1993, 268, 18200 – 18204.
  19. Wang X, Su B, Lee H.G, Li X, Perry G, Smith M.A, Zhu X. Impaired balance of mitochondrial fission and fusion in Alzheimer's disease. J Neurosci, 2009, 29, 9090–9103.
  20. Regulska M, Leskiewicz M, Budziszewska B, Kutner A,  Jantas  D,  Basta-Kaim  A:  Inhibitory  effects of  1,25-dihydroxyvitamin  D(3)  and  its  low-calce-mic  analogues  on  staurosporine-induced  apoptosis. Pharmacol Rep, 2007, 59, 393-401.
  21. Schaeffer E.l, FigueiroI I.M, GattazI W.F: Insights into Alzheimer disease pathogenesis from studies in transgenic animal models. Clinics (Sao Paulo), 2011, 66, 45-54.
  22. Cassel J.C, Jeltsch H, Neufang B, Lauth D, Szabo B, Jackisch R: 1995. Downregulation of muscarinic and 5-HT1B-mediated modulation of [3H] acetylcholine release in hippocampal slices of rats with fimbria- fornix lesions and intrahippocampal grafts of septal origin.Brain Res, 1995, 704, 153-166.
  23. Woolley M.L, Bentley J.C, Sleight A.J, Marsden C.A, Fone K.C: A role for 5-ht6 receptors in retention of spatial learning in the Morris water maze. Neuropharmacol, 2001, 41, 210–219.
  24. Cools R, Roberts A.C, Robbins T.W: Serotoninergic regulation of emotional and behavioural control processes. Trends Cogn Sci, 2008, 12, 31-40.
  25. Li L, Cao D, Kim H, Lester R, Fukuchi K:  Simvastatin enhances learning and memory independent of amyloid load in mice. Ann Neurol, 2006, 60, 729–739.
  26. Bokor H, Csaki A, Kocsis K, Kiss J: Cellular architecture of the nucleus reuniens thalami and its putative aspartatergic / glutamatergic projection to the hippocampus and medical septum in the rat. Eur J NeuroSci, 2002, 16, 1227-1239.
  27. Maiese K. Triple play: Promoting neurovascular longevity with nicotinamide, WNT and erythropoietin in diabetes mellitus.  Biomed Pharmacother, 2008; 62 :218-32.
  28. Winter Y, Korchounov A, Zhukova T.V: Depression in elderly patients with Alzheimer dementia or vascular dementia and its influence on their quality of life. J.Neurosci Rural Pract, 2011, 2, 27-32.
  29. Jakab R.L, Goldman-Rakic P.S: 5-Hydroxytryptamine 2A serotonin receptors in the primate cerebral cortex: Possible site of action of hallucinogenic and antipsychotic drugs in pyramidal cell apical dendrites. Proc. Natl. Acad. Sci, 1998, 95, 735–740.
  30. Aghajanian G.K, Marek G.J: Serotonin induces excitatory postsynaptic potentials in apical dendrites of neocortical pyramidal cells. Neuropharmacol, 1997, 36, 589–599.
  31. Raymond J.R, Mukhin Y.V,Gelasco A, Turner J, Collinsworth G, Gettys T.W, Grewal J.S, Garnovskaya M. N: Multiplicity of mechanisms of serotonin receptor signal transduction. Pharmacol Ther, 2001, 92, 179-212.
  32. Chang M, Zhang L.S, Tam J.P, Sanders-Bush E: Dissecting G protein-coupled receptor signalling pathways with membrane-permeable blocking peptides - Endogenous 5-HT2C receptors in choroid plexus epithelial cells. J. Biol. Chem, 2000, 275, 7021–7029.
  33. Meneses A, Manuel-Apolinar L, Castillo C, Castillo E: Memory consolidation and amnesia modify 5-HT6 receptors expression in rat brain: an autoradiographic study. Behav Brain Res, 2007, 178, 53–61.
  34. Mayeux and Richard: Early Alzheimer’s Disease. N Engl J Med, 2010, 362, 2194-201.
  35. Cussac D, Newman-Tancredi A, Duqueyroix D, Pasteau V, Millan M.J: Differential activation of Gq/1 and Gi(3) proteins at 5-hydroxytryptamine(2C) receptors revealed by antibody capture assays: Influence of receptor reserve and relationship to agonist-directed trafficking. Mol. Pharmacol, 2002, 62, 578–589.
  36. Andrew J.T, Sarah C.R. L: The 5-HT3 receptor as a therapeutic target. Expert Opin Ther Targets, 2007, 11, 527–540.
  37. Okouchi M, Ekshyyan O, Maracine M, Aw  T.Y: Neuronal  apoptosis  in neurodegeneration. Antioxid Redox Signal, 2007, 9, 1059-1096.
  38. Vickers S.P, Dourish C.T: Serotonin receptor ligands and the treatment of obesity. Curr. Opin. Invest. Drugs, 2004, 5, 377–388.
  39. Galligan J.J: Ligand-gated ion channels in the enteric nervous system. Neurogastroenterol. Motil, 2002, 14, 611–623.
  40. Li J.W, Watanabe M, Fujisawa Y, Shibuya T: Relation between age-related changes in hyperemotionality and serotonergic neuronal activities in the rat limbic system. Nihon Shinkei Seishin Yakurigaku Zasshi, 1995, 15, 231-238.
  41. Wang L, Miller J.P, Gado M.H, McKeel D.W, Rothermich M, Miller M.I: Abnormalities of hippocampal surface structure in very mild dementia of the Alzheimer's type. Neuroimage, 2006, 30, 52–60.
  42. Jakeman L.B, To Z.P, Eglen R.M, Wong E.H.F, Bonhaus D.W: (1994). Quantitative autoradiography of 5-HT4 receptors in brains of three species using two structurally distinct radio-ligands, [3H] GR 113808 and [3H] BIMU-1. Neuropharmacol, 1994, 33, 1027- 1038.
  43. Domenech T, Beleta J, Fernandez A.G, Gristwood R.W, Cruz Sanchez F, Tolosa E, Palacios J.M: Identification and characterization of serotonin 5-HT4 receptor binding sites in human brain: comparison with other mammalian species. Mol. Brain Res, 1994, 21, 1760-1890.
  44. Costall B, Naylor R.J: The pharmacology of the 5-HT4 receptor. Int. Clin. Psychopharmacol, 1993, 8, 11-18.
  45. Iversen L.L: The Ferrier lecture, 1983. Amino acids and peptides: fast and slow chemical signals in the nervous system? Proc. R. Soc, 1984, 221, 245-260.
  46. Sarkisyan G, Hedlund P.B: The 5-HT7 receptor is involved in allocentric spatial memory information processing. Behav. Brain Res, 2009, 202, 26–31.
  47. Bockaert J, Ansanay H, Waeber C, Sebben M, Fagni, L, Dumuis A: 5-HT4 receptors. Potential therapeutic implications in neurology and psychiatry. CNS Drugs, 1994, 1, 6-15.
  48. Frey U, Huang Y.Y, Kandel E.R: Effects of cAMP stimulate a late stage of LTP in hippocampal CAI neurons. Science, 1993, 260, 1661-1664.
  49. Rowchoudury S.M, Anderson E.G: Serotonin facilitates long term potentiation in area CA1 of rat hippocampus via 5-HT4 receptors. J. Neurosci, 1995 (in press).
  50. Kumar R, Jaggi A.S, Singh N: Effects of Erythropoietin on Memory Deficits and Brain Oxidative Stress in the Mouse models of Dementia. Korean J.Physiol Pharmacol, 2010, 14, 345-352.
  51. Barthet G,  Framery,B.N, Florence G, Lucie P, Eric R, Sylvie C,   Bockaert,J.I, Dumuis A: 5-Hydroxytryptamine4 Receptor Activation of the Extracellular Signal-regulated Kinase Pathway Dependson Src Activation but Not on G Protein or-ArrestinSignaling. Mol. Biol. Cell, 2007, 18, 1979-1991.
  52. Plecita-Hlavata L, Lessard M, Santorova J, Bewersdorf J, Jezek  P:  Mitochondrial  oxidative  phosphorylation and  energetic  status  are  ref lected  by  morphology  of mitochondrial network in INS-1E and HEP-G2 cells viewed  by  4Pi  microscopy.  Biochim  Biophys  Acta, 2008,  1777, 834-846.
  53. Hen R: Of mice and ?ies-commonalities among 5-HT receptors. Trends Pharmacol. Sci, 1992, 13, 160 – 165.
  54. Witz P, Amlaiky N, Plassat J.L: 1990. Cloning and characterization of a Drosophila serotonin receptor that activates adenylate cyclase. Proc. Natl. Acad. Sci, 1990, 87, 8940 – 8944.
  55. Langlois M, Fischmeister R: 5-HT4 receptor ligands: applica-tions and new prospects. J Med Chem, 2003, 46, 319–344.
  56. Meneses A: Effects of the 5-HT6 receptor antagonist Ro 04-6790 on learning consolidation. Behav Brain Res, 2001, 118, 107–110.
  57. Woolley M.L, Marsden C.A, Fone K.C: 5-ht 6 receptors. Curr Drug Targets CNS Neurol Disord, 2004, 3, 59–79.
  58. Menses A: Tianeptine: 5-HT uptake sites and 5-HT(1–7) receptors modulate memory formation in an autoshaping Pavlovian/instrumental task. Neurosci. Biobehav. Rev, 2002, 26, 309–319.
  59. Lipton S.A:  Paradigm shift in neuroprotection by NMDA receptor blockade: memantine and beyond. Nat Rev Drug Discov, 2006, 5, 160–170.
  60. Marion S, Weiner D.M, Caron M.G: RNA editing induces variation in desensitization and trafficking of 5-hydroxytryptamine 2c receptor isoforms. J. Biol. Chem, 2004, 279, 2945–2954.
  61. Stackman R.W, Eckenstein F, Frei B, Kulhanek D, Nowlin J, Quinn J.F: Prevention of age-related spatial memory deficits in a transgenic mouse model of Alzheimer's disease by chronic Ginkgo biloba treatment. Exper Neurol, 2003, 184, 510–520.
  62. Branchek T. A, Blackburn T. P: 5-ht6 receptors as emerging targets for drug discovery. Annu Rev Pharmacol Toxicol, 2000, 40, 319 – 334.
  63. Yamada K, Tanaka T, Han D, Senzaki K, Kameyama T, Nabeshima T. Protective effects of idebenone and α-tocopherol on β-amyloid-(1-42)-induced learning and memory deficits in rats; implication of oxidative stress in β-amyloid-induced neurotoxicity in vivo. Eur J Neurosci, 1999, 11, 83–90.
  64. Waeber C, Sebben M, NieoullonI A, Bockaert J, Dumuis A: Regional distribution and ontogeny of 5-HT4binding sites in rodent brain. Neuropharmacol, 1994, 33, 527-541.
  65. Bentley, J.C, Marsden C.A, Sleight A.J, FONE K.C.F: 5-HT6 antisense oligonucleotide i.c.v. affects rat performance in the watermaze and feeding. British Association for Psychopharmacology Meeting, Cambridge, 13–17th July 1997, 255.
  66. Glass J.D, Grossman G.H, Farnbauch L, DiNardo L: Midbrain raphe modulation of nonphotic circadian clock resetting and 5-HT release in the mammalian suprachiasmatic nucleus.  J. Neurosci, 2003, 23, 7451–7460.
  67. Hedlund P.B, Kelly L, Mazur C, Lovenberg T, Sutcliffe J.G, Bonaventure P: 8-OH-DPAT acts on both 5-HT1A and 5-HT7 receptors to induce hypothermia in rodents. Eur. J. Pharmacol, 2004, 487, 125–132.
  68. Savitz J, Lucki I, Drevets W.C:  5-HT1A receptor function in major depressive disorder. Prog Neurobiol, 2009, 88, 17–31.
  69. Wolff M, Benhassine N, costet P, Hen R, Segu L, Buhot M.C: Delay- dependent working memory impairment in young-adult and aged 5-HT1BKO mice as assessed in a radial-arm water maze. Learn. Mem, 2003, 10, 401-409.
  70. Jasper J.R, Kosaka A, TO, Z.P, Chang D.J, Eglen R.M: Cloning, expression and pharmacology of a truncated splice variant of the human 5-HT7 receptor (h5-HT7b). Br.J.Pharmacol, 1997,122,   126–132.
  71. Heidmann D.E.A, Metcalf M.A, Kohen R: Four 5-hydroxytryptamine7 (5-HT7) receptor isoforms in human and rat produced by alternative splicing: species differences due to altered intron-exon organization. J. Neurochem, 1997, 68, 1372 – 1381.
  72. Wang R.Y, Aghajanian G.K: Inhibition of neurons in the amygdala by dorsal raphe stimulation: mediation through a direct serotonergic pathway. Brain Res, 1977, 120, 85–102.
  73. Tecott L.H, Maricq A.V, Julius D: Nervous system distribution of the serotonin 5-HT3 receptor. Proc. Natl. Acad. Sci. USA, 1993, 90, 1430–1434.
  74. Shif O, Gillette K, Damkaoutis C.M, Carrano C, Robbins S.J, Hoffman J.R:  Effects of Ginkgo biloba administered after spatial learning on water maze and radial arm maze performance in young adult rats. Pharm Biochem Behav, 2006, 84, 17–25.
  75. Barnes and Sharp: A review of central 5-HT receptors and their function. Neuropharmacol, 1999, 38, 1083-1152.
  76. Pytliak M., Vargova V.: Serotonin receptor from molecular biology to clinical application. Physiological research, 2011, 60, 15-25.
  77. Bartus R.T, Dean R.L.III, Beer B, Lippa A.S: The cholinergic hypothesis of geriatric memory dysfunction. Science, 1982, 217, 408–414.
  78. Weible A.P, McEchron M.D, Disterhoft J.F: Cortical involvement in acquisition and extinction of trace eyeblink conditioning. Behav. Neurosci, 2000, 114, 1058–1067.
  79. Lipton S.A: Paradigm shift in NMDA receptor antagonist drug development: molecular mechanism of uncompetitive inhibition by memantine in the treatment of Alzheimer's disease and other neurologic disorders. J Alzheimers Dis, 2004, 6, 61–74.
  80. Aracava Y, Pereira E.F, Maelicke A: Memantine blocks alpha7 nicotinic acetylcholine receptors more potently than N-methyl-D-aspartate receptors in rat hippocampal neurons. J Pharmacol Exp Ther, 2005, 312, 1195–1205.
  81. Lovell M.A, Markesbery W.R: Oxidatively modified RNA in mild cognitive impairment. Neurobiol Dis, 2008, 29, 169–175.
  82. Conte V, Uryu K, Fujimoto S, Yao Y, Rokach J, Longhi L:  Vitamin E reduces amyloidosis and improves cognitive function in Tg2576 mice following repetitive concussive brain injury. J Neurochem: 2004, 90, 758–764.
  83. Yermakova A.V, O'Banion M.K: Downregulation of neuronal  cyclooxygenase-2 expression in end stage Alzheimer's disease. Neurobiol. Aging, 2001, 22, 823-836.
  84. Sleight A.J, Boess F.G, Bos M, Bourson  A: The putative 5-ht6 receptor: localization and function. Ann N Y Acad Sci, 1998, 861, 91 – 96.
  85. Frautschy S.A, Hu W, Kim P, Miller S.A, Chu T, Harris-White M.E, Cole G.M: Phenolic anti-inflammatory antioxidant reversal of Abeta-induced cognitive deficits and neuropathology. Neurobiol Aging, 2001, 22, 993–1005.
  86. Hoozemans J.J, Rozemuller A.J, Janssen I, De Groot C.J, Veerhuis R, Eikelenboom P: Cyclooxygenase expression in microglia and neurons in Alzheimer's disease and control brain. Acta Neuropathol. (Berl.), 2001, 101, 2-8.
  87. Hoozemans J.J, van Haastert  E.S., Veerhuis R, Arendt T, Scheper W, Eikelenboom  P, Rozemuller A.J: Maximal COX-2 and ppRb expression in neurons occurs during early Braak stages prior to the maximal activation of astrocytes and microglia in Alzheimer's disease. J. Neuroinflamm, 2005, 2, 27.
  88. Ziegler-Graham K, Brookmeyer R, Johnson E, Arrighi H.M: Worldwide variation in the doubling time of Alzheimer's disease incidence rates. Alzheimers Dement, 2008, 4, 316-323.
  89. Casolini P, Catalani A, Zuena A, Angelucci L:  Inhibition of COX-2 reduces the age-dependent increase of hippocampal inflammatory markers, cortico-sterone secretion, and behavioral impairments in the rat. J Neurosci Res, 2002, 68, 337–343.
  90. Luciana O, Frederico G.G, Silvia R.C.P, Leda F.O.S, Glaura C.F, Angela M.R: Correlations among central serotonergic parameters and age- related emotional and cognitive changes assessed through the elevated T-maze and the morris water maze. Age, 2010, 32, 187-196.
  91. Raymond J, Turner J, Gelasco A, Ayiku  H, Coaxum S, Arthur J, Garnovskaya M: 5-HT receptor signal transduction pathways. In: Roth, BL., editor. The Receptors: The Serotonin Receptors: From Mol. Pharmacol, 2006, 143-206.
  92. Anekonda T.S: Resveratrol--a boon for treating Alzheimer's disease? Brain Res. Brain Res. Rev, 2006, 52, 316-326.
  93. Familian A, Boshuizen R.S, Eikelenboom P, Veerhuis R: Inhibitory effect of minocycline on amyloid beta fibril formation and human microglial activation. Glia, 2006, 53, 233-240.
  94. McGrew L, Chang M.S, Sanders-Bush E: Phospholipase D activation by endogenous 5- hydroxytryptamine 2C receptors is mediated by Galpha13 and pertussis toxin-insensitive Gbetagamma subunits. Mol. Pharmacol, 2002, 62, 1339–1343.
  95. Ballard C.G, Chalmers K.A, Todd C: Cholinesterase inhibitors reduce cortical Aβ in dementia with Lewy bodies. Neurol, 2007, 68, 1726–1729.
  96. Jellingei Kurt A.:Update on Alzheimer disease. Eurppean medical journal,2015,3,82-90.
  97. Lu D, Mahmood A, Goussev A, Schallert T, Qu C, Zhang Z.G: Atorvastatin reduction of intravascular thrombosis, increase in cerebral microvascular patency and integrity, and enhancement of spatial learning in rats subjected to traumatic brain injury. J Neurosurg, 2004, 101, 813–821.
  98. Butterfield D.A, Reed T.T, Perluigi M, De Marco C, Coccia R, Keller J.N, Markesbery W.R, Sultana R: Elevated levels of 3-nitrotyrosine in brain from subjects with amnestic mild cognitive impairment: implications for the role of nitration in the progression of Alzheimer's disease. Brain Res, 2007, 1148, 243–248.
  99. Petersen R.C, Smith G.E, Waring S.C, Ivnik R.J, Tangalos E.G, Kokmen E: Mild cognitive impairment: clinical characterization and outcome. Arch Neurol, 1999, 56, 303-308.
  100.  Jicha G.A, Parisi J.E, Dickson D.W, Johnson K, Cha R, Ivnik R.J, Tangalos E.G, Boeve B.F,Knopman D.S, Braak H, Petersen R.C. Neuropathologic outcome of mild cognitive impairmentfollowing progression to clinical dementia. Arch Neurol, 2006,  63, 674–681.
  101. Witz P, Amlaiky N, Plassat J.L: 1990. Cloning and characterization of a Drosophila serotonin receptor that activates adenylate cyclase. Proc. Natl. Acad. Sci, 1990, 87, 8940 – 8944.
  102. Watkins P.B, Zimmerman H.J, Knapp M.J, Gracon S.I, Lewis K.W: Hepatotoxic effects of tacrine administration in patients with Alzheimer's disease. JAMA, 1994, 271, 992–998.
  103. Marcos B, Gil-Bea F.J, Hirst W, Garc?´a-Alloza M, Ram?´rez M.J:  Lack of localization of 5-HT6 receptors on cholinergic neurons:implication of multiple neurotransmitter systems in 5-HT6 receptor-mediated acetylcholine release. Eur J Neurosci, 2006, 24: 1299–1306.
  104. Reynolds G.P, Mason S.L, Meldrum A, De Keczer S, Parnes H, Eglen R.M, Wong E.H.F: 5-Hydroxytryptamine (5-HT)4 receptors in post mortem human brain tissue: distribution, pharmacology and effects of neurodegenerative diseases. Br. J. Pharmacol , 1995, 114, 993-998.
  105. Feng Y, Paul I.A, LeBlanc M.H. Nicotinamide reduces hypoxic ischemic brain injury in the    newborn rat. Brain Res Bull, 2006, 69, 117-22.
  106. De  Felice  F.G,  Velasco  P.T,  Lambert  M.P,  Viola  K, Fernandez  S.J,  Ferreira  S.T: Abeta  oligomers  induce  neuronal  oxidative  stress  through  an N-methyl-D-aspartate  receptor-dependent  mechanism that is blocked by the Alzheimer drug memantine. J Biol Chem, 2007, 282, 11590-11601.
  107. Qu C, Lu D, Goussev A, Schallert T, Mahmood A, Chopp M. Effect of atorvastatin on spatial memory, neuronal survival, and vascular density in female rats after traumatic brain injury. J Neurosurg, 2005, 103, 695–701.
  108. Stowe R.L, Barnes N.M: Cellular distribution of 5-HT7 receptor mRNA in rat brain. Br. J. Pharmacol, 1998, 123.