Decrease of Nicotinic Receptors in the Nigrostriatal System in Parkinson's Disease

Smoking is associated with a lower incidence of Parkinson's disease (PD), which might be related to a neuroprotective action of nicotine. Postmortem studies have shown a decrease of cerebral nicotinic acetylcholine receptors (nAChRs) in PD. In this study, we evaluated the decrease of nAChRs in PD in vivo using positron emission tomography (PET), and we explored the relationship between nAChRs density and PD severity using both clinical scores and the measurement of striatal dopaminergic function. Thirteen nondemented patients with PD underwent two PET scans, one with 6-[18F]fluoro-3,4-dihydroxy-l-phenylalanine (6-[18F]fluoro-l-DOPA) to measure the dopaminergic function and another with 2-[18F]fluoro-3-[2(S)-2-azetidinylmethoxy]pyridine (2-[18F]fluoro-A-85380), a radiotracer with high affinity for the nAChRs. Distribution volumes (DVs) of 2-[18F]fluoro-A-85380 measured in the PD group were compared with those obtained from six nonsmoking healthy controls, with regions-of-interest and voxel-based approaches. Both analyses showed a significant (P<0.05) decrease of 2-[18F]fluoro-A-85380 DV in the striatum (10%) and substantia nigra (14.9%) in PD patients. Despite the wide range of PD stages, no correlation was found between DV and the clinical and PET markers of PD severity.

[1]  I. McKeith,et al.  Cerebral atrophy in Parkinson's disease with and without dementia: a comparison with Alzheimer's disease, dementia with Lewy bodies and controls. , 2004, Brain : a journal of neurology.

[2]  Masanori Ichise,et al.  Widespread decrease of nicotinic acetylcholine receptors in Parkinson's disease , 2006, Annals of neurology.

[3]  J. Rinne,et al.  A postmortem study of brain nicotinic receptors in Parkinson's and Alzheimer's disease , 1991, Brain Research.

[4]  Hiroto Kuwabara,et al.  Discovery of (-)-7-methyl-2-exo-[3'-(6-[18F]fluoropyridin-2-yl)-5'-pyridinyl]-7-azabicyclo[2.2.1]heptane, a radiolabeled antagonist for cerebral nicotinic acetylcholine receptor (alpha4beta2-nAChR) with optimal positron emission tomography imaging properties. , 2008, Journal of medicinal chemistry.

[5]  H. Fukuyama,et al.  Quantification of nicotinic acetylcholine receptors in Parkinson's disease with 123I-5IA SPECT , 2007, Journal of the Neurological Sciences.

[6]  Jean-Dominique Gallezot,et al.  In vivo imaging of human cerebral nicotinic acetylcholine receptors with 2-18F-fluoro-A-85380 and PET. , 2005, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[7]  M. Romanelli,et al.  Cholinergic nicotinic receptors: Competitive ligands, allosteric modulators, and their potential applications , 2003, Medicinal research reviews.

[8]  L. Forno,et al.  Loss of alpha-conotoxinMII- and A85380-sensitive nicotinic receptors in Parkinson's disease striatum. , 2004, Journal of neurochemistry.

[9]  C. Crouzel,et al.  Characterization of the nicotinic ligand 2-[18F]fluoro-3-[2(S)-2-azetidinylmethoxy]pyridine in vivo. , 1998, Life sciences.

[10]  E. Perry,et al.  Nicotinic acetylcholine receptor distribution in Alzheimer's disease, dementia with Lewy bodies, Parkinson's disease, and vascular dementia: in vitro binding study using 5-[(125)i]-a-85380. , 2004, Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology.

[11]  D. Price,et al.  Reductions in [3H]nicotinic acetylcholine binding in Alzheimer's disease and Parkinson's disease , 1988, Neurology.

[12]  S. Gauthier,et al.  Comparative Alterations of Nicotinic and Muscarinic Binding Sites in Alzheimer's and Parkinson's Diseases , 1992, Journal of neurochemistry.

[13]  E. Hirsch,et al.  Cigarette smoke and nicotine protect dopaminergic neurons against the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine Parkinsonian toxin , 2003, Brain Research.

[14]  C. Patlak,et al.  Graphical Evaluation of Blood-to-Brain Transfer Constants from Multiple-Time Uptake Data. Generalizations , 1985, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[15]  M. Quik.  Smoking, nicotine and Parkinson's disease , 2004, Trends in Neurosciences.

[16]  E. London,et al.  2-, 5-, and 6-Halo-3-(2(S)-azetidinylmethoxy)pyridines: synthesis, affinity for nicotinic acetylcholine receptors, and molecular modeling. , 1998, Journal of medicinal chemistry.

[17]  A. Hufnagel,et al.  Alteration of the in vivo nicotinic receptor density in ADNFLE patients: a PET study. , 2006, Brain : a journal of neurology.

[18]  P. Remy,et al.  Core assessment program for surgical interventional therapies in Parkinson's disease (CAPSIT‐PD) , 1999, Movement disorders : official journal of the Movement Disorder Society.

[19]  J. Langston,et al.  Chronic Oral Nicotine Normalizes Dopaminergic Function and Synaptic Plasticity in 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Lesioned Primates , 2006, The Journal of Neuroscience.

[20]  S. Thobois.  Proposed dose equivalence for rapid switch between dopamine receptor agonists in Parkinson's disease: a review of the literature. , 2006, Clinical therapeutics.

[21]  M. Quik,et al.  5-Iodo-A-85380 binds to alpha-conotoxin MII-sensitive nicotinic acetylcholine receptors (nAChRs) as well as alpha4beta2* subtypes. , 2002, Journal of neurochemistry.

[22]  Marcel Ricard,et al.  Biodistribution and radiation dosimetry of 18F-fluoro-A-85380 in healthy volunteers. , 2003, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[23]  C Crouzel,et al.  Imaging central nicotinic acetylcholine receptors in baboons with [18F]fluoro-A-85380. , 1999, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[24]  C Crouzel,et al.  Synthesis and nicotinic acetylcholine receptor in vivo binding properties of 2-fluoro-3-[2(S)-2-azetidinylmethoxy]pyridine: a new positron emission tomography ligand for nicotinic receptors. , 1999, Journal of medicinal chemistry.

[25]  S. Folstein,et al.  "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. , 1975, Journal of psychiatric research.

[26]  A. C. Collins,et al.  Subunit composition and pharmacology of two classes of striatal presynaptic nicotinic acetylcholine receptors mediating dopamine release in mice. , 2004, Molecular pharmacology.

[27]  Christopher C Rowe,et al.  Simplified quantification of nicotinic receptors with 2[18F]F-A-85380 PET. , 2005, Nuclear medicine and biology.

[28]  D Wyper,et al.  Nicotinic Acetylcholine Receptor Distribution in Alzheimer's Disease, Dementia with Lewy Bodies, Parkinson's Disease, and Vascular Dementia: In Vitro Binding Study Using 5-[125I]-A-85380 , 2004, Neuropsychopharmacology.

[29]  M. Campbell,et al.  Parkinson’s Disease Protects Against Smoking? , 2005, Behavioural neurology.

[30]  S. Grady,et al.  Compensation in pre‐synaptic dopaminergic function following nigrostriatal damage in primates , 2006, Journal of neurochemistry.

[31]  Jörg Steinbach,et al.  Norchloro-fluoro-homoepibatidine: specificity to neuronal nicotinic acetylcholine receptor subtypes in vitro. , 2004, Farmaco.

[32]  M. Quik,et al.  Stimulation of non-α7 nicotinic receptors partially protects dopaminergic neurons from 1-methyl-4-phenylpyridinium-induced toxicity in culture , 2002, Neuroscience.

[33]  E. Perry,et al.  Nicotine binding in human striatum: elevation in schizophrenia and reductions in dementia with Lewy bodies, Parkinson’s disease and Alzheimer’s disease and in relation to neuroleptic medication , 2000, Neuroscience.

[34]  D Oakes,et al.  Assessment of neuroimaging techniques as biomarkers of the progression of Parkinson's disease , 2003, Experimental Neurology.

[35]  Monique Ernst,et al.  2 [18F]F‐A85380: PET imaging of brain nicotinic acetylcholine receptors and whole body distribution in humans , 2003, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[36]  J. Bucerius,et al.  In vitro evaluation of nicotinic acetylcholine receptors with 2-[18F]F-A85380 in Parkinson's disease. , 2006, Nuclear medicine and biology.

[37]  L. Forno,et al.  Loss of α‐conotoxinMII‐ and A85380‐sensitive nicotinic receptors in Parkinson's disease striatum , 2004 .

[38]  Philippe Hantraye,et al.  Dopaminergic function and dopamine transporter binding assessed with positron emission tomography in Parkinson disease. , 2002, Archives of neurology.

[39]  K. Jellinger,et al.  Pathology of Parkinson's disease. Changes other than the nigrostriatal pathway. , 1991, Molecular and chemical neuropathology.

[40]  S. Grady,et al.  Nigrostriatal Damage Preferentially Decreases a Subpopulation of α6β2* nAChRs in Mouse, Monkey, and Parkinson's Disease Striatum , 2007, Molecular Pharmacology.

[41]  D. Irving,et al.  Alteration in nicotine binding sites in Parkinson's disease, Lewy body dementia and Alzheimer's disease: Possible index of early neuropathology , 1995, Neuroscience.

[42]  C. Gotti,et al.  Neuronal nicotinic receptors: from structure to pathology , 2004, Progress in Neurobiology.

[43]  J. Hughes,et al.  Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinico-pathological study of 100 cases. , 1992, Journal of neurology, neurosurgery, and psychiatry.

[44]  C S Patlak,et al.  Graphical Evaluation of Blood-to-Brain Transfer Constants from Multiple-Time Uptake Data , 1983, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[45]  S. Pappatà,et al.  In Vivo Imaging of Human Cerebral Acetylcholinesterase , 1996, Journal of neurochemistry.

[46]  E. Perry,et al.  Cholinergic nicotinic receptor involvement in movement disorders associated with Lewy body diseases. An autoradiography study using [125I]α-conotoxinMII in the striatum and thalamus , 2005, Experimental Neurology.