Abstract
A significant proportion of patients with Alzheimer's disease (AD) exhibit extrapyramidal features that are referred to as parkinsonism (AD/Park) to distinguish the clinical and pathological features that differ from Parkinson's disease (PD). Previous results from this laboratory have shown that, although the presynaptic components of the dopamine (DA) system are markedly affected in AD/Park, the pathology is not similar to PD (Murray et al. 1995; Joyce et al. 1997). In the present study, we determined whether the parkinsonian symptoms in AD/Park might also reflect changes in numbers of postsynaptic DA receptors. We analyzed the binding of [125I]epidepride biding to DA D2/D3 receptors and [3H]SCH 23390 to D1 receptors by autoradiography in the striatum of six patients with PD, nine patients with AD, seven patients with AD/Park, and 14 neurologically intact control subjects. D2 receptors were reduced in the caudate and putamen of the AD/Park group (by 42 and 27% of controls, respectively) but not reduced in AD or PD. D1 receptors were elevated by 36% in the putamen of the PD group. Dopamine receptor changes are, therefore, not similar in PD, AD, and AD/Park. The elevation in D1 receptors in PD may contribute to the unwanted side effects of L-dopa treatment. The loss of D2 receptors in AD/Park, not observed in AD lacking overt parkinsonian symptomatology, may contribute to the presence of parkinsonian features and lack of responsiveness to L-dopa.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Antonini A, Leender KL, Vontober P, Maguire RP, Missimer J, Psylla M, Gunther I . (1997): Complementary PET studies of striatal neuronal function in the differential diagnosis between multiple system atrophy and Parkinson's disease. Brain 120: 2187–2195
Arai H, Schmidt ML, Lee VM, Hurtig HI, Greenberg BD, Adler CH, Trojanowski JQ . (1992): Epitope analysis of senile plaque components in the hippocampus of patients with Parkinson's disease. Neurology 42: 1315–1322
Artymyshyn R, Smith A, Wolfe BB . (1990): The use of 3H standards in 125I autoradiography. J Neurosci Meth 32: 185–192
Bernheimer H, Brikmayer W, Hornykiewicz O, Jellinger K, Seitelberger F . (1973): Brain dopamine and the syndromes of Parkinson and Huntington. J Neurol Sci 20: 415–455
Bokobza B, Ruberg M, Scatton B, Javoy-Agid F, Agid Y . (1984): [3H]spiperone binding, dopamine, and HVA concentrations in Parkinson's disease and supranuclear palsy. Eur J Pharmacol 99: 167–175
Braak H, Braak E . (1990): Alzheimer's disease: Striatal amyloid deposits and neurofibrillary changes. J Neuropathol Exp Neurol 49: 215–224
Cortés R, Probst A, Palacios JM . (1988): Decreased densities of dopamine D1 receptors in the putamen and hippocampus in senile dementia of the Alzheimer type. Brian Res 475: 164–167
Cross AJ, Crow TJ, Ferrier IN, Johnson JA, Markakis D . (1984): Striatal dopamine receptors in Alzheimer-type dementia. Neurosci Lett 52: 1–6
Ditter SM, Mirra SS . (1987): Neuropathological and clinical features of Parkinson's disease in Alzheimer's disease patients. Neurology 37: 754–760
Duret M, Goldman S, Messina D, Hildebrand J . (1989): Effect of L-dopa on dementia-related rigidity. Acta Neurol Scand 80: 64–67
Giros B, Jaber M, Jones SR, Wightman RM, Caron MG . (1996): Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter. Nature 379: 606–612
Guttman M, Seeman P, Reynolds GP, Riederer P, Jellinger K, Tourtellotte WW . (1986): Dopamine D2 receptor density remains constant in treated Parkinson's disease. Ann Neurol 19: 487–492
Hornykiewicz O, Kish SJ . (1986): Biochemical pathophysiology of Parkinson's disease. In Yahr MD, Bergmann KJ, (eds), Advances in Neurology, Vol 45: Biochemical Pathophysiology of Parkinson's disease New York, Raven Press, pp, 19–34
Joyce JN . (1991): Differential response of striatal dopamine receptor subtypes and cholinergic muscarinic receptors to the loss of dopamine: I. Effects of intranigral or intracerebroventricular 6-hydroxydopamine lesions of the mesostriatal dopamine system. Exp Neurol 113: 161–276
Joyce JN . (1993): Differential response of striatal dopamine receptor subtypes and cholinergic muscarinic receptors to the loss of dopamine: III. Effects in Parkinson's disease. Brain Res 600: 156–160
Joyce JN, Sapp DW, Marshall JF . (1986a): Human striatal dopamine receptors are organized in compartments. Proc Natl Acad Sci USA 83: 8002–8006
Joyce JN, Marshall JF, Bankiewicz KS, Kopin IJ, Jacobowitz DM . (1986b): Hemiparkinsonism in a monkey after unilateral internal carotid artery infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is associated with regional ipsilateral changes in striatal dopamine D2 receptor density. Brian Res 382: 360–364
Joyce JN, Lexow N, Bird E, Winokur A . (1988): Organization of dopamine D1 and D2 receptors in human striatum: Receptor autoradiographic studies in Huntington's disease and schizophrenia. Synapse 2: 546–547
Joyce JN, Janowsky A, Neve KA . (1991): Characterization and distribution of [125I]epidepride binding to dopamine D2 receptors in basal ganglia and cortex of human brian. J Pharmacol Exp Ther 257: 1253–1263
Joyce JN, Meador-Woodruff JH . (1997): Linking the family of D2 receptors to neuronal circuits in human brain: Insights into schizophrenia. Neuropsychopharmacology 16: 375–384
Joyce JN, Smutzer G, Whittey C, Myers A, Bannon M . (1997): Dopamine transporter and tyrosine hydroxylase mRNAs altered differently in substantia nigra of Parkinson's, Alzheimer with Parkinsonism, and Alzheimer's disease. Mov Dis 12: 855–897
Khachaturian ZS . (1985): Diagnosis of Alzheimer's disease. Arch Neurol 42: 1097–1105
Kish SJ, Shannak K, Hornykiewicz O . (1988): Uneven pattern of dopamine loss in the striatum of patients with idiopathic Parkinson's disease. New Engl J Med 318: 876–880
Le Moine C, Bloch B . (1995): D1 and D2 dopamine receptor gene expression in the rat striatum: Sensitive cRNA probes demonstrate prominent segregation of D1and D2 mRNAs in distinct neuronal populations of the dorsal and ventral striatum. J Comp Neurol 355: 418–426
Leverenz J, Sumi SM . (1986): Parkinson's disease in patients with Alzheimer's disease. Arch Neurol 43: 662–664
Lévesque D, Martres M-P, Diaz J, Griffon N, Lammers CH, Sokoloff P, Schwartz J-C . (1995): A paradoxical regulation of the dopamine D3 receptor expression suggests the involvement of an anterograde factor from dopamine neurons. Proc Natl Acad Sci USA 92: 1719–1723
Liu Y, Stern Y, Chun MR, Jakobs DM, Yau P, Goldman JE . (1997): Pathological correlates of extrapyramidal signs in Alzheimer's Disease. Ann Neurol 41: 368–374
Merello M, Sabe L, Texon A, Migliorelli R, Petracchi M, Leiguarda R, Starkstein S . (1994): Extrapyramidalism in Alzheimer's disease: Prevalence, psychiatric, and neuropsychological correlates. J Neurol Neurosurg Psychiat 57: 1503–1509
Mölsä PK, Marttila RJ, Rinne UK . (1984): Extrapyramidal signs in Alzheimer's disease. Neurology 43: 1114–1116
Mölsä PK, Säkö E, Paljärvi L, Rinne JO, Rinne UK . (1987): Alzheimer's disease: Neuropathological correlates of cognitive and motor disorders. Acta Neurol Scand 75: 376–384
Murray AM, Ryoo H, Gurevich E, Joyce JN . (1994): Localization of dopamine D3 receptors to mesolimbic and D2 receptors to mesostriatal regions of human forebrain. Proc Natl Acad Sci USA 91: 11271–11275
Murray AM, Weihmueller F, Marshall JF, Hurtig HI, Gottlieb GL, Joyce JN . (1995): Damage to dopamine systems differs between Parkinson's disease and Alzheimer's with Parkinsonism. Ann Neurol 37: 300–312
Pizzolato G, Chierichetti F, Rossato A, Cagnin A, Fabbri M, Dam M, Ferlin G, Battistin L . (1995): Alterations of striatal dopamine D2 receptors contribute to deteriorated response to L-dopa in Parkinson's disease: A [123I]-IBZM SPET study. J Neural Transm 45: 113–122
Pizzolato G, Chierichetti F, Rossato A, Fabbri M, Cagnin A, Dam M, Ferlin G, Battistin L . (1996): Reduced striatal dopamine receptors in Alzheimer's disease: Single photon emission tomography study with the D2 tracer [123I]-IBZM. Neurology 47: 1065–1068
Reisine TD, Yamamura HI, Bird ED, Spokes E, Enna SJ . (1978): Pre- and postsynaptic neurochemical alterations in Alzheimer's disease. Brain Res 159: 477–480
Rinne JO, Rinne JK, Laakso K, Lonnberg P, Rinne UK . (1985): Dopamine D1 receptors in the parkinsonian brain. Brain Res 16: 306–310
Rinne JO, Säkö E, Paljarvi L, Mölsä PK, Rinne UK . (1986): Brian dopamine D2 receptors in senile dementia. J Neural Transm 65: 51–62
Rinne UK, Rinne JO, Rinne JK, Laakso K, Laihinen A, Lonnberg P . (1983): Brain receptor changes in Parkinson's disease in relation to the disease process and treatment. J Neural Transm 18: 279–286
Rioux L, Frohna PA, Joyce JN, Schnieder JS . (1997): Effects of chronic levodopa treatment on pre- and postsynaptic markers of dopaminergic function in striatum of parkinsonian monkeys. Mov Dis 12: 148–158
Roberts SJ, Hanaway J . (1971): Atlas of the Human Brain in Section Baltimore, MD, Lea and Febiger
Ryoo HL, Pierottie D, Joyce JN . (1998): Dopamine D3 receptor is decreased, and D2receptor is elevated in the striatum of Parkinson's disease. Mov Dis, in press.
Seeman P, Bzowej NH, Guan HC, Bergeron C, Reynolds GP, Bird ED, Riederer P, Jellinger K, Tourtelotte WW . (1987): Human brian D1 and D2 dopamine receptors in schizophrenia, Alzheimers’, Parkinson's and Huntington's diseases. Neuropsychopharmacology 1: 5–15
Schulz JB, Klockgether T, Peterse D, Jauch M, Muiller-Schauenburg W, Spieker S, Voigt K, Dichgans J . (1994): Multiple system atrophy: Natural history, MRI morphology, and dopamine receptor imaging with123IBZM-SPECT. J Neurol Neurosurg Psychiatry 57: 1047–1056
Sibley DR, Monsma FJ, Shen Y . (1993): Molecular neurobiology of D1 and D2 dopamine receptors. In Waddington JL, (ed), Neuroscience and Psychopharmacology: D1, D2 Dopamine Receptor Interactions San Diego, CA, Academic Press, 1–21
Sokoloff P, Giros B, Martres MP, Bouthenet ML, Schwartz JC . (1990): Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. Nature 347: 146–151
Tyrrell PJ, Sawle GV, Ibañez V, Bloomfield PM, Leenders KL, Frackowiak RS, Rossor MN . (1990): Clinical and positive emission tomographic studies in the extrapyramidal syndrome of dementia of the Alzheimer type. Arch Neurol 47: 1318–1323
Acknowledgements
This research was supported by U.S. Public Health Service Grants MH 56824, AG 09215, and AG 10124 (Alzheimer Disease Center Core).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Joyce, J., Murray, A., Hurtig, H. et al. Loss of Dopamine D2 Receptors in Alzheimer's Disease with Parkinsonism But Not Parkinson's or Alzheimer's Disease. Neuropsychopharmacol 19, 472–480 (1998). https://doi.org/10.1016/S0893-133X(98)00044-X
Received:
Revised:
Accepted:
Issue date:
DOI: https://doi.org/10.1016/S0893-133X(98)00044-X
Keywords
This article is cited by
-
β-Amyloid and Lithium Affect the Magnitude of Phasic Dopamine Release in the Shell of the Nucleus Accumbens
Neuroscience and Behavioral Physiology (2021)
