Differential alterations in nicotinic receptor alpha6 and beta3 subunit messenger RNAs in monkey substantia nigra after nigrostriatal degeneration.
Our previous studies showed that alpha4, alpha6, alpha7, beta2, beta3 and beta4 nicotinic acetylcholine receptor messenger RNAs are present in monkey substantia nigra, with a particularly intense and localized labelling of the alpha6 and beta3 subunit messenger RNAs to this brain region. Because loss of nigrostriatal neurons is a central feature of Parkinson's disease and evidence suggests that nicotinic agonists potentiate antiparkinsonian effects of L-dopa, experiments were done to determine whether nicotinic receptor subunit messenger RNAs and binding sites were altered in the basal ganglia after nigrostriatal degeneration. Squirrel monkeys (Saimiri sciureus) were rendered parkinsonian by systemic injection of the selective dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine. Behavioral studies showed that this treatment decreased baseline motor activity to 36+/-11% of control. One month after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration, caudate and putamen dopamine levels were reduced to 51+/-15% and 43+/-6% of control, respectively, while the number of tyrosine hydroxylase-positive neurons in the substantia nigra was 75+/-6% of control. Despite the reduction in nigral cell number after nigrostriatal degeneration, there were no changes in alpha4, alpha7, beta2 and beta4 messenger RNA levels in the substantia nigra. In contrast, alpha6 mRNA levels were significantly increased (143+/-10%) and the beta3 transcript decreased (62+/-6%) in the substantia nigra after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Declines were also observed in [125I]epibatidine binding in both the caudate-putamen and substantia nigra, with no change in alpha7 receptor binding. These results may suggest a dissociation in the regulation of receptor messenger RNA and binding sites, and/or that there are differential alterations in the different receptor subtypes measured using [125I]epibatidine. The changes in the two nicotinic receptor subunit messenger RNAs, alpha6 and beta3, which exhibit a selective localization to the substantia nigra, may indicate that nicotinic receptors containing these subunits are altered after nigrostriatal degeneration.
Quik
M
M
The Parkinson's Institute, 1170 Morse Avenue, Sunnyvale, CA 94089, USA. mquik@parkinsoninstitute.org
Polonskaya
Y
Y
Gillespie
A
A
K Lloyd
G
G
Langston
J W
JW
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000818:Animals; D001479:Basal Ganglia / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000378:metabolism; D002038:Bungarotoxins / Q000378:metabolism; D002421:Caudate Nucleus / Q000378:metabolism; D003342:Corpus Striatum; D004298:Dopamine / Q000378:metabolism; D006719:Homovanillic Acid / Q000378:metabolism; D008297:Male; D009410:Nerve Degeneration / Q000378:metabolism*; D009474:Neurons / Q000201:enzymology; D018722:Nicotinic Agonists / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics; D011699:Putamen / Q000378:metabolism; D011725:Pyridines / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000235:genetics*; D012453:Saimiri; D013378:Substantia Nigra / Q000166:cytology / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D019086:Bridged Bicyclo Compounds, Heterocyclic; D002038:Bungarotoxins; D018722:Nicotinic Agonists; D020033:Protein Isoforms; D011725:Pyridines; D012333:RNA, Messenger; D011978:Receptors, Nicotinic; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; C082748:epibatidine; D004298:Dopamine; D006719:Homovanillic Acid