Smith Andrew M, Dhawan Gurpreet K, Zhang Zhenfa, Siripurapu Kiran B, Crooks Peter A, Dwoskin Linda P
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0082, United States.
Biochem Pharmacol. 2009 Oct 1;78(7):889-97. doi: 10.1016/j.bcp.2009.07.010. Epub 2009 Jul 23.
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.
吸烟是一个重大的健康问题，且与临床抑郁症密切相关。抑郁症与大脑细胞外去甲肾上腺素（NE）浓度降低有关。吸烟者可能是在自我治疗，并通过尼古丁刺激去甲肾上腺素（NE）释放来缓解抑郁。几种抗抑郁药会抑制去甲肾上腺素转运体（NET）功能，从而增加细胞外NE浓度。像安非他酮这样的抗抑郁药也会抑制烟碱受体（nAChR）功能。本研究确定了一种最近发现的新型nAChR拮抗剂N,N'-十二烷-1,12-二基-双-3-吡啶鎓二溴化物（bPiDDB）是否能抑制尼古丁诱发的超融合大鼠海马切片中NE的释放。先前的研究确定，bPiDDB在体外能有效（IC(50)=2 nM）抑制尼古丁诱发的纹状体[³H]多巴胺（DA）释放、在体内能抑制伏隔核中尼古丁诱发的DA释放以及大鼠的尼古丁自我给药行为。在本研究中，尼古丁刺激大鼠海马切片释放[³H]NE（EC(50)=50 microM）。bPiDDB抑制（IC(50)=430 nM；I(max)=90%）30 microM尼古丁诱发的[³H]NE释放。为作比较，非选择性nAChR拮抗剂美加明和α7拮抗剂甲基lycaconitine也抑制尼古丁诱发的[³H]NE释放（IC(50)分别为31和275 nM；I(max)分别为91%和72%）。增加尼古丁浓度并不能克服bPiDDB和美加明的抑制作用；Schild回归斜率不同于1，这与变构抑制一致。因此，bPiDDB抑制介导尼古丁诱发纹状体[³H]DA释放的nAChRs的效力比抑制介导尼古丁诱发海马[³H]NE释放的nAChRs的效力强200倍。
