title: Differential declines in striatal nicotinic receptor subtype function after nigrostriatal damage in mice.
abstract: Nigrostriatal damage leads to a reduction in striatal nicotinic acetylcholine receptors (nAChRs) in rodents, monkeys, and patients with Parkinson's disease. The present studies were undertaken to investigate whether these nAChR declines are associated with alterations in striatal nAChR function and, if so, to identify the receptor subtypes involved. To induce nigrostriatal damage, mice were injected with the selective dopaminergic toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We measured [(125)I]3 beta-(4-iodophenyl)tropane-2 beta-carboxylic acid isopropyl ester (RTI-121, dopamine transporter), (125)I-alpha-conotoxin MII (putative alpha 6-containing sites in the central nervous system), (125)I-epibatidine (multiple sites), 5-[(125)I]iodo-3-[2(S)-azetidinylmethoxy]pyridine-2HCl ([(125)I]A85380; beta2-containing sites), and (125)I-alpha-bungarotoxin (alpha 7-containing sites) binding in brains from control and MPTP-treated mice, as well as nAChR function by [(3)H]dopamine release, [(3)H]GABA release, and [(86)Rb(+)] efflux. After MPTP treatment, declines were observed in striatal dopamine transporter levels, both binding and functional measures of striatal alpha-conotoxin MII-sensitive nAChRs, and selected measures of striatal alpha-conotoxin MII-resistant nAChRs. In contrast, (125)I-alpha-bungarotoxin binding sites were not altered after nigrostriatal damage. The changes in striatal nAChRs were selective, with no declines in cortex, thalamus, or septum. Those striatal binding and functional measures of nAChRs that decreased with MPTP treatment correlated with dopamine transporter declines, an observation suggesting that the binding and functional changes in nAChRs are limited to dopaminergic terminals. The present results are the first to demonstrate differential alterations in nAChR subtype function after nigrostriatal damage, with a close correspondence between changes in receptor binding sites and function. These data suggest that the declines in nAChR sites observed in Parkinson's disease brains may be of functional significance.
authors.affiliation: The Parkinson's Institute, Sunnyvale, California 94089-1605, USA. mquik@parkinsonsinstitute.org
authors.forename: Maryka
authors.initials: M
authors.lastname: Quik
authors.forename: Jocelyn D
authors.initials: JD
authors.lastname: Sum
authors.forename: Paul
authors.initials: P
authors.lastname: Whiteaker
authors.forename: Sarah E
authors.initials: SE
authors.lastname: McCallum
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Marks
authors.forename: John
authors.initials: J
authors.lastname: Musachio
authors.forename: J Michael
authors.initials: JM
authors.lastname: McIntosh
authors.forename: Allan C
authors.initials: AC
authors.lastname: Collins
authors.forename: Sharon R
authors.initials: SR
authors.lastname: Grady
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000818:Animals; D020916:Conotoxins / Q000633:toxicity; D003342:Corpus Striatum / Q000293:injuries* / Q000378:metabolism / Q000502:physiology; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D020267:MPTP Poisoning; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009538:Nicotine / Q000378:metabolism; D011188:Potassium / Q000378:metabolism; D011954:Receptors, Dopamine / Q000502:physiology; D011978:Receptors, Nicotinic / Q000378:metabolism*
chemical_list: D020916:Conotoxins; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D011954:Receptors, Dopamine; D011978:Receptors, Nicotinic; C098872:alpha-conotoxin MII; D009538:Nicotine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D011188:Potassium; D004298:Dopamine