Abstract
Serotonin (5-HT) neuron and neurotransmitter loss in normal aging and neuropsychiatric diseases of late life may contribute to behavioral changes commonly observed in the elderly population. Extensive evidence implicates a deficit in serotonergic neurotransmission in the development of major depression. It has been further suggested that the age-related changes in 5-HT neurons may predispose the elderly to develop depression. There is also increasing evidence that a combination of disturbances in cholinergic and serotonergic function may play a role in cognitive impairment in Alzheimer's disease (AD), with serotonergic dysfunction potentially responsible for a significant portion of the behavioral aspects of the disease. This implication of the 5-HT system in aging and age-related cognitive and mood disorders rests in large part on post mortem studies and animal models, which are limited in their capacity to predict dynamic human biochemical-behavior relationships or to accurately model the living human brain. Initial applications of functional brian imaging with positron emission tomography (PET) in the in vivo study of the brain in aging, depression, and dementia focused on characterizing alterations in physiological measurements of cerebral metabolism and perfusion. However, recent advances in PET radiochemistry, instrumentation, and image processing have paved the way for noninvasive means to test specific hypotheses regarding the direct involvement of 5-HT neurons in the behavioral features of aging and to define and monitor therapeutic regimens for neuropsychiatric conditions of late life. Coupling of clinical trials in well-characterized subject populations with PET imaging using ligands specific for 5-HT receptor subtypes and transporter proteins promises to increase our understanding of the role of the 5-HT system in affective and cognitive aspects of treatment response. Longitudinal studies in aging, late-life depression, and AD are also needed to evaluate the complex interplay between neurodegenerative processes and serotonergic neurotransmission.
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References
Agren H, Reibring L . (1994): PET studies of presynaptic monoamine metabolism in depressed patients and healthy volunteers. Pharmacopsychiatry 27: 2–6
Albert M, Sandor T, Moss M, Jolesz F . (1992): Measurement of age-related differences in gray matter, white matter, and cerebrospinal fluid. Radiology 185(P):200
Alder J, Chen C-H, Francis P, Hope T, Heath P, Bowen D . (1995): Pre and postsynaptic serotonergic markers in a community acquired study of Alzheimer's disease. Soc Neurosci Abstr 21(Part 3):1977
Alexopoulos GS, Abrams RC . (1991): Depression in Alzheimer's disease. Psychiatr Clin NA 14: 327–340
Alexopoulos G, Young R, Shindledecker R . (1992): Brain computed tomography findings in geriatric depression and primary degenerative dementia. Biol Psychiatry 31: 591–599
Alexopoulos G, Meyers B, Young R, Mattis S, Kakuma T . (1993): The course of geriatric depression with “reversible dementia”: A controlled study. Am J Psychiatry 150: 1693–1699
Alexopoulos G, Meyers B, Young R, Kakuma T, Feder M, Einhorn A, Rosendahl E . (1996): Recovery in geriatric depression. Arch Gen Psychiatry 53: 305–312
Altman HJ, Nordy D, Ogren S . (1984): Role of serotonin in memory: Facilitation by alaproclate and zimeldine. Psychopharmacology 84: 496–502
Altman HJ, Normile HJ, Galloway MP, Ramirez A, Azmitia EC . (1990): Enhanced spatial discrimination learning in rats following 5, 7-DHT-induced serotonergic deafferentation of the hippocampus. Brain Res 518: 61–66
Andersson A, Adolfsson R, Eriksson K, Marcusson J . (1991): Platelet [3H]paroxetine binding to 5-HT uptake sites in Alzheimer's disease. Neurobiol Aging 12: 531–534
Andersson A, Sundman I, Marcusson J . (1992): Age stability of human brain 5-HT terminals studied with [3H]paroxetine binding. Gerontology 38: 127–132
Arai H, Ichimiya Y, Kosaka K, Moroji T, Iizuka R . (1992): Neurotransmitter changes in early- and late-onset Alzheimer-type dementia. Prog Neuropsychopharmacol Biol Psychiatry 16: 883–890
Arango V, Ernsberger P, Marzuk P, Chen J-S, Tierney H, Stanley M, Reis D, Mann J . (1990): Autoradiographic demonstration of increased serotonin 5-HT2 and β-adrenergic receptor binding sites in the brain of suicide victims. Arch Gen Psychiatry 47: 1038–1047
Arango V, Underwood M, Mann J . (1992): Alterations in monoamine receptors in the brian of suicide victims. J Clin Psychopharmacol 12(Suppl.):8S–12S
Arango V, Underwood M, Gubbi A, Mann J . (1995): Localized alterations in pre- and postsynaptic serotonin binding sites in the ventrolateral prefrontal cortex of suicide victims. Brain Res 688: 121–133
Arora R, Meltzer H . (1989a): 3H-imipramine binding in the frontal cortex of suicides. Psychiatr Res 30: 125–135
Arora R, Meltzer H . (1989b): Serotonergic measures in the brains of suicide victims: 5-HT2 binding sites in the frontal cortex of suicide victims and control subjects. Am J Psychiatry 146: 730–736
Arora R, Emery O, Meltzer H . (1991): Serotonin uptake in the blood platelets of Alzheimer's disease patients. Neurology 41: 1307–1309
Arranz B, Eriksson A, Mellerup E, Plenge P, Marcusson J . (1993): Effect of aging in human cortical pre- and postsynaptic serotonin binding sites. Brain Res 620: 163–166
Ashworth S, Hume S, Lammertsma A, Opacka-Juffry J, Shah F, Pike V . (1996): Development of central 5-HT2A receptor radioligands for PET: Comparison of [3H]RP 62203 and [3H]SR 46349B kinetics in rat brain. Nucl Med Biol 23: 245–250
Azmitia EC, Whitaker-Azmitia PM . (1991): Awakening the sleeping giant: Anatomy and plasticity of the brain serotonergic system. J Clin Psychiatry 52: 4–16
Baldwin RC, Tomenson B . (1995): Depression in later life. A comparison of symptoms and risk factors in early and late onset cases. Br J Psychiatry 167: 649–652
Barnes J, Barnes N, Costall B, Naylor R, Tyers M . (1989): 5-HT3 receptors mediate inhibition of acetylcholine release in cortical tissue. Nature 338: 762–763
Baxter L, Schwartz J, Phelps M, Mazziotta J, Guze B, Selin C, Gerner R, Sumida R . (1989): Reduction of prefrontal cortex glucose metabolism common to three types of depression. Arch Gen Psychiatry 46: 243–250
Beats B, Levy R, Forstl H . (1991): Ventricular enlargement and caudate hyperdensity in elderly depressives. Biol Psychiatry 30: 452–458
Bench C, Friston K, Brown R, Scott L, Frackowiak R, Dolan R . (1992): The anatomy of melancholia—Focal abnormalities of cerebral blood flow in major depression. Psychol Med 22: 607–615
Bergman I, Brane G, Gottfries CG, Jostell K-G, Karlsson I, Svennerholm L . (1983): Alaproclate: A pharmacokinetic and biochemical study in patients with dementia of the Alzheimer type. Psychopharmacology 80: 279–283
Biegon A, Greuner N . (1992): Age-related changes in serotonin 5HT2 receptors on human blood platelets. Psychopharmacology 180: 210–212
Biver F, Goldman S, Luxen A, Monclus M, Forestini M, Mendlewicz J, Lotstra F . (1994): Multicompartmental study of fluorine-18 altanserin binding to brain 5HT2 receptors in humans using positron emission tomography. Eur J Nucl Med 21: 937–946
Biver F, Lotstra F, Monclus M, Wikler D, Damhaut P, Mendlewicz J, Goldman S . (1996): Sex difference in 5HT2 receptors in the living human brain. Neurosci Lett 204: 25–28
Biver F, Lotstra F, Monclus M, Dethy S, Damhaut P, Wikler D, Luxen A, Goldman S . (1997): In vivo binding of [18F]altanserin to rat brain 5HT2 receptors: A film and electronic autoradiographic study. Nucl Med Biol 24: 357–360
Blazer D, Hughes D, George L . (1987): The epidemiology of depression in an elderly community population. Gerontologist 27: 281–287
Blier P, de Montigny C, Chaput Y . (1990): A role for the serotonin system in the mechanism of action of antidepressant treatments: preclinical evidence. J Clin Psychiatry 51: 14–20
Blin J, Baron JC, Dubois B, Crouzel C, Fiorelli M, Attar-Levy D, Pillon B, Fournier D, Vidailhet M, Agid Y . (1993): Los of brain 5HT2 receptors in Alzheimer's disease. Brain 116: 497–510
Bonne O, Krausz Y, Shapira B, Bocher M, Karger H . Gorfine M, Chisin R, Lerer B . (1996): Increased cerebral blood flow in depressed patients responding to electroconvulsive therapy. J Nucl Med 37: 1075–1080
Bonte FJ, Ross ED, Chehabi HH, Devous MD . (1986): SPECT study of regional cerebral blood flow in Alzheimer disease. J Comput Assist Tomogr 10: 579–583
Bonte FJ, Hom J, Tintner R, Weiner MF . (1990): Single photon tomography in Alzheimer disease and the dementias. Semin Nucl Med 20: 342–352
Borson S, Barnes R, Kukull W . Okimoto J, Veith R, Inui T, Carter W, Raskind M . (1986): Symptomatic depression in elderly medical outpatients. I. Prevalence, demography, and health service utilization. J Am Geriatr Soc 34: 341–347
Bowen DM, Allen SJ, Benton JS, Goodhardt MJ, Haan EA, Palmer AM, Sims NR, Smith CCT, Spillane JA, Esiri MM, Neary D, Snowdon JS, Wilcock GK, Davison AN . (1983): Biochemical assessment of serotonergic and cholinergic dysfunction and cerebral atrophy in Alzheimer's disease. J Neurochem 41: 266–272
Bowen DM, Najlerahim A, Procter A, Francis P, Murphy E . (1989): Circumscribed changes of the cerebral cortex in neuropsychiatric disorders of late life. Proc Natl Acad Sci USA 86: 9504–9508
Briley M, Langer S, Raisman R, Sechter D, Zarifian E . (1980): Tritiated imipramine binding sites are decreased in platelets of untreated depressed patients. Science 209: 303–305
Burke WJ, Chung HD, Huang JS, Huang SS, Haring JH, Strong R, Marshall GL, Joh TH . (1988): Evidence for retrograde degeneration of epinephrine neurons in Alzheimer's disease. Ann Neurol 24: 532–536
Burns A, Tyrrell P . (1992): Association of age with regional cerebral oxygen utilization: A positron emission tomography study. Age Aging 21: 316–320
Carli M, Tranchina S, Samanin R . (1992): 8-Hydroxy-2-(di-n-propylamino)tetralin, 5-HT1A receptor agonist, impairs performance in a passive avoidance task. Eur J Pharmacol 211: 227–234
Casey D . (1994): Depression in the elderly. South Med J 87 (5): 559–563
Chan-Palay V . (1976): Serotonin axons in the supra- and subependymal plexuses and in the leptomeninges: Their roles in local alterations of cerebrospinal fluid and vasomotor activity. Brian Res 102: 103–130
Chawluk J, Alavi A, Hurtig H, Dann R, Rosen M, Kushner MJ, Silver FL, Reivich M . (1985): Altered patterns of regional cerebral glucose metabolism in aging and dementia. J Cereb Blood Flow Metab 5(Suppl. 1):S121–S122
Cheetham S, Crompton M, Katona C, Horton R . (1988): Brain 5-HT2 receptor binding sites in depressed suicide victims. Brain Res 443: 272–280
Chen C-H, Hope R, Alder J, Eastwood S, Gedling K, McDonald B, Francis P, Esiri M, Bowen D . (1995): Loss of paroxetine binding in the neocortex is associated with depression in Alzheimer's disease. In Iqbal K, Mortimer J, Winblad B, Wisniewski H (eds), Research Advances in Alzheimer's Disease and Related Disorders. New York, John Wiley & Sons Ltd, pp 467–473
Chen C-H, Alder J, Bowen D, Esiri M, McDonald B, Hope T, Jobst K, Francis P . (1996): Presynaptic serotonergic markers in community-acquired cases of Alzheimer's disease: Correlations with depression and neuroleptic medication. J Neurochem 66: 1592–1598
Cheng AVT, Ferrier IN, Morris CM, Jabeen S, Sahgal A, McKeith IG, Edwardson JA, Perry RH, Perry EK . (1991): Cortical serotonin-S2 receptor binding in Lewy body dementia, Alzheimer's and Parkinson's diseases. J Neurol Sci 106: 50–55
Coffey CE, Wilkinson WE, Parashos IA, Soady SAR, Sullivan RJ, Patterson LJ, Figiel GS, Webb MC, Spritzer CE, Djang WT . (1992): Quantitative cerebral anatomy of the aging human brain: A cross-sectional study using magnetic resonance imaging. Neurology 42: 527–536
Condon B, Wyper D, Grant R, Patterson J, Hadley D, Teasdale G, Rowan J . (1986): Use of magnetic resonance imaging to measure intracranial cerebrospinal fluid volume. Lancet 1: 1355–1357
Costall B, Barnes JM, Hamon M, Muller WE, Briley M . (1990): Biochemical models for cognition enhancers. Pharmacopsychiatry 23(Suppl. 2):85–88
Cowen P . (1993): Serotonin receptor subtypes in depression: Evidence from studies in neuroendocrine regulation. Clin Neuropharmacol 16(Suppl. 3):6–18
Craik F, Jennings J . (1992): Human Memory. In Craik F, Salthouse T (eds), The Handbook of Aging and Cognition. New York, Lawrence Elrbaum Publishers, pp 51–111
Cross AJ . (1990): Serotonin in Alzheimer-type dementia and other dementing illness. Ann NY Acad Sci 600: 405–417
Cross A, Crow T, Ferrier I, Johnson J, Bloom S, Corsellis J . (1984): Serotonin receptor changes in dementia of Alzheimer type. J Neurochem 43: 1574–1581
Cross P, Gurland B . (1986): The Epidemiology of Dementing Disorders (Contract report prepared for the Office of Technology Assessment, U.S. Congress). Washington, DC, U.S. Government Printing Office
Crouzel C, Guillaume M, Barre L, Lemaire C, Pike V . (1992): Ligands and tracers for PET studies of the 5-HT system—current status [review]. Int J Radiat Appl Instrum Part B, Nucl Med Biol 19: 857–870
Crow T, Cross A, Cooper S, Deakin J, Ferrier I, Johnson J . Joseph M, Owen FMP, Lofthouse R, Corsellis J, Chambers D, Blessed G, Perry E, Perry R, Tomlinson B . (1984): Neurotransmitter receptors and monoamine metabolites in the brains of patients with Alzheimer-type dementia and depression, and suicides. Neuropharmacology 23: 1561–1569
Curcio C, Kemper T . (1984): Nucleus raphe dorsalis in dementia of the Alzheimer type: Neurofibrillary changes and neuronal packing density. J Neuropathol Exp Neurol 43: 359–368
Cutler NR, Haxby JV, Duara R, Grady CL, Kay AD, Kessler RM, Sundaram M, Rapoport SI . (1985): Clinical history, brain metabolism, and neuropsychological function in Alzheimer disease. Ann Neurol 18: 298–309
D'Amato R, Zwieg R, Whitehouse P, Wenk G, Singer H, Mayeaux R, Price D, Snyder S . (1987): Aminergic systems in Alzheimer's disease and Parkinson's disease. Ann Neurol 22: 229–239
Davies P, Maloney AJ . (1976): Selective loss of central cholinergic neurons in Alzheimer's disease [letter]. Lancet 2: 1403
Dawson T, Wamseley J . (1983): Autoradiographic localization of [3H]imipramine binding sites: Association with serotonergic neurons. Brain Res Bull 11: 325–334
DeKosky S, Palmer A . (1994): Neurochemistry of aging. In Albert M, Knoefel J (eds), Clinical Neurology of Aging. New York, Oxford Press, pp 79–101
DeKosky S, Scheff S, Markesberry W . (1985): Laminar organization of cholinergic circuits in human frontal cortex in Alzheimer's disease and aging. Neurology 35: 1425–1431
DeKosky S, Shih W-J, Schmitt F, Coupal J, Kirkpatrick C . (1990): Assessing utility of single photon emission computerized tomography (SPECT) scan in Alzheimer's disease: Correlation with cognitive severity. Alzheimer's Disease Related Disorders 4: 14–23
de Leon M, Ferris S, George A, Christman D, Fowler J, Gentes C, Reisberg B, Gee B, Emmerich M, Yonekura Y, Brodie J, Kricheff I, Wolf A . (1983): Positron emission tomographic studies of aging and Alzheimer disease. Am J Neuroradiol 4: 568–571
de Montigny C . (1984): Electroconvulsive shock treatment enhance responsiveness of forebrain neurons to serotonin. J Pharmacol Exp Ther 228: 230–234
Delgado P, Charney D, Price L, Aghajanian G, Landis H, Heninger G . (1990): Serotonin function and the mechanism of antidepressant action. Arch Gen Psychiatry 47: 411–418
Denys A, Maunoury C, Cuenod C, Boller F, Jehenson P . (1992): Amygdala and hippocampal formation MR measurements: diagnostic value in early stage of Alzheimer disease. Radiology 185(P):200
Descarries L, Beaudet A, Watkins K . (1975): Serotonin nerve terminals in adult rat neocortex. Brain Res 100: 563–588
Devanand D, Sano M, Tang M-X, Taylor S, Gurland B, Wilder D, Stern Y, Mayneux R . (1996): Depressed mood and the incidence of Alzheimer's disease in the elderly living in the community. Arch Gen Psychiatry 53: 175–182
Dewar D, Graham D, McCulloch J . (1990): 5-HT2 receptors in dementia of Alzheimer type: A quantitative autoradiographic study of frontal cortex and hippocampus. J Neural Transm 2: 129–137
Dewey S, Tan P, Smith G, King P, Pappas N, MacGregor R, Ding Y-S, Shea C, Alexoff D, Martin T, Gatley S, Fowler J, Wolf A . (1994): PET and in vivo microdialysis studies of SR 46349B, a new and selective 5-HT2 antagonist. Soc Neurosci Abstr 20: 1552
D'haenen H, Bossuyt A, Mertens J, Bossuyt-Piron C, Gijsemans M, Kaufman L . (1992): SPECT Imaging of serotonin2 receptors in depression. Psychiatr Res: Neuroimaging 45: 227–237
Diksic M, Nagahiro S, Chaly T, Sourkes T, Yamamoto Y, Feindel W . (1991): Serotonin synthesis rate measured in living dog brain by positron emission tomography. J Neurochem 56: 153–160
Diksic M, Nagahiro S, Grdisa M . (1995): The regional rate of serotonin synthesis estimated by the δ-methyl-tryptophan method in rat brain from a single time point. J Cereb Blood Flow Metab 15: 806–813
Dillon K, Gross-Isseroff R, Israeli M, Biegon A . (1991): Autoradiographic analysis of serotonin 5-HT1A receptor binding in the human brain postmortem: Effects of age and alcohol. Brain Res 554: 56–64
Drevets WC, Videen TO, Price JL, Preskorn SH, Carmichael ST, Raichle ME . (1992): A functional anatomical study of unipolar depression. J Neurosci 12: 3628–3641
Drevets W, Price J, Simpson J, Todd R, Reich T, Raichle M . (1996): State- and trait-like neuroimaging abnormalities in depression: effects of antidepressant treatment. Soc Neurosci Abstr 22: 264
Duara R, Grady C, Haxby J, Ingvar D, Sokoloff L, Margolin R, Manning R, Cutler NR, Rappaport SI . (1984): Human brain glucose utilization and cognitive function in relation to age. Ann Neurol 16: 702–713
Duara R, Grady C, Haxby J, Sundaram M, Cutler NR, Heston L, Moore A, Schlageter N, Larson S, Rappaport SI . (1986): Positron emission tomography in Alzheimer's disease. Neurology 36: 879–887
Edwards E, Harkins K, Wright G, Henn F . (1991): 5-HT1b receptors in an animal model of depression. Neuropharmacology 30: 101–105
Ellis P, Beeston R, McIntosh C, Salmond C, Cooke R . (1992): Platelet 3H-imipramine binding during recovery from depression. Acta Psychiatr Scand 86: 108–112
Engleman E, Murphy J, Zhou F, Hingtgen J . (1992): Response suppression induced with selective 5-HT agonists can be differentially blocked with LY53857 in an animal model of depression. Neurochem Res 176: 483–488
Erkinjuntti T, Lee DH, Gao F, Steenhuis R, Eliasziw M, Fry R, Merskey H, Hachinski VC . (1993): Temporal lobe atrophy on magnetic resonance imaging in the diagnosis of early Alzheimer's disease. Arch Neurol 50: 305–310
Ernst RL, Hay JW . (1994): The US economic and social costs of Alzheimer's disease revisited. Am J Public Health 84: 1261–1264
Evans D, Funkenstein H, Albert M, Scherr P, Cook N, Chown M, Herbert L, Hennekens C, Taylor J . (1989): Prevalence of Alzheimer's disease in a community population of older persons: Higher than previously reported. JAMA 262: 2551–2556
Figiel G, Krishnan K, Doraiswamy P, Rao V, Nemeroff C, Boyko O . (1991): Subcortical hyperintensities on brain magnetic resonance imaging: A comparison between late age onset and early onset elderly depressed subjects. Neurobiol Aging 12: 245–247
Fisher P, Simanyi M, Danielczyk W . (1990): Depression in dementia of the Alzheimer type and in multi-infarct dementia. Am J Psychiatry 147: 1484–1487
Fitz AG, Teri L . (1994): Depression, cognition, and functional ability in patients with Alzheimer's disease. J Am Geriatr Soc 42: 186–191
Fletcher A, Pike VW, Cliffe IA . (1995): Visualization and characterization of 5-HT receptors and transporters in vivo and in man. Semin Neurosci 7: 421–431
Foster NL, Chase TN, Mansi L, Brooks R, Fedio P, Patronas NJ, Di Chiro G . (1984): Cortical abnormalities in Alzheimer's disease. Ann Neurol 16: 649–654
Francis PT, Pangalos MN, Stephens PH, Bartlett JR, Bridges PK, Malizia AL, Neary D, Proctor AW, Thomas DJ, Bowen DM . (1993): Antemortem measurements of neurotransmission: Possible implications for pharmacotherapy of Alzheimer's disease and depression. J Neurol Neurosurg Psychiatry 56: 80–84
Frankfurt M, McKittrick C, Mendelson S, McEwen B . (1994): Effect of 5, 7-dihydroxy-tryptamine, ovariectomy and gonadal steroids on serotonin receptor binding in rat brain. Neuroendocrinology 59: 245–250
Friedland RP, Budinger TF, Ganz E, Yano Y, Mathis CA, Koss B, Ober BA, Huesman RH, Derenzo SE . (1983): Regional cerebral metabolic alterations in dementia of the Alzheimer type: Positron emission tomography with 18F-fluorodeoxyglucose. J Comput Assist Tomogr 7: 590–598
Frlich L, Eilles C, Ihl R, Maurer K, Lanczik M . (1989): Stage-dependent reductions of regional cerebral blood flow measured by HMPAO-SPECT in dementia of Alzheimer type. Psychiatry Res 29: 347–350
Frost J . (1990: Imaging the serotonergic system by positron emission tomography. Ann NY Acad Sci 600: 272–280
Fuxe K, Calza L, Benfenati F, Zini I, Agnatti L . (1983): Quantitative autoradiographic localization of [3H]imipramine binding sites in the brain of the rat. Relationship to ascending 5-hydroxytryptamine neuron systems. Proc Natl Acad Sci USA 80: 3836–3840
German DC, White CLD, Sparkman DR . (1987): Alzheimer's disease: Neurofibrillary tangles in nuclei that project to the cerebral cortex. Neuroscience 21: 305–312
Gilewski MJ, Farberow NL, Gallagher DE, Thompson LW . (1991): Interaction of depression and bereavement on mental health in the elderly. Psychol Aging 6: 67–75
Golden RN, Gilmore JH, Corrigan MHN, Ekstrom RD, Knight BT, Garbutt JC . (1991): Serotonin, suicide, and aggression: clinical studies. J Clin Psychiatry 52: 61–69
Gonzales G, Carillo C . (1993): Blood serotonin levels in postmenopausal women: Effects of age and serum oestradiol levels. Maturitas 17: 23–29
Gottfries C . (1990): Neurochemical aspects on aging and disease with cognitive impairment. J Neurosci Res 27: 541–547
Gross-Isseroff R, Salama D, Isreli M, Biegon A . (1990): Autoradiographic analysis of [3H]ketansterin binding in the human brain postmortem: effect of suicide. Brain Res 507: 208–215
Hajdu MA, McElmurry RT, Heistad DD, Baumbach GL . (1993): Effects of aging on cerebral vascular responses to serotonin in rats. Am J Physiol 264: H2136–2140
Halliday GM, McCann HL, Pamphlett R, Brooks WS, Creasey H, McCusker E, Cotton RGH, Broe GA, Harper CG . (1992): Brain stem serotonin-synthesizing neurons in Alzheimer's disease: A clinicopathological correlation. Acta Neuropathol 84: 638–650
Hayakawa H, Okamoto Y, Shimizu M, Nishida A, Motohashi N, Yamawaki S . (1995): Single or repeated treatment with electroconvulsive shock increases number of serotonin uptake binding sites in the frontal cortex. Biol Psychiatry 31: 1–5
Holman BL, Nagel JS, Johnson KA, Hill TC . (1991): Imaging dementia with SPECT. Ann NY Acad Sci 620: 165–174
Hoyer D, Martin G . (1997): 5-HT receptor classification and nomenclature: Towards a harmonization with the human genome. Neuropharmacology 36: 419–428
Hrdina P, Foy B, Hepner A, Summers R . (1990): Antidepressant binding sites in brain: Autoradiographic comparison of [3H]paroxetine and [3H]imipramine localization and relationship to serotonin transporter. J Pharmacol Exp Ther 252: 410–418
Hrdina P, Demeter E, Vu T, Sotonyi P, Palkovits M . (1993): 5-HT uptake sites and 5-HT2 receptors in brain of antidepressant-free suicide victims/depressives: Increase in 5-HT2 sites in cortex and amygdala. Brain Res 614: 37–44
Hume SP, Ashworth S, Opacka-Juffry J, Ahier RG, Lammertsma AA, Pike VW, Cliffe IA, Fletcher A, White AC . (1994): Evaluation of [O-methyl-3H]WAY-100635 as an in vivo radioligand for 5-HT1A receptors in rat brain. Eur J Pharmacol 271: 515–523
Husain M, Knight D, Doraiswamy P, Krishnan K, Nemeroff C . (1991): Platelet [3H]-imipramine binding and leukoencephalopathy in geriatric depression. Biol Psychiatry 29: 665–670
Inestrosa N, Alarcon R, Arrigada J, Donoso A, Alverez J . (1993): Platelet of Alzheimer patients: Increased counts and subnormal uptake of accumulation of [14C]5-hydroxytryptamine. Neurosci Lett 163: 8–10
Iyo M, Yamasaki T . (1993): The detection of age-related decrease of dopamine D1, D2 and serotonin 5-HT2 receptors in living human brain. Prog Neuro-Psychopharmacol Biol Psychiatry 17: 415–421
Jack CR, Petersen RC, O'Brien PC, Tangalos EG . (1992): MR-based hippocampal volumetry in the diagnosis of Alzheimer disease. Neurology 42: 183–188
Jacobs B, Azmitia E . (1992): Structure and function of the brain serotonin system. Physiol Rev 72: 165–229
Jaffe E, De Frias V, Ibarra C . (1993): Changes in basal and stimulated release of endogenous serotonin from different nuclei of rats subjected to two models of depression. Neurosci Lett 162: 157–160
Jagust WJ, Budinger TF, Reed BR . (1987): The diagnosis of dementia with single photon emission computed tomography. Arch Neurol 44: 258–262
Jagust WJ, Reed BR, Seab PJ, Budinger TF . (1990): Alzheimer disease: Age at onset and single-photon emission computed tomographic patterns of regional cerebral blood flow. Arch Neurol 47: 628–633
Jamieson DG, Chawluk JB, Alavi A, Hurtig HI, Rosen M, Bais S, Dann R, Kushner M, Reivich M . (1987): The effect of disease severity on local cerebral glucose metabolism in Alzheimer's disease. J Cereb Blood Flow Metab 7: S410
Jansen KLR, Faull RLM, Dragunow M, Synek BL . (1990): Alzheimer's disease: Changes in hippocampal N-methyl-D-aspartate, quisqualate, neurotensen, adenosine, benzodiazepine, serotonin and opioid receptors—An autoradiographic study. Neuroscience 39: 613–627
Jernigan TL, Press GA, Hesselink JR . (1990): Methods for measuring brain morphologic features on magnetic resonance images. Arch Neurol 47: 27–32
Kennedy GJ, Kelman HR, Thomas C . (1991): Persistence and remission of depressive symptoms in late life. Am J Psychiatry 148: 174–178
Kennett G . (1991): Mechanisms of serotonergic affect control. In Schwarcz R, Young S, Brown R (eds), Kynurenine and Serotonin Pathways. New York, Plenum Press, pp 231–243
Komahashi T, Ohmori K, Nakana T, Fujinuma H, Higashimoto T, Nakaya M, Kuroda J, Asahi H, Yoshikawa J, Mastumura S . (1994): Epidemiological survey of dementia and depression among the aged living in the community in Japan. Jpn J Psychiatry Neurol 48: 517–526
Koren P, Diver-Haber A, Adunsky A, Rabinowitz M, Hershkowitz M . (1993): Uptake of serotonin into platelets of senile dementia of the Alzheimer type patients. J Gerontol 48: B93–B96
Kostowski W, Dyr W, Krzascik P, Jarbe T, Archer T . (1992): 5-hydroxytryptamine1A receptor agonists in animal models of depression and anxiety. Pharmacol Toxicol 71: 24–30
Kovachich G, Aronson C, Brunswick D . (1992): Effect of repeated administration of antidepressants on serotonin uptake sites in limbic and neocortical structures of rat brain determined by quantitative autoradiography. Neuropsychopharmacology 7: 317–324
Kral VA, Emery OB . (1989): Long-term follow-up of depressive pseudodementia of the aged. Can J Psychiatry—Revue Canadienne de Psychiatrie 34: 445–446
Kuhl D, Metter E, Riege W, Phelps M . (1982): Effects of human aging on patterns of local cerebral glucose utilization determined by the [18F]fluorodeoxyglucose method. J Cereb Blood Flow Metab 2: 163–171
Kumar A, Newberg A, Alavi A, Berlin J, Smith R, Reivich M . (1993): Regional cerebral glucose metabolism in late-life depression and Alzheimer disease: A preliminary positron emission tomography study. Proc Natl Acad Sci USA 90: 7019–7023
Kumar A, Miller D, Samuels S, Burke L, Ewbank D, Gottlieb G . (1994): MRI volumetrics in late life depression and Alzheimer's disease. Biol Psychiatry 35: 615–747
Lawlor BA, Sunderland T, Mellow AM, Molchan SE, Martinez R, Murphy DL . (1991): A pilot placebo-controlled study of chronic m-CPP administration in Alzheimer's disease. Biol Psychiatry 30: 140–144
Lawrence K, De Paermentier F, Cheetham S, Crompton M, Katona C, Horton R . (1990): Brain 5-HT uptake sites, labelled with [3H]paroxetine, in antidepressant-free depressed suicides. Brain Res 526: 17–22
Leake A, Fairbairn A, McKeith I, Ferrier I . (1991): Studies on the serotonin uptake binding site in major depressive disorder and control post-mortem brain: Neurochemical and clinical correlates. Psychiatry Res 39: 155–165
Lemaire C, Cantineau R, Guillaume M, Plenevaux A, Christiaens L . (1991): Fluorine-18altanserin: A radioligand for the study of serotonin receptors with PET: Radiolabeling and in vivo biologic behavior in rats. J Nucl Med 32: 2266–2272
Leysen J . (1990): Gaps and peculiarities in 5-HT2 receptor studies. Neuropsychopharmacology 3: 361–369
Little J, Broocks A, Martin A, Hill J, Tune L, Mack C, Cantillon M, Molchan S, Murphy D, Sunderland T . (1995): Serotonergic modulation of anticholinergic effects on cognition and behavior in elderly humans. Psychopharmacology 120: 280–288
Loessner A, Alavi A, Lewandrowski K-U, Mozley D, Souder E, Gur R . (1995): Regional cerebral function determined by FDG-PET in healthy volunteers: Normal patterns and changes with age. J Nucl Med 36: 1141–1149
Lundkvist C, Halldin C, Ginovart N, Nyberg S, Swahn C-G, Carr A, Brunner F, Farde L . (1996): [11C]MDL 100907, a radioligand for selective imaging of 5-HT2A receptors with positron emission tomography. Life Sci 58: 187–192
Luscombe G P, Martin KF, Hutchins LJ, Gosden J, Heal DJ . (1993): Mediation of the antidepressant-like effect of 8-OH-DPAT in mice by postsynaptic 5-HT1A receptors. Br J Pharmacol 108: 669–677
Maes M, Meltzer H . (1995): The serotonin hypothesis of major depression. In Bloom F, Kupfer D (eds), Psychopharmacology: The Fourth Generation of Progress. New York, Raven Press, Ltd, pp 933–944
Mann DMA, Yates PO, Marcyniuk B . (1984): Alzheimer's presenile dementia, senile dementia of Alzheimer type and Down's syndrome in middle age form an age-related continuum of pathological changes. Neuropathol Appl Neurobiol 10: 185–207
Mann J, Malone K, Diehl D, Perel J, Cooper T, Mintun M . (1996): Demonstration in vivo of reduced serotonin responsivity in the brain of untreated depressed patients. Am J Psychiatry 153: 174–182
Marcusson J, Morgan D, Winblad B, Finch C . (1984a): Serotonin-2 binding sites in human frontal cortex and hippocampus. Selective loss of S-2A sites with age. Brain Res 311: 51–56
Marcusson J, Oreland L, Winblad B . (1984b): Effect of age on human brain serotonin (S-1) binding sites. J Neurochem 43: 1699–1705
Marcusson J, Alafuzoff I, Backstrom I, Ericson E, Gottfries C, Winblad B . (1987): 5-Hydroxytryptamine-sensitive [3H]im-ipramine binding of protein nature in the human brain. II. Effect of normal aging and dementia disorders. Brain Res 425: 137–145
Marcyniuk B, Mann DM, Yates PO . (1986): The topography of cell loss from locus coeruleus in Alzheimer's disease. J Neurol Sci 76: 335–345
Martin A, Friston K, Colebatch J, Frackowiak R . (1991): Decreases in regional cerebral blood flow with normal aging. J Cereb Blood Flow Metab 11: 684–689
Mathis CA, Simpson NR, Mahmood K, Kinahan PE, Mintun MA . (1994): [11C]Way 100635: A radioligand for imaging 5-HT1A receptors with positron emission tomography. Life Sci 55: PL403–407
Mathis CA, Huang Y, Simpson NR, Mahmood K, Gerdes JM, Price JC . (1995): [11C]MDL 100,907: A potent and selective antagonist of 5-HT2A receptors labelled with 11C at two different positions. J Labelled Compd Radiopharm 27: 316–318
Mathis CA, Mahmood K, Huang Y, Simpson NR, Gerdes JM, Price JC . (1996): Synthesis and preliminary in vivo evaluation of [11C]MDL 100907: A potent and selective radioligand for the 5-HT2A receptor system. Med Chem Res 6: 1–10
Matsubara S, Arora R, Meltzer H . (1991): Serotonergic measures in suicide brain: 5HT1A binding sites in frontal cortex of suicide victims. J Neural Transm 85: 181–194
Mayberg H . (1994): Frontal lobe dysfunction in secondary depression. J Neuropsychiatry 428–442
Mayberg H, Brannan S, Liotti M, Mahurin R, Brickman J, Silva J, Tekell C, Jerebek P, Martin C, Fox P . (1996): The role of the cingulate in mood homeostasis. Soc Neurosci Abstr 22: 267
McBean DE, Sharkey J, Ritchie IM, Kelly PA . (1990): Evidence for a possible role for serotonergic systems in the control of cerebral blood flow. Brain Res 537: 307–310
McBean DE, Sharkey J, Ritchie IM, Kelly PA . (1991): Cerebrovascular and functional consequences of 5-HT1A receptor activation. Brain Res 555: 159–163
McBride P, Brown R, DeMeo M, Keilp J, Mieczkowski T, Mann J . (1994): The relationship of platelet 5-HT2 receptor indices to major depressive disorder, personality traits, and suicidal behavior. Biol Psychiatry 35: 295–308
McGuire M, Rabins P . (1994): Mood disorders. In Coffey C, Cummings J (eds), The American Psychiatric Press Textbook of Geriatric Neuropsychiatry. Washington, DC/London, American Psychiatric Press, Inc, pp 244–260
McLoughlin D, Lucey J, Dinan T . (1994): Central serotonergic hyperresponsivity in late-onset Alzheimer's disease. Am J Psychiatry 151: 1701–1703
Meltzer CC, Leal JP, Mayberg HS, Wagner HJ, Frost JJ . (1990): Correction of PET data for partial volume effects in human cerebral cortex by MR imaging. J Comp Assist Tomogr 14: 561–570
Meltzer C, Nichols T, Mintun M . (1995): Effect of resolution on recovery of gray matter activity in FDG PET. J Nucl med 36: 114P
Meltzer C, Zubieta J, Brandt J, Tune L, Mayberg H, Frost J . (1996): Regional hypometabolism in Alzheimer disease as measured by PET following correction for effects of partial volume averaging. Neurology 47: 454–461
Meltzer H . (1990): Role of serotonin in depression. Ann NY Acad Sci 600: 486–500
Middlemiss D, Palmer A, Edel N, Bowen D . (1986): Binding of the novel serotonin agonist 8-hydroxy-2-(di-n-propylamino) tetralin in normal and Alzheimer brain. J Neurochem 46: 993–996
Mueller-Gaertner H, Links J, Prince J, Bryan R, McVeigh E, Leal J, Davatzikos C, Frost J . (1992): Measurement of radiotracer concentration in brain gray matter using positron emission tomography: MRI-based correction for partial volume effects. J Cereb Blood Flow Metab 12: 571–583
Murphy D, DeCarli C, Schapiro M, Rapoport S, Horwitz B . (1992): Age-related differences in volumes of subcortical nuclei, brain matter, and cerebrospinal fluid in healthy men as measured with magnetic resonance imaging. Arch Neurol 49: 839–845
Myers BL, Badia P . (1995): Changes in circadian rhythms and sleep quality with aging: Mechanisms and interventions. Neurosci Biobehav Rev 19: 553–571
Newman ME, Shapira B, Lerer B . (1992): Regulation of 5-hydroxytryptamine1A receptor function in rat hippocampus by short- and long-term administration of 5-hydroxytryptamine1A agonist and antidepressants. J Pharmacol Exp Ther 260: 16–20
Nishizawa S, Benkelfat C, Young SN, Leyton M, Mzengeza S, Demontigny C, Blier P, Diksic M . (1997): Differences between males and females in rates of serotonin synthesis in human brain. Proc Natl Acad Sci USA 94: 5308–5313
Nordberg A . (1992): Neuroreceptor changes in Alzheimer disease. Cerebrovasc Brain Metab Rev 4: 303–328
Normile H, Altman H . (1992): Effects of combined acetylcholinesterase inhibition and serotonergic receptor blockade on age-associated memory impairments in rats. Neurobiol Aging 13: 735–740
Nybäck H, Nyman H, Blomqvist G, Sjögren I, Stone-Elander S . (1991): Brain metabolism in Alzheimer dementia: Studies of 11C-deoxyglucose accumulation, CSF monoamine metabolites and neuropsychological test performance in patients and healthy subjects. J Neurol Neurosurg Psychiatry 54: 672–678
Nyth A, Gottfries C . (1990): The clinical efficacy of citalopram in treatment of emotional disturbances in dementia disorders. BR J Psychiatry 157: 894–901
Osman S, Lundkvist C, Pike V, Halldin C, McCarron J, Swahn C-G, Ginovart N, Luthra S, Bench C, Grasby P, Wikström H, Barf T, Cliffe I, Fletcher A, Farde L . (1996): Characterization of the radioactive metabolites of the 5-HT1A receptor radioligande, [O-methyl-11C]WAY-100635, in monkey and human plasma by HPLC: Comparison of the behaviour of an identified radioactive metabolite with parent radioligand in monkey using PET. Nucl Med Biol 23: 627–634
Owen F, Cross A, Crow T, Deakin J, Ferrier I, Lofthouse R M P . (1983): Brain 5-HT2 receptors and suicide. Lancet ii: 1256
Owen F, Chambers DR, Cooper SJ, Crow TJ, Johnson JA, Lofthouse R, Poulter M . (1986): Serotonergic mechanisms in brains of suicide victims. Brain Res 362: 185–188
Palacios J, Waeber C, Hoyer D, Mengod G . (1990): Distribution of serotonin receptors. Ann NY Acad Sci 600: 36–52
Palmer AM, Francis PT, Benton JS, Sims NR, Mann DMA, Neary D, Snowden JS, Bowen DM . (1987a): Presynaptic serotonergic dysfunction in patients with Alzheimer's disease. J Neurochem 48: 8–15
Palmer AM, Middlemiss DN, Bowen DM . (1987b): [3H]8-OH-DPAT binding in Alzheimer's disease: An index of pyramidal cell loss? In Dourish C, Ahlenius A, Hutson P (eds), Brain 5-HT1A Receptors. Chichester, Ellis Horwood Ltd, pp 286–299
Palmer AM, Stratmann GC, Proctor AWP, Bowen DM . (1988): Possible neurotransmitter basis of behavioral changes in Alzheimer's disease. Ann Neurol 23: 616–620
Parmelee P, Katz I, Lawton M . (1989): Depression among institutionalized aged: Assessment and prevalence estimation. J Gerontol 44: M22–M29
Paul S, Rehavi M, Skolnick P, Ballenger J, Goodwin F . (1981): Depressed patients have decreased binding of tritiated imipramine to platelet serotonin “transporter.”Arch Gen Psychiatry 38: 1315–1317
Pauwels PJ . (1997): 5HT1B/D receptor antagonists. Gen Pharmacol 29: 293–303
Peroutka SJ . (1994): Molecular biology of serotonin (5-HT) receptors. Synapse 18: 241–260
Perry EK, Tomlinson BE, Blessed G, Bergmann K, Gibson PH, Perry RH . (1978): Correlation of cholinergic abnormalities with senile plaques and mental test scores in senile dementia. Br Med J 2: 1457–1459
Perry E, Marshall E, Blessed G, Tomlinson B, Perry R . (1983): Decreased imipramine binding in the brains of patients with depressive illness. Br J Psychiatry 142: 188–192
Pike V, McCarron J, Lammertsma A, Osman S, Hume S, Sargent P, Bench C, Cliffe I, Fletcher A, Grasby P . (1996): Exquisite delineation of 5-HT1A receptors in human brain with PET and [carbonyl-11C]WAY-100635. Eur J Pharmacol 301: R5–R7
Polinsky RJ, Noble J, Di Chiro G, Nee LE, Feldman RG, Brown RT . (1987): Dominantly inherited Alzheimer disease: Cerebral glucose metabolism. J Neurol Neurosurg Psychiatry 50: 752–757
Price J, Mathis C, Simpson N, Mahmood K, Mintun M . (1996): Kinetic modeling of serotonin-1A binding in monkeys using [11C]WAY 100635 and PET. In Meyers R, Cunningham V, Bailey D, Jones T (eds), Quantification of Brain Function Using PET. San Diego, Academic Press, pp 257–261
Proctor AW, Francis PT, Stratmann GC, Bowen DM . (1992): Serotonergic pathology is not widespread in Alzheimer patients without prominent aggressive symptoms. Neurochem Res 17: 917–922
Quirion R, Richard J . (1987): Differential effects of selective lesions of cholinergic and dopaminergic neurons on serotonin-type 1 receptors in rat brain. Synapse 1: 124–130
Quirion R, Richard J, Dam TV . (1985): Evidence for the existence of serotonin type-2 receptors on cholinergic terminals in rat cortex. Brain Res 333: 345–349
Rapp P, Amaral D . (1992): Individual differences in the cognitive and neurobiological consequences of normal aging. Trends Neurosci 15: 340–345
Reiman E, Caselli R, Yun L, Chen K, Bandy D, Minoshima S, Thibodeau S, Osborne D . (1996): Preclinical evidence of Alzheimer's disease in persons homozygous for the epsilon 4 allele for apolipoprotein E. N Engl J Med 334: 752–758
Reinikainen KJ, Soininen H, Reikkinen PJ . (1990): Neurotransmitter changes in Alzheimer's disease: Implications to diagnostics and therapy. J Neurosci Res 27: 576–586
Reynolds C, Kupfer D, Hoch C, Stack J, Houck P, Sewitch D . (1986): Two-year follow-up of elderly patients with mixed depression and dementia. Clinical and electroencephalographic sleep findings. J Am Geriatr Soc 34: 793–799
Reynolds G, Arnold L, Rossor M, Iversen L, Mountjoy C, Roth M . (1984): Reduced binding of [3H]Ketanserin to cortical 5-HT2 receptors in severe dementia of the Alzheimer type. Neurosci Lett 44: 47–51
Richter-Levin G, Segal M . (1990): Age-related cognitive deficits in rats are associated with a combined loss of cholinergic and serotonergic functions. Ann NY Acad Sci 600: 254–257
Riekkinen M, Tolonen R, Riekkinen P Jr . (1994): Interaction between 5-HT1A and nicotinic cholinergic receptors in the regulation of water maze navigation behavior. Brain Res 649: 174–180
Rinaldi-Carmona M, Congy C, Simiand J, Oury-Donat F, Soubrie P, Breliere JC, Le Fur G . (1993): Repeated administration of SR 46349B, a selective 5-hydroxytrypta-mine 2 antagonist, up-regulates 5-hydroxytryptamine 2 receptors in mouse brain. Mol Pharmacol 43: 84–89
Robinson D, Rickels K, Feighner J, Fabre L, Gammans R, Shrotriya R, Alms D, Andary J, Messina M . (1990): Clinical effects of the 5-HT1A partial agonists in depression: A composite analysis of buspirone in the treatment of depression. J Clin Psychopharmacol 10: 67S–76S
Robinson SE . (1983): Effect of specific serotonergic lesions on cholinergic neurons in the hippocampus, cortex and striatum. Life Sci 32: 345–353
Robson L, Gower A, Kendall D, Marsden C . (1993): Age-related behavioural, neurochemical and radioligand binding changes in the central 5-HT system of Sprague-Dawley rats. Psychopharmacology 113: 274–281
Sadzot B, Lemaire C, Maquet P, Salmon E, Plenevaux A, Degueldre C, Hermanne J, Guillaume M, Cantineau R, Comar D, Franck G . (1995): Serotonin 5HT2 receptor imaging in the human brain using positron emission tomography and a new radioligand, [81F]altanserin: Results in young normal controls. J Cereb Blood Flow Metab 15: 787–797
Salmon E, Maquet P, Sadzot B, Degueldre C, Lemaire C, Franck G . (1991): Decrease of frontal metabolism demonstrated by positron emission tomography in a population of healthy elderly volunteers. Acta Neurol Belg 91: 288–295
Saudou F, Hen R . (1994): 5-hydroxytryptamine receptor subtypes in vertebrates and invertebrates. Neurochem Int 25: 503–532
Schneider LS, Severson J, Chui H, Pollock V, Sloane R, Fredrickson E . (1988): Platelet H3-imipramine binding in Alzheimer's disease patients with agitation and delusions. Psychiatry Res 25: 311–322
Schone W, Ludwig M . (1993): A double-blind study of paroxetine compared with fluoxetine in elderly patients with major depression. J Clin Psychopharmacol 13(Suppl 2):34S–39S
Seab JP, Jagust WP, Wong STS, Roos MS, Reed BR, Budinger TF . (1988): Quantitative NMR measurements of hippocampal atrophy in Alzheimer's disease. Magn Reson Med 8: 200–208
Shapira B, Lerer B, Kindler S, Lichtenberg P, Gropp C, Cooper T, Calev A . (1992): Enhanced serotonergic responsivity following electroconvulsive therapy in patients with major depression. Br J Psychiatry 160: 223–229
Sharpley AL, Elliott JM, Attenburrow MJ, Cowen PJ . (1994): Slow wave sleep in humans: Rose of 5-HT2A and 5-HT2C receptors. Neuropharmacology 33: 467–471
Shefer VF . (1972): Absolute numbers of neurons and thickness of the cerebral cortex during aging, senile and vascular dementia, and Pick's and Alzheimer's diseases. Neurosci Behav Physiol 6: 319–324
Shih J, Young H . (1978): The alteration of serotonin binding sites in aged human brained. Life Sci 23: 1441–1448
Shuttleworth EC, Huber SJ, Paulson GW . (1987): Depression in patients with dementia of the Alzheimer type. J Natl Med Assoc 79: 733–736
Small G, Mazziotta J, Collins M . (1995): Apolipoprotein E type 4 allele and cerebral glucose metabolism in relatives at risk for familial Alzheimer disease. JAMA 273: 942–947
Sparks D . (1989): Aging and Alzheimer's disease. Altered cortical serotonergic binding. Arch Neurol 46: 138–140
Sparks D, Markesbery W, Slevin J . (1986): Alzheimer's disease: Monoamines and spiperone binding reduced in nucleus basalis. Ann Neurol 19: 602–604
Staner L, Kempanaers C, Simonnet M-P, Fransolet L, Mendlewicz J . (1992): 5-HT2 receptor antagonism and slow-wave sleep in major depression. Acta Psychiatr Scand 86: 133–137
Stanley M, Mann J . (1983): Increased serotonin-2 binding sites in the frontal cortex of suicide victims. Lancet i: 214–216
Stanley M, Virgilio J, Gershon S . (1982): Tritiated imipramine binding sites are decreased in the frontal cortex of suicides. Science 216: 1337–1339
Stockmeier C, Dilley G, Shapiro L, Overholser J, Thompson P, Meltzer H . (1996): Serotonin receptors in suicide victims with major depression. Neuropsychopharmacology 16: 162–173
Strosznajder J, Samochocki M, Duran M . (1994): Aging diminishes serotonin-stimulated arachidonic acid uptake and cholinergic receptor-activated arachidonic acid release in rat brain cortex membrane. J Neurochem 62: 1048–1054
Suehiro M, Scheffel U, Dannals R, Ravert H, Ricaurte G, Wagner H Jr . (1993a): A PET radiotracer for studying serotonin uptake sites: Carbon-11-McN-5652Z. J Nucl Med 34: 120–127
Suehiro M, Scheffel U, Ravert H, Dannals R, Wagner H Jr . (1993b): [11C](+)McN5652 as a radiotracer for imaging serotonin uptake sites with PET. Life Sci 53: 883–892
Szabo Z, Kao P, Scheffel U, Suehiro M, Mathews W, Ravert H, Musachio J, Marenco S, Kim S, Ricaurte G, Wong D, Wagner H, Dannals R . (1995a): Positron emission tomography imaging of serotonin transporters in the human brain using [11C](')McN5652. Synapse 20: 37–43
Szabo Z, Scheffel U . Suehiro M, Dannals R, Kim S, Ravert H, Ricaurte G, Wagner H . (1995b): Positron emission tomography of 5-HT transporter sites in the baboon brain with [11C]McN5652. J Cereb Blood Flow Metab 15: 798–805
Takada H, Nagata K, Hirata Y, Satoh Y, Watahiki Y, Sugawara J, Yokoyama E, Kondoh Y, Shishido F, Inugami A, Fujita H, Ogawa T, Murakami M, Iida H, Kanno I . (1992): Age-related decline of cerebral oxygen metabolism in normal population detected with positron emission tomography. Neurol Res 14(Suppl.):128–131
Tejani-Butt S, Yang J, Pawlyk A . (1995): Altered serotonin transporter sites in Alzheimer's disease raphe and hippocampus. Neuro Report 6: 1207–1210
Teri L, Reifler B . (1987): Depression and dementia. In Carstensen L, Edelstein B (eds), Handbook of Clinical Gerontology. New York, Pergamon Press, pp 112–119
Terry RD, Peck A, DeTeresa R, Schechter R, Horoupian DS . (1981): Some morphometric aspects of the brain in senile dementia of the Alzheimer type. Ann Neurol 10: 184–192
Tork I . (1990): Anatomy of the serotonergic system. Ann NY Acad Sci 600: 9–35
Tsuiki K, Mück-Seler C, Diksic M . (1995a): Autoradiographic evaluation of the influence of hypothalamic 5, 7-dihydroxytryptamine lesion on brain serotonin synthesis. Biochem Pharmacol 49: 633–642
Tsuiki K, Yamamoto Y, Diksic M . (1995b): Effect of acute fluoxetine treatment on the brain serotonin synthesis as measured by the δ-methyl-L-tryptophan autoradiographic method. J Neurochem 65: 250–256
Venero J, de la Roza C, Machado A, Cano J . (1993): Age-related changes on monoamine turnover in hippocampus of rats. Brain Res 631: 89–96
Vizi ES, Harsing LG, Zsilla G . (1981): Evidence of the modulatory role of serotonin in acetylcholine release from striatal interneurons. Brain Res 212: 89–99
Whitehouse PJ, Struble RG, Hedreen JC, Clark AW, Price DL . (1985): Alzheimer's disease and related dementias: Selective involvement of specific neuronal systems. CRC Crit Rev Clin Neurobiol 1: 319–339
Wiernsperger N . (1990): Serotonin 5-HT2 receptors and brain circulation. J Cardiovasc Pharmacol 16: S20–S24
Wong D, Wagner HJ, Dannals R, Links J, Frost J, Ravert H, Wilson A, Rosenbaum A, Gjedde A, Douglass K, Petronis J, Folstein M, Toung J, Burns H, Kuhar M . (1984): Effects of age on dopamine and serotonin receptors measured by positron tomography in the living human brain. Science 226: 1393–1396
Yamaguchi T, Yamagata A . (1991): Serotonergic ligand binding in aging brain of experimental animals. Neurochem Res 16: 469–473
Yoshii F, Barker W, Chang J, Loewenstein D, Apicella A, Smith D, Boothe T, Ginsberg M, Pascal S, Duara R . (1988): Sensitivity of cerebral glucose metabolism to age, gender, brain volume, brain atrophy, and cerebrovascular risk factors. J Cereb Blood Flow Metab 8: 654–661
Zhang L, Ma W, Barker J, Rubinow D . (1994): Sexual differences in mRNA expression and binding distribution of 5-HT1A and 5-HT2 receptors in rat hippocampus. Soc Neurosci Abstr 21: 1548
Zola-Morgan S, Squire L, Rempel N, Clower R, Amaral D . (1992): Enduring memory impairment in monkeys after ischemic damage to the hippocampus. J Neurosci 12: 2582–2596
Zubenko G, Moossy J, Martinez A, Rao G, Classen D, Rosen J, Kopp U . (1991): Neuropathologic and neurochemical correlates of psychosis in primary dementia. Arch Neurol 48: 619–624
Zweig R, Swiergiel T, Steele C, Price D, Ross C . (1995): The dorsal raphe and depression in Alzheimer's disease. Soc Neurosci Abstr 21 (Part 3):1977
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This work was supported in part by PHS grants MH52247, AG05133, MH01210, MH00295, MH37869, MH49936, NS22899, and MH49815, and the Radiological Society of North America Research and Education Fund.
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Meltzer, C., Smith, G., DeKosky, S. et al. Serotonin in Aging, Late-Life Depression, and Alzheimer's Disease: The Emerging Role of Functional Imaging. Neuropsychopharmacol 18, 407–430 (1998). https://doi.org/10.1016/S0893-133X(97)00194-2
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DOI: https://doi.org/10.1016/S0893-133X(97)00194-2
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