Teng L, Crooks P A, Sonsalla P K, Dwoskin L P
College of Pharmacy and Graduate Center for Toxicology, University of Kentucky, Lexington 40536-0082, USA.
J Pharmacol Exp Ther. 1997 Mar;280(3):1432-44.
Lobeline is currently being developed as a substitution therapy for tobacco smoking cessation. Activation of CNS dopamine (DA) systems results in the reinforcing properties of nicotine. The present study compared the effects of lobeline and nicotine on rat striatum. Both lobeline and nicotine evoked [3H]overflow from striatal slices superfused in the presence of pargyline and nomifensine in the buffer. Marked DA depletion (42-67%) and a concomitant 2-fold increase in dihydroxyphenylacetic acid (DOPAC) in slices superfused with high concentrations (30-100 microM) of lobeline were observed. The effect of nicotine (10 microM) was inhibited in a concentration-dependent manner by mecamylamine (1-100 microM). However, lobeline (0.1-100 microM)-evoked [3H]overflow was calcium-independent, and was not antagonized by mecamylamine (1-100 microM), suggesting a mechanism of action other than stimulation of nicotinic receptors. Lobeline inhibited [3H]DA uptake into synaptosomes (IC50 = 80 +/- 12 microM) and vesicles (IC50 = 0.88 +/- 0.001 microM), whereas nicotine (< or =100 microM) did not inhibit synaptosomal or vesicular [3H]DA uptake. In the absence of pargyline and nomifensine in the buffer, endogenous DA was detected in superfusate only in those slices exposed to the highest concentration (100 microM) of lobeline. However, endogenous DOPAC concentration was increased in a concentration-dependent manner, indicating that lobeline exposure resulted in increased cytosolic DA which was rapidly metabolized to DOPAC. Under these conditions, lobeline (10-100 microM) also significantly depleted (66-85%) DA content; however, no change in DOPAC content was observed. The results suggest that, unlike nicotine, lobeline increases DA release by potent inhibition of DA uptake into synaptic vesicles, and a subsequent alteration in presynaptic DA storage.
洛贝林目前正被开发用作戒烟的替代疗法。中枢神经系统多巴胺（DA）系统的激活会导致尼古丁的强化特性。本研究比较了洛贝林和尼古丁对大鼠纹状体的影响。在缓冲液中存在帕吉林和诺米芬辛的情况下，洛贝林和尼古丁都会引起灌流的纹状体切片中[3H]的溢出。观察到在灌流高浓度（30 - 100微摩尔）洛贝林的切片中，多巴胺明显耗竭（42 - 67%），同时二羟基苯乙酸（DOPAC）增加了2倍。尼古丁（10微摩尔）的作用被美加明（1 - 100微摩尔）以浓度依赖的方式抑制。然而，洛贝林（0.1 - 100微摩尔）引起的[3H]溢出与钙无关，并且不受美加明（1 - 100微摩尔）的拮抗，这表明其作用机制不是刺激烟碱受体。洛贝林抑制[3H]多巴胺摄取到突触体（IC50 = 80 ± 12微摩尔）和囊泡（IC50 = 0.88 ± 0.001微摩尔）中，而尼古丁（≤100微摩尔）不抑制突触体或囊泡对[3H]多巴胺的摄取。在缓冲液中不存在帕吉林和诺米芬辛的情况下，仅在暴露于最高浓度（100微摩尔）洛贝林的那些切片的灌流液中检测到内源性多巴胺。然而，内源性DOPAC浓度以浓度依赖的方式增加，表明暴露于洛贝林会导致胞质多巴胺增加，并迅速代谢为DOPAC。在这些条件下，洛贝林（10 - 100微摩尔）也显著降低（66 - 85%）多巴胺含量；然而，未观察到DOPAC含量的变化。结果表明，与尼古丁不同，洛贝林通过强力抑制多巴胺摄取到突触小泡中以及随后改变突触前多巴胺储存来增加多巴胺释放。
