Enhanced attenuation of nicotine discrimination in rats by combining nicotine-specific antibodies with a nicotinic receptor antagonist.
Enhanced attenuation of nicotine discrimination in rats by combining nicotine-specific antibodies with a nicotinic receptor antagonist.
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通过将尼古丁特异性抗体与尼古丁受体拮抗剂相结合，增强了大鼠尼古丁歧视的衰减。
DOI：
10.1016/j.pbb.2012.03.026
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发表时间：
2012-07
影响因子：
3.6
通讯作者：
Pentel, Paul R.
中科院分区：
文献类型：
--
作者：
LeSage, Mark G.;Shelley, David;Pravetoni, Marco;Pentel, Paul R.
烟草成瘾需要多种中枢烟碱乙酰胆碱受体（nachr）被尼古丁激活。在动物实验中，nAChR拮抗剂和尼古丁免疫均可降低尼古丁对nAChR的激活，并阻断多种成瘾相关行为。然而，nAChR拮抗剂用于戒烟的临床应用受到剂量相关副作用的限制，并且免疫接种不能可靠地在吸烟者中产生足够的抗体水平以提高戒烟率。将这些方法结合起来可能是解决每种方法的局限性，同时提高总体疗效的一种方法。本研究考察了单克隆尼古丁特异性抗体Nic311和尼古丁受体拮抗剂甲胺（mecamylamine， MEC）被动免疫对尼古丁鉴别刺激作用的单独和联合作用。采用双水平操作辨别程序训练大鼠区分0.4 mg/kg尼古丁和生理盐水。采用2 × 2设计，对Nic311 （160 mg/kg静脉注射）和递增剂量的MEC（0.03、0.1、0.3和1.0 mg/kg s.c）对尼古丁辨别的拮抗作用进行了评估。在所有四个测试阶段中，Nic311单独产生了24-48%的尼古丁杠杆反应（%NLR）降低。MEC产生了剂量依赖性的%NLR下降，在两个最低剂量下没有影响，在两个最高剂量下衰减80-93%。Nic311联合MEC在每次MEC剂量下显著抑制%NLR（在所有四个测试阶段降低85-92%）。非常低剂量的MEC单独无效，当与Nic311联合使用时，完全阻断了尼古丁的识别。这些数据表明，尼古丁特异性抗体和MEC可以协同抑制尼古丁的主观效应，提示低剂量的MEC可以显著提高免疫治疗的疗效。
Tobacco addiction requires activation by nicotine of a variety of central nicotinic acetylcholine receptors (nAChRs). In animals, both nAChR antagonists and immunization against nicotine can reduce nAChR activation by nicotine and block a variety of addiction-relevant behaviors. However, clinical use of nAChR antagonists for smoking cessation is limited by dose-related side effects, and immunization does not reliably produce sufficient antibody levels in smokers to enhance smoking cessation rates. Combining these approaches may be one way of addressing the limitations of each while enhancing overall efficacy. This study examined the individual and combined effects of passive immunization with the monoclonal nicotine-specific antibody Nic311 and the nicotinic receptor antagonist mecamylamine (MEC) on nicotine’s discriminative stimulus effects. Rats were trained to discriminate 0.4 mg/kg nicotine from saline using a two-lever operant discrimination procedure. Antagonism of nicotine discrimination by Nic311 (160 mg/kg i.v.) and ascending doses of MEC (0.03, 0.1, 0.3, and 1.0 mg/kg s.c.) was assessed across four consecutive daily 2-min extinction test sessions using a 2 × 2 design. Nic311 alone produced a 24-48% reduction in % nicotine-lever responding (%NLR) across all four test sessions. MEC produced a dose-dependent decrease in %NLR, with no effect at the two lowest doses and 80-93% attenuation at the two highest doses. Nic311 combined with MEC significantly suppressed %NLR at every MEC dose (85-92% reduction across all four test sessions). Very low doses of MEC that were ineffective alone completely blocked nicotine discrimination when combined with Nic311. These data demonstrate that nicotine-specific antibodies and MEC can work synergistically to suppress the subjective effects of nicotine and suggest that low doses of MEC may significantly enhance the efficacy of immunotherapy.
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影响因子：
3.4
作者：
LeSage, MG;Keyler, DE;Pentel, PR
通讯作者：
Pentel, PR
影响因子：
3.4
作者：
Mansbach, RS;Chambers, LK;Rovetti, CC
通讯作者：
Rovetti, CC
DOI：
10.1016/j.pbb.2010.12.023
发表时间：
2011-04
期刊：
Pharmacology, biochemistry, and behavior
影响因子：
--
作者：
Levin ED;Slade S;Wells C;Petro A;Rose JE
通讯作者：
Rose JE
影响因子：
4.7
作者：
Papke, Roger L.;Dwoskin, Linda P.;Stokes, Clare
通讯作者：
Stokes, Clare
影响因子：
3.6
作者：
LeSage, MG;Keyler, DE;Pentel, PR
通讯作者：
Pentel, PR