PT  - JOURNAL ARTICLE
AU  - Maryka Quik
AU  - Jocelyn D. Sum
AU  - Paul Whiteaker
AU  - Sarah E. McCallum
AU  - Michael J. Marks
AU  - John Musachio
AU  - J. Michael Mcintosh
AU  - Allan C. Collins
AU  - Sharon R. Grady
TI  - Differential Declines in Striatal Nicotinic Receptor Subtype Function after Nigrostriatal Damage in Mice
AID  - 10.1124/mol.63.5.1169
DP  - 2003 May 01
TA  - Molecular Pharmacology
PG  - 1169--1179
VI  - 63
IP  - 5
4099  - http://molpharm.aspetjournals.org/content/63/5/1169.short
4100  - http://molpharm.aspetjournals.org/content/63/5/1169.full
SO  - Mol Pharmacol2003 May 01; 63
AB  - 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 [125I]3β-(4-iodophenyl)tropane-2β-carboxylic acid isopropyl ester (RTI-121, dopamine transporter),125I-α-conotoxin MII (putative α6-containing sites in the central nervous system), 125I-epibatidine (multiple sites), 5-[125I]iodo-3-[2(S)-azetidinylmethoxy]pyridine-2HCl ([125I]A85380; β2-containing sites), and125I-α-bungarotoxin (α7-containing sites) binding in brains from control and MPTP-treated mice, as well as nAChR function by [3H]dopamine release, [3H]GABA release, and [86Rb+] efflux. After MPTP treatment, declines were observed in striatal dopamine transporter levels, both binding and functional measures of striatal α-conotoxin MII-sensitive nAChRs, and selected measures of striatal α-conotoxin MII-resistant nAChRs. In contrast, 125I-α-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. The American Society for Pharmacology and Experimental Therapeutics