Smith_2009_Biochem.Pharmacol_78(7)_889

Smoking is a significant health concern and strongly correlated with clinical depression. Depression is associated with decreased extracellular NE concentrations in brain. Smokers may be self-medicating and alleviating their depression through nicotine stimulated norepinephrine (NE) release. Several antidepressants inhibit NE transporter (NET) function, thereby augmenting extracellular NE concentrations. Antidepressants, such as bupropion, also inhibit nicotinic receptor (nAChR) function. The current study determined if a recently discovered novel nAChR antagonist, N,N'-dodecane-1,12-diyl-bis-3-picolinium dibromide (bPiDDB), inhibits nicotine-evoked NE release from superfused rat hippocampal slices. Previous studies determined that bPiDDB potently (IC(50)=2 nM) inhibits nicotine-evoked striatal [(3)H]dopamine (DA) release in vitro, nicotine-evoked DA release in nucleus accumbens in vivo, and nicotine self-administration in rats. In the current study, nicotine stimulated [(3)H]NE release from rat hippocampal slices (EC(50)=50 microM). bPiDDB inhibited (IC(50)=430 nM; I(max)=90%) [(3)H]NE release evoked by 30 microM nicotine. For comparison, the nonselective nAChR antagonist, mecamylamine, and the alpha7 antagonist, methyllycaconitine, also inhibited nicotine-evoked [(3)H]NE release (IC(50)=31 and 275 nM, respectively; I(max)=91% and 72%, respectively). Inhibition by bPiDDB and mecamylamine was not overcome by increasing nicotine concentrations; Schild regression slope was different from unity, consistent with allosteric inhibition. Thus, bPiDDB was 200-fold more potent inhibiting nAChRs mediating nicotine-evoked [(3)H]DA release from striatum than those mediating nicotine-evoked [(3)H]NE release from hippocampus.