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Localization of 5-HT1A and 5-HT2A positive cells in the brainstems of control age-matched and Alzheimer individuals

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Abstract

Serotonin receptor 1A and 2A positive cells in postmortem brainstems were demonstrated via immunohistochemistry in eight control age-matched elderly individuals and eight Alzheimer patients. The 5-HT1A positive cells were found in substantia nigra, pontile nucleus, and vagal as well as dorsal raphe nucleus, while 5-HT2A receptor positive cells were found in motor, sensory and spinal trigeminal nuclei, pontile nucleus, substantia nigra, and nucleus solitarius. A comparison in density of positive cells per unit area was made between control age-matched and Alzheimer individuals. Statistically significant differences (p ≤ 0.01) in density were observed in 5-HT1A cells in pontile, dorsal raphe, and vagal nuclei between control age-matched and Alzheimer, and in 5-HT2A positive cells in the sensory trigeminal nucleus, between control and Alzheimer. This de novo study indicated the presence of 5-HT1A and 5-HT2A receptor positive cells in the above nuclei of human brainstem and revealed differences in density between control age-matched and Alzheimer, indicating possible functional derangements in Alzheimer patients in these areas. In addition, colocalization studies indicated that 5-HT1A receptors were in cholinergic cells and gamma-aminobutyric acid positive fibers were linked to 5-HT2A receptor positive cells. It is hoped that understanding these two important 5-HT receptors and their localization might lead to advances in future therapeutic development.

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References

  • Abe K, Kato G, Katafuchi T, Tamae A, Furue H, Yoshimura M (2009) Responses to 5-HT in morphologically identified neurons in the rat substantia gelatinosa in vitro. Neuroscience 159:316–324

    Article  CAS  PubMed  Google Scholar 

  • Arango V, Underwood MD, Mann JJ (2002) Serotonin brain circuits involved in major depression and suicide. Prog Brain Res 136:443–453

    Article  CAS  PubMed  Google Scholar 

  • Banerjee P, Mehta M, Kanjilal B (2007) The 5-HT receptor: a signaling 1A hub linked to emotional balance. In: Chattopadhyay A (ed) Serotonin receptors in neurobiology. CRC, Boca Raton, pp 133–156

    Google Scholar 

  • Bibancos T, Jardim DL, Aneas I, Chiavegatto S (2007) Social isolation and expression of serotonergic neurotransmission-related genes in several brain areas of male mice. Genes Brain Behav 6:529–539

    Article  CAS  PubMed  Google Scholar 

  • Brodal A (1981) Neurological anatomy, 3rd edn. Oxford University Press, Oxford, 1053pp

  • Burnet PW, Eastwood SL, Lacey K, Harrison PJ (1995) The distribution of 5-HT1A and 5-HT2A receptor mRNA in human brain. Brain Res 676:157–168

    Article  CAS  PubMed  Google Scholar 

  • Costall B, Barnes JM, Hamon M, Müller WE, Briley M (1990) Biochemical models for cognition enhancers. Pharmacopsychiatry 23(Suppl 2):85–88

    Article  PubMed  Google Scholar 

  • Curran AK, Leiter JC (2007) Baroreceptor-mediated inhibition of respiration after peripheral and central administration of a 5-HT1A receptor agonist in neonatal piglets. Exp Physiol 92:757–767

    Article  CAS  PubMed  Google Scholar 

  • Delgado M, Caicoya AG, Greciano V, Benhamú B, López-Rodríguez ML, Fernández-Alfonso MS, Pozo MA, Manzanares J, Fuentes JA (2005) Anxiolytic-like effect of a serotonergic ligand with high affinity for 5-HT1A, 5-HT2A and 5-HT3 receptors. Eur J Pharmacol 511:9–19

    Article  CAS  PubMed  Google Scholar 

  • Frazer A, Hensler JG (1999) Serotonin receptors. In: Siegel GJ, Agranoff BW, Albers RW, Fisher SK, Uhler MD (eds) Basic neurochemistry: molecular, cellular, and medical aspects. Lippincott-Raven, Philadelphia, pp 263–292

    Google Scholar 

  • Freitas RL, Bassi GS, de Oliveira AM, Coimbra NC (2008) Serotonergic neurotransmission in the dorsal raphe nucleus recruits in situ 5-HT(2A/2C) receptors to modulate the post-ictal antinociception. Exp Neurol 213:410–418

    Article  CAS  PubMed  Google Scholar 

  • Hall H, Lundkvist C, Halldin C, Farde L, Pike VW, McCarron JA, Fletcher A, Cliffe IA, Barf T, Wikström H, Sedvall G (1997) Autoradiographic localization of 5-HT1A receptors in the post-mortem human brain using [3H]WAY-100635 and [11C]way-100635. Brain Res 745:96–108

    Article  CAS  PubMed  Google Scholar 

  • Hoyer D, Clarke DE, Fozard JR, Hartig PR, Martin GR, Mylecharane EJ, Saxena PR, Humphrey PP (1994) International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (Serotonin). Pharmacol Rev 46:157–203

    CAS  PubMed  Google Scholar 

  • Jordan D (2005) Vagal control of the heart: central serotonergic (5-HT) mechanisms. Exp Physiol 90:175–181

    Article  CAS  PubMed  Google Scholar 

  • Kennett GA, Dourish CT, Curzon G (1987) Antidepressant-like action of 5-HT1A agonists and conventional antidepressants in an animal model of depression. Eur J Pharmacol 134:265–274

    Article  CAS  PubMed  Google Scholar 

  • Kroeze WK, Kristiansen K, Roth BL (2002) Molecular biology of serotonin receptors structure and function at the molecular level. Curr Top Med Chem 2:507–528

    Article  CAS  PubMed  Google Scholar 

  • Lazarov NE (2002) Comparative analysis of the chemical neuroanatomy of the mammalian trigeminal ganglion and mesencephalic trigeminal nucleus. Prog Neurobiol 66:19–59

    Article  CAS  PubMed  Google Scholar 

  • Li WP, Chan WY, Lai HW, Yew DT (1997) Terminal dUTP nick end labeling (TUNEL) positive cells in the different regions of the brain in normal aging and Alzheimer patients. J Mol Neurosci 8:75–82

    Article  CAS  PubMed  Google Scholar 

  • Li Q, Lu G, Antonio GE, Mak YT, Rudd JA, Fan M, Yew DT (2007) The usefulness of the spontaneously hypertensive rat to model attention-deficit/hyperactivity disorder (ADHD) may be explained by the differential expression of dopamine-related genes in the brain. Neurochem Int 50:848–857

    Article  CAS  PubMed  Google Scholar 

  • Lira A, Zhou M, Castanon N, Ansorge MS, Gordon JA, Francis JH, Bradley-Moore M, Lira J, Underwood MD, Arango V, Kung HF, Hofer MA, Hen R, Gingrich JA (2003) Altered depression-related behaviors and functional changes in the dorsal raphe nucleus of serotonin transporter-deficient mice. Biol Psychiatry 54:960–971

    Article  CAS  PubMed  Google Scholar 

  • Liu Q, Wong-Riley MT (2010) Postnatal changes in the expressions of serotonin 1A, 1B, and 2A receptors in ten brain stem nuclei of the rat: implication for a sensitive period. Neuroscience 165:61–78

    Article  CAS  PubMed  Google Scholar 

  • Lorke DE, Kwong WH, Chan WY, Yew DT (2003) Development of catecholaminergic neurons in the human medulla oblongata. Life Sci 73(10):1315–1331

    Article  CAS  PubMed  Google Scholar 

  • Lorke DE, Lu G, Cho E, Yew DT (2006) Serotonin 5-HT2A and 5-HT6 receptors in the prefrontal cortex of Alzheimer and normal aging patients. BMC Neurosci 7:36

    Article  PubMed  Google Scholar 

  • Lundberg J, Borg J, Halldin C, Farde L (2007) A PET study on regional coexpression of 5-HT1A receptors and 5-HTT in the human brain. Psychopharmacology (Berl) 195:425–433

    Article  CAS  Google Scholar 

  • Meyer LC, Fuller A, Mitchell D (2006) Zacopride and 8-OH-DPAT reverse opioid-induced respiratory depression and hypoxia but not catatonic immobilization in goats. Am J Physiol Regul Integr Comp Physiol 290:R405–R413

    CAS  PubMed  Google Scholar 

  • Müller CP, Carey RJ, Huston JP, De Souza Silva MA (2007) Serotonin and psychostimulant addiction: focus on 5-HT1A-receptors. Prog Neurobiol 81:133–178

    Article  PubMed  Google Scholar 

  • Nalivaiko E, Ootsuka Y, Blessing WW (2005) Activation of 5-HT1A receptors in the medullary raphe reduces cardiovascular changes elicited by acute psychological and inflammatory stresses in rabbits. Am J Physiol Regul Integr Comp Physiol 289:R596–R604

    CAS  PubMed  Google Scholar 

  • Ogren SO, Eriksson TM, Elvander-Tottie E, D'Addario C, Ekström JC, Svenningsson P, Meister B, Kehr J, Stiedl O (2008) The role of 5-HT(1A) receptors in learning and memory. Behav Brain Res 195:54–77

    Article  PubMed  Google Scholar 

  • Ozawa Y, Okado N (2002) Alteration of serotonergic receptors in the brain stems of human patients with respiratory disorders. Neuropediatrics 33:142–149

    Article  CAS  PubMed  Google Scholar 

  • Popa D, Léna C, Fabre V, Prenat C, Gingrich J, Escourrou P, Hamon M, Adrien J (2005) Contribution of 5-HT2 receptor subtypes to sleep-wakefulness and respiratory control, and functional adaptations in knock-out mice lacking 5-HT2A receptors. J Neurosci 25:11231–11238

    Article  CAS  PubMed  Google Scholar 

  • Ramanathan S, Glatt SJ (2009) Serotonergic system genes in psychosis of Alzheimer dementia: meta-analysis. Am J Geriatr Psychiatry 17:839–846

    Article  PubMed  Google Scholar 

  • Raote I, Bhattacharya A, Panicker MM (2007) Serotonin 2A (5-HT2A) receptor function: ligand-dependent mechanisms and pathways. In: Chattopadhyay A (ed) Serotonin receptors in neurobiology. CRC, Boca Raton, pp 105–132

    Google Scholar 

  • Raul L (2003) Serotonin2 receptors in the nucleus tractus solitarius: characterization and role in the baroreceptor reflex arc. Cell Mol Neurobiol 23:709–726

    Article  CAS  PubMed  Google Scholar 

  • Rocchi A, Micheli D, Ceravolo R, Manca ML, Tognoni G, Siciliano G, Murri L (2003) Serotoninergic polymorphisms (5-HTTLPR and 5-HT2A): association studies with psychosis in Alzheimer disease. Genet Test 7:309–314

    Article  CAS  PubMed  Google Scholar 

  • Salmon E (2007) A review of the literature on neuroimaging of serotoninergic function in Alzheimer's disease and related disorders. J Neural Transm 114:1179–1185

    Article  CAS  PubMed  Google Scholar 

  • Sawaguchi T, Ozawa Y, Patricia F, Kadhim H, Groswasser J, Sottiaux M, Takashima S, Nishida H, Kahn A (2003) Serotonergic receptors in the midbrain correlated with physiological data on sleep apnea in SIDS victims. Early Hum Dev 75(Suppl):S65–S74

    Article  CAS  PubMed  Google Scholar 

  • Saxena PR (1995) Serotonin receptors: subtypes, functional responses and therapeutic relevance. Pharmacol Ther 66:339–368

    Article  CAS  PubMed  Google Scholar 

  • Schreiber R, Melon C, De Vry J (1998) The role of 5-HT receptor subtypes in the anxiolytic effects of selective serotonin reuptake inhibitors in the rat ultrasonic vocalization test. Psychopharmacology (Berl) 135:383–391

    Article  CAS  Google Scholar 

  • Shelton RC, Sanders-Bush E, Manier DH, Lewis DA (2009) Elevated 5-HT 2A receptors in postmortem prefrontal cortex in major depression is associated with reduced activity of protein kinase A. Neuroscience 158:1406–1415

    Article  CAS  PubMed  Google Scholar 

  • Shen WZ, Luo ZB, Zheng DR, Yew DT (1989) Immunohistochemical studies on the development of 5-HT (serotonin) neurons in the nuclei of the reticular formations of human fetuses. Pediatr Neurosci 15:291–295

    Article  CAS  PubMed  Google Scholar 

  • Sumiyoshi T, Bubenikova-Valesova V, Horacek J, Bert B (2008) Serotonin1A receptors in the pathophysiology of schizophrenia: development of novel cognition-enhancing therapeutics. Adv Ther 25:1037–1056

    Article  CAS  PubMed  Google Scholar 

  • Tiu SC, Li WY, Luo CB, Yew DT (1993) Habenulo-interpeduncular descending pathways and their relationship to enkephalin- and somatostatin-immunoreactive neurons in the interpeduncular nucleus of human fetuses. Neuroscience 53:489–493

    Article  CAS  PubMed  Google Scholar 

  • Ulak G, Mutlu O, Tanyeri P, Komsuoglu FI, Akar FY, Erden BF (2010) Involvement of serotonin receptor subtypes in the antidepressant-like effect of trim in the rat forced swimming test. Pharmacol Biochem Behav 95:308–314

    Article  CAS  PubMed  Google Scholar 

  • Wai SM, Kindler PM, Lam ET, Zhang A, Yew DT (2004) Distribution of neuropeptide Y-immunoreactive neurons in the human brainstem, cerebellum, and cortex during development. Cell Mol Neurobiol 24:667–684

    Article  CAS  PubMed  Google Scholar 

  • Wai MS, Shi C, Kwong WH, Zhang L, Lam WP, Yew DT (2008) Development of the human insular cortex: differentiation, proliferation, cell death, and appearance of 5HT-2A receptors. Histochem Cell Biol 130:1199–1204

    Article  CAS  PubMed  Google Scholar 

  • Wesołowska A (2002) In the search for selective ligands of 5-HT5, 5-HT6 and 5-HT7 serotonin receptors. Pol J Pharmacol 54:327–341

    PubMed  Google Scholar 

  • Yan Z (2002) Regulation of GABAergic inhibition by serotonin signaling in prefrontal cortex: molecular mechanisms and functional implications. Mol Neurobiol 26:203–216

    Article  CAS  PubMed  Google Scholar 

  • Yew DT, Chan WY (1999) Early appearance of acetylcholinergic, serotoninergic, and peptidergic neurons and fibers in the developing human central nervous system. Microsc Res Tech 45:389–400

    Article  CAS  PubMed  Google Scholar 

  • Yew DT, Luo CB, Zheng DR, Guan YL, Lin YQ, Chen WZ (1990) Development and localization of enkephalin and substance P in the nucleus of tractus solitarius in the medulla oblongata of human fetuses. Neuroscience 34:491–498

    Article  CAS  PubMed  Google Scholar 

  • Yew DT, Pang KM, Mok YC (1991) Immunohistochemical and ultrastructural studies of the various nuclei of the trigeminal complex in the human newborn. Neuroscience 45:23–35

    Article  CAS  PubMed  Google Scholar 

  • Yew DT, Luo CB, Shen WZ (1992) Immunohistochemical localization of enkephalin and substance P in the nucleus caudalis of the spinal trigeminal V in the medulla oblongata of the human fetus. Neuroscience 51:185–190

    Article  CAS  PubMed  Google Scholar 

  • Yew DT, Webb SE, Lam ET (1996) Neurotransmitters and peptides in the developing human facial nucleus. Neurosci Lett 206:65–68

    Article  CAS  PubMed  Google Scholar 

  • Yew DT, Li WP, Webb SE, Lai HW, Zhang L (1999a) Neurotransmitters, peptides, and neural cell adhesion molecules in the cortices of normal elderly humans and Alzheimer patients: a comparison. Exp Gerontol 34:117–133

    Article  CAS  PubMed  Google Scholar 

  • Yew DT, Wong HW, Li WP, Lai HW, Yu WH (1999b) Nitric oxide synthase neurons in different areas of normal aged and Alzheimer's brains. Neuroscience 89:675–686

    Article  CAS  PubMed  Google Scholar 

  • Yew DT, Chan WY, Luo CB, Zheng DR, Yu MC (1999c) Neurotransmitters and neuropeptides in the developing human central nervous system. A review. Biol Signals Recept 8:149–159

    Article  CAS  PubMed  Google Scholar 

  • Yuen EY, Jiang Q, Chen P, Feng J, Yan Z (2008) Activation of 5-HT2A/C receptors counteracts 5-HT1A regulation of n-methyl-D-aspartate receptor channels in pyramidal neurons of prefrontal cortex. J Biol Chem 283:17194–17204

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong S.A.R., China

    L. Y. Yeung & David T. Yew

  2. Stanley Ho Centre for Emerging Infectious Diseases, School of Public Health, Faculty of Medicine, Chinese University of Hong Kong, Shatin, New Territories, Hong Kong S.A.R., Hong Kong

    H. F. Kung

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  1. L. Y. Yeung
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  2. H. F. Kung
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Correspondence to David T. Yew.

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Yeung, L.Y., Kung, H.F. & Yew, D.T. Localization of 5-HT1A and 5-HT2A positive cells in the brainstems of control age-matched and Alzheimer individuals. AGE 32, 483–495 (2010). https://doi.org/10.1007/s11357-010-9152-x

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  • DOI: https://doi.org/10.1007/s11357-010-9152-x

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