Nicotine partially protects against paraquat-induced nigrostriatal damage in mice; link to alpha6beta2* nAChRs.
Epidemiological studies indicate that smoking is a negative, and exposure to pesticides, a positive risk factor for Parkinson's disease (PD). The purpose of this study was to assess the interplay between these two factors in a rodent model of nigrostriatal damage. To approach this, mice were administered nicotine, the agent in smoke implicated in neuroprotection. They were then treated for 3 weeks with the pesticide, paraquat, while nicotine was continued. Paraquat treatment decreased (25%) nigral dopaminergic neurons, consistent with previous results. Chronic nicotine administration significantly protected against nigral cell damage, with only a 16% decline in mice treated with both nicotine and paraquat. Paraquat treatment also decreased (14%) the striatal dopamine transporter, an effect that was partially prevented by nicotine. These changes in the striatal dopamine transporter paralleled those in a select striatal alpha6beta2* nicotinic receptor (nAChR) subtype. In contrast, striatal alpha4beta2* nAChRs were not decreased with paraquat treatment, suggesting they are on a differential subset of dopaminergic terminals. The results show that nicotine treatment partially protects against paraquat-induced declines in nigrostriatal dopaminergic neurons to which a select population of alpha6beta2* nAChRs are localized. Moreover, these data support epidemiological findings that environmental influences can elicit opposing effects on nigrostriatal dopaminergic integrity.
Khwaja
Mirium
M
The Parkinson's Institute, Sunnyvale, CA 94089, USA.
McCormack
Alison
A
McIntosh
J Michael
JM
Di Monte
Donato A
DA
Quik
Maryka
M
D000704:Analysis of Variance; D000818:Animals; D001345:Autoradiography / Q000379:methods; D001930:Brain Injuries / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000493:pharmacokinetics; D002452:Cell Count / Q000379:methods; D020916:Conotoxins / Q000493:pharmacokinetics; D003342:Corpus Striatum / Q000187:drug effects* / Q000473:pathology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004347:Drug Interactions; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009538:Nicotine / Q000627:therapeutic use*; D018722:Nicotinic Agonists / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018733:Nicotinic Antagonists / Q000493:pharmacokinetics; D010269:Paraquat; D011485:Protein Binding / Q000187:drug effects; D011725:Pyridines / Q000493:pharmacokinetics; D011978:Receptors, Nicotinic / Q000502:physiology*; D013378:Substantia Nigra / Q000187:drug effects* / Q000473:pathology
D019086:Bridged Bicyclo Compounds, Heterocyclic; D020916:Conotoxins; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011725:Pyridines; D011978:Receptors, Nicotinic; C098872:alpha-conotoxin MII; C559463:alpha6beta2 nicotinic acetylcholine receptor; D009538:Nicotine; C082748:epibatidine; D010269:Paraquat; D004298:Dopamine