Nicotine is neuroprotective when administered before but not after nigrostriatal damage in rats and monkeys.
Nicotine reduces dopaminergic deficits in parkinsonian animals when administered before nigrostriatal damage. Here we tested whether nicotine is also beneficial when given to rats and monkeys with pre-existing nigrostriatal damage. Rats were administered nicotine before and after a unilateral 6-hydroxydopamine lesion of the medial forebrain bundle, and the results compared with those in which rats received nicotine only after lesioning. Nicotine pre-treatment attenuated behavioral deficits and lessened lesion-induced losses of the striatal dopamine transporter, and alpha6beta2* and alpha4beta2* nicotinic receptors (nAChRs). By contrast, nicotine administered 2 weeks after lesioning, when 6-hydroxydopamine-induced neurodegenerative effects are essentially complete, did not improve these same measures. Similar results were observed in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned monkeys. Nicotine did not enhance striatal markers when administered to monkeys with pre-existing nigrostriatal damage, in contrast to previous data that showed improvements when nicotine was given to monkeys before lesioning. These combined findings in two animal models suggest that nicotine is neuroprotective rather than neurorestorative against nigrostriatal damage. Receptor studies with (125)I-alpha-conotoxinMII and the alpha-conotoxinMII analog E11A were next performed to determine whether nicotine treatment pre- or post-lesioning differentially affected expression of alpha6alpha4beta2* and alpha6(nonalpha4)beta2* nAChR subtypes in striatum. The observations suggest that protection against nigrostriatal damage may be linked to striatal alpha6alpha4beta2* nAChRs.
Huang
Luping Z
LZ
Basic Research Department, The Parkinson's Institute, Sunnyvale, California 94085, USA.
Parameswaran
Neeraja
N
Bordia
Tanuja
T
Michael McIntosh
J
J
Quik
Maryka
M
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000661:Amphetamine; D000704:Analysis of Variance; D000818:Animals; D001345:Autoradiography; D003042:Cocaine / Q000031:analogs & derivatives / Q000378:metabolism; D020916:Conotoxins / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology*; D003367:Cotinine / Q000097:blood; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D007456:Iodine Isotopes / Q000378:metabolism; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D020258:Neurotoxicity Syndromes / Q000209:etiology / Q000473:pathology* / Q000517:prevention & control*; D009538:Nicotine / Q000008:administration & dosage*; D016627:Oxidopamine / Q000633:toxicity; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012453:Saimiri; D013378:Substantia Nigra / Q000187:drug effects / Q000473:pathology*; D013997:Time Factors
D020916:Conotoxins; D007456:Iodine Isotopes; D018696:Neuroprotective Agents; C098872:alpha-conotoxin MII; C079213:RTI 121; D009538:Nicotine; D016627:Oxidopamine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000661:Amphetamine; D003042:Cocaine; D003367:Cotinine; D004298:Dopamine