反复给予尼古丁可显著增强含 alpha6beta2 的烟碱型乙酰胆碱受体介导的尼古丁诱导的多巴胺释放中 bPiDDB 的抑制效力。

Repeated nicotine administration robustly increases bPiDDB inhibitory potency at alpha6beta2-containing nicotinic receptors mediating nicotine-evoked dopamine release.

机构信息

Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA.

出版信息

Biochem Pharmacol. 2010 Aug 1;80(3):402-9. doi: 10.1016/j.bcp.2010.03.018. Epub 2010 Mar 25.

DOI:10.1016/j.bcp.2010.03.018

PMID:20346923

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3779887/

Abstract

The novel nicotinic receptor (nAChR) antagonist, N,N'-dodecane-1,12-diyl-bis-3-picolinium dibromide (bPiDDB), and its chemically reduced analog, r-bPiDDB, potently inhibit nicotine-evoked dopamine (DA) release from rat striatal slices. Since tobacco smokers self-administer nicotine repeatedly, animal models incorporating repeated nicotine treatment allow for mechanistic evaluation of therapeutic candidates following neuroadaptive changes. The current study determined the ability of bPiDDB, r-bPiDDB and alpha-conotoxin MII (alpha-CtxMII), a peptide antagonist selective for alpha6beta2-containing nAChRs, to inhibit nicotine-evoked [(3)H]DA release from striatal slices from rats repeatedly administered nicotine (0.4mg/kg for 10 days) or saline (control). Concomitant exposure to maximally effective concentrations of r-bPiDDB (1nM) and alpha-CtxMII (1nM) resulted in inhibition of nicotine-evoked [(3)H]DA release no greater than that produced by either antagonist alone, suggesting that r-bPiDDB inhibits alpha6beta2-containing nAChRs. Repeated nicotine treatment increased locomotor activity, demonstrating behavioral sensitization. Concentration-response curves for nicotine-evoked [(3)H]DA release were not different between nicotine-treated and control groups. Maximal inhibition for alpha-CtxMII was greater following repeated nicotine compared to control (I(max)=90% vs. 62%), with no change in potency. bPiDDB was 3-orders of magnitude more potent in inhibiting nicotine-evoked [(3)H]DA release in nicotine-treated rats compared to control rats (IC(50)=5pM vs. 6nM), with no change in maximal inhibition. Neither a shift to the left in the concentration response nor a change in maximal inhibition was observed for r-bPiDDB following repeated nicotine. Thus, repeated nicotine treatment may differentially regulate the stoichiometry, conformation and/or composition of alpha6beta2-containing nAChRs mediating nicotine-evoked striatal DA release. Therefore, bPiDDB and r-bPiDDB appear to target different alpha6beta2-containing nAChR subtypes.

摘要

新型烟碱型乙酰胆碱受体 (nAChR) 拮抗剂 N,N'-十二烷-1,12-二基-双-3-吡啶翁二溴化物（bPiDDB）及其化学还原类似物 r-bPiDDB 能强有力地抑制大鼠纹状体切片中尼古丁诱导的多巴胺 (DA) 释放。由于烟民反复自行摄取尼古丁，因此纳入重复尼古丁处理的动物模型可以在神经适应变化后对治疗候选物进行机制评估。本研究旨在确定 bPiDDB、r-bPiDDB 和 alpha-芋螺毒素 MII（alpha-CtxMII）（一种对 alpha6beta2 型烟碱型乙酰胆碱受体具有选择性的肽类拮抗剂）抑制经尼古丁（0.4mg/kg，10 天）或生理盐水（对照）重复处理的大鼠纹状体切片中尼古丁诱导的 [(3)H]DA 释放的能力。同时暴露于最大有效浓度的 r-bPiDDB（1nM）和 alpha-CtxMII（1nM）导致的尼古丁诱导的 [(3)H]DA 释放抑制作用并不比任何一种拮抗剂单独作用时更强，表明 r-bPiDDB 抑制 alpha6beta2 型烟碱型乙酰胆碱受体。重复尼古丁处理增加了运动活动，表明出现行为敏化。尼古丁诱导的 [(3)H]DA 释放的浓度-反应曲线在尼古丁处理组和对照组之间没有差异。与对照组相比，重复尼古丁处理后 alpha-CtxMII 的最大抑制作用更大（I(max)=90% vs. 62%），但效力没有变化。与对照组相比，bPiDDB 在抑制尼古丁诱导的 [(3)H]DA 释放方面的效力要强 3 个数量级（IC(50)=5pM vs. 6nM），最大抑制作用没有变化。在重复尼古丁处理后，r-bPiDDB 的浓度反应曲线没有向左移位，最大抑制作用也没有变化。因此，重复尼古丁处理可能会以不同的方式调节介导尼古丁诱导的纹状体 DA 释放的 alpha6beta2 型烟碱型乙酰胆碱受体的组成、构象和/或组成。因此，bPiDDB 和 r-bPiDDB 似乎针对不同的 alpha6beta2 型烟碱型乙酰胆碱受体亚型。