Bupropion inhibits nicotine-evoked [3H]overflow from rat striatal slices preloaded with [3H]dopamine and from rat hippocampal slices preloaded with [3H]norepinephrine
Bupropion inhibits nicotine-evoked [3H]overflow from rat striatal slices preloaded with [3H]dopamine and from rat hippocampal slices preloaded with [3H]norepinephrine
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DOI：
10.1124/jpet.102.033852
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发表时间：
2002-09-01
影响因子：
3.5
通讯作者：
Dwoskin, LP
中科院分区：
文献类型：
--
作者：
Miller, DK;Sumithran, SP;Dwoskin, LP
安非他酮是一种有效的抗抑郁药和戒烟药，可抑制多巴胺和去甲肾上腺素转运蛋白（分别为DAT和NET）。最近，安非他酮已被报道，非竞争性抑制α 3 β 2，α 3 β 4，和α 4 β 2烟碱乙酰胆碱受体（nAChR）在非洲爪蟾卵母细胞或建立的细胞系中表达。本研究使用功能性神经递质释放测定、预先加载[H-3]多巴胺（[H-3]DA）的灌流大鼠纹状体切片中尼古丁诱发的[H-3]溢出和预先加载[H-3]去甲肾上腺素（[H-3]NE）的海马切片中尼古丁诱发的[H-3]溢出，评估安非他酮诱导的天然α 3 β 2（*）和α 3 β 4（*）nAChR抑制。使用Schild分析评价抑制机制。为了消除安非他酮与DAT或NET的相互作用，将诺米芬辛或地昔帕明分别包含在灌注缓冲液中。在[H-3]DA释放测定中，高安非他酮浓度（100 μ M）引起内在活性。然而，所检测的浓度（1 nM-100 μ M）均未诱发[H-3]NE溢出，因此在该测定中没有内在活性。此外，安非他酮抑制尼古丁诱发的[H-3]DA溢出（IC 50 = 1.27 μ M）和尼古丁诱发的[H-3]NE溢出（IC 50 = 323 nM）在安非他酮浓度远低于引发的内在活动。Schild分析的结果表明，安非他酮竞争性抑制尼古丁诱发的[H-3]DA溢出，而受体储备的证据后，获得安非他酮抑制尼古丁诱发的[H-3]NE溢出的评估。因此，在抑制DAT和NET功能的相同浓度范围内，安非他酮分别作为大鼠纹状体和海马中α 3 β 2（*）和α 3 β 4（*）nAChR的拮抗剂。安非他酮产生的nAChR和转运蛋白抑制的组合可能有助于其作为戒烟剂的临床疗效。
Bupropion, an efficacious antidepressant and smoking cessation agent, inhibits dopamine and norepinephrine transporters (DAT and NET, respectively). Recently, bupropion has been reported to noncompetitively inhibit alpha3beta2, alpha3beta4, and alpha4beta2 nicotinic acetylcholine receptors (nAChRs) expressed in Xenopus oocytes or established cell lines. The present study evaluated bupropion-induced inhibition of native alpha3beta2(*) and alpha3beta4(*) nAChRs using functional neurotransmitter release assays, nicotine-evoked [H-3]overflow from superfused rat striatal slices preloaded with [H-3]dopamine ([H-3]DA), and nicotine-evoked [H-3]overflow from hippocampal slices preloaded with [H-3]norepinephrine ([H-3]NE). The mechanism of inhibition was evaluated using Schild analysis. To eliminate the interaction of bupropion with DAT or NET, nomifensine or desipramine, respectively, was included in the superfusion buffer. A high bupropion concentration (100 muM) elicited intrinsic activity in the [H-3]DA release assay. However, none of the concentrations (1 nM-100 muM) examined evoked [H-3]NE overflow and, thus, were without intrinsic activity in this assay. Moreover, bupropion inhibited both nicotine-evoked [H-3]DA overflow (IC50 = 1.27 muM) and nicotine-evoked [H-3]NE overflow (IC50 = 323 nM) at bupropion concentrations well below those eliciting intrinsic activity. Results from Schild analyses suggest that bupropion competitively inhibits nicotine-evoked [H-3]DA overflow, whereas evidence for receptor reserve was obtained upon assessment of bupropion inhibition of nicotine-evoked [H-3]NE overflow. Thus, bupropion acts as an antagonist at alpha3beta2(*) and alpha3beta4(*) nAChRs in rat striatum and hippocampus, respectively, across the same concentration range that inhibits DAT and NET function. The combination of nAChR and transporter inhibition produced by bupropion may contribute to its clinical efficacy as a smoking cessation agent.