Nornicotine inhibition of dopamine transporter function in striatum via nicotinic receptor activation.
Nornicotine, a tobacco alkaloid and N-demethylated nicotine metabolite, releases DA from superfused rat striatal slices in a mecamylamine-sensitive manner, indicating nicotinic receptor (nAChR) modulation of this response. The current study determined the effect of nornicotine on rat striatal dopamine transporter (DAT) function using in vivo voltammetry. In a dose-related and mecamylamine-sensitive manner, nornicotine (0.35-12.0 mg/kg, s.c.) decreased DA clearance, suggesting that nornicotine inhibits striatal DAT function via a nAChR-mediated mechanism. Furthermore, the nAChRs mediating the nornicotine-induced inhibition of DAT function appear to be different from those activated by nicotine which increases DA clearance. Understanding the actions of nornicotine in brain may have significance for emerging therapeutics and for the management of nicotine dependence.
Middleton
Lisa S
LS
Department of Pharmaceutical Sciences, University of Kentucky, Lexington, Kentucky 40536, USA.
Crooks
Peter A
PA
Wedlund
Peter J
PJ
Cass
Wayne A
WA
Dwoskin
Linda P
LP
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D007306:Insecticides / Q000494:pharmacology; D008297:Male; D008464:Mecamylamine / Q000494:pharmacology; D008657:Metabolic Clearance Rate / Q000187:drug effects / Q000502:physiology; D009538:Nicotine / Q000031:analogs & derivatives* / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D013997:Time Factors; D014029:Tobacco Use Disorder / Q000378:metabolism / Q000503:physiopathology
D050483:Dopamine Plasma Membrane Transport Proteins; D007306:Insecticides; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D008464:Mecamylamine; D009538:Nicotine; C005311:nornicotine; D000109:Acetylcholine; D004298:Dopamine