Nicotinic receptor modulation of dopamine transporter function in rat striatum and medial prefrontal cortex.
Nicotine activates nicotinic acetylcholine receptors (nAChRs) on dopamine (DA) terminals to evoke DA release, which subsequently is taken back up into the terminal via the DA transporter (DAT). nAChRs may modulate DAT function thereby contributing to the regulation of synaptic DA concentrations. The present study determined the dose-response for nicotine (0.1-0.8 mg/kg, s.c.) to modulate DA clearance in striatum and medial prefrontal cortex (mPFC) using in vivo voltammetry in urethane anesthetized rats and determined if this effect was mediated by nAChRs. Exogenous DA (200 microM) was pressure-ejected at 5-min intervals until reproducible baseline signals were obtained. Subsequently, nicotine or saline was administered, and DA pressure ejection continued at 5-min intervals for 60 min. In both striatum and mPFC, signal amplitude decreased by approximately 20% across the 60-min session in saline-injected rats. A monophasic dose-response curve was found in striatum, with a maximal 50% decrease in signal amplitude after 0.8 mg/kg. In contrast, a U-shaped dose-response curve was found in mPFC, with a maximal 50% decrease in signal amplitude after 0.4 mg/kg. Onset of nicotine response occurred 10 to 15 min after injection in both brain regions; however, the amount of time before maximal response was 45 and 30 min in striatum and mPFC, respectively. Mecamylamine (1.5 mg/kg) completely inhibited the nicotine-induced (0.8 and 0.4 mg/kg) decrease in signal amplitude in striatum and mPFC, respectively, indicating mediation by nAChRs. Thus, nicotine enhances DA clearance in striatum and mPFC in a mecamylamine-sensitive manner, indicating that nAChRs modulate DAT function in these brain regions.
Middleton
Lisa S
LS
College of Pharmacy, University of Kentucky, Lexington, Kentucky 40536, USA.
Cass
Wayne A
WA
Dwoskin
Linda P
LP
D000818:Animals; D004298:Dopamine / Q000494:pharmacology; D050483:Dopamine Plasma Membrane Transport Proteins; D008297:Male; D008464:Mecamylamine / Q000494:pharmacology; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins / Q000378:metabolism*; D008657:Metabolic Clearance Rate; D017072:Neostriatum / Q000378:metabolism*; D009419:Nerve Tissue Proteins; D009538:Nicotine / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020239:Receptor Cross-Talk; D011978:Receptors, Nicotinic / Q000378:metabolism*
D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D011978:Receptors, Nicotinic; C493216:Slc6a3 protein, rat; D008464:Mecamylamine; D009538:Nicotine; D004298:Dopamine