Sazetidine-A, a Selective α4β2 Nicotinic Receptor Desensitizing Agent and Partial Agonist, Reduces Nicotine Self-Administration in Rats
Sazetidine-A, a Selective α4β2 Nicotinic Receptor Desensitizing Agent and Partial Agonist, Reduces Nicotine Self-Administration in Rats
复制标题
DOI：
10.1124/jpet.109.162073
复制
发表时间：
2010-03-01
影响因子：
3.5
通讯作者：
Kellar, Kenneth J.
中科院分区：
文献类型：
--
作者：
Levin, Edward D.;Rezvani, Amir H.;Kellar, Kenneth J.
对烟草成瘾的适当治疗仍然是个问题。治疗的部分问题是对尼古丁导致成瘾的药理学方面缺乏了解。除了激活烟碱型乙酰胆碱受体外，尼古丁还能使它们脱敏。目前尚不清楚尼古丁的每一种行为对其特定行为的影响有多大。沙氮替丁-A(SAZ-A)是一种新型的烟碱受体脱敏剂和部分激动剂，对α-4-β2受体具有高选择性。目前的实验是为了确定SAZ-A是否会减少大鼠的尼古丁自我给药，并表征其辅助作用。成年雄性Spraogue-Dawley大鼠被允许自我给予尼古丁。在最初的食物颗粒训练和10次尼古丁自我给药训练之后，大鼠被给予SAZ-A(0.1-3 mg/kg S.C.)。或采用重复措施平衡设计的盐水车。与相同大鼠注射生理盐水后的表现相比，SAZ-A在3 mg/kg剂量下显著减少了尼古丁的自我给药。在第二项研究中，长期服用这种剂量的沙泽替丁-A在10次疗程中显著减少了尼古丁的自我给药，但效果并未明显减弱。在这个剂量范围内，SAZ-A对运动活动只有轻微的影响，在长达1小时的疗程中，活动没有任何总体下降。SAZ-A显著减少了食物自我给药，但这种影响小于其对尼古丁自我给药的影响。SAZ-A是一种选择性的α4β2脱敏剂和部分激动剂，有效地减少尼古丁的自我给药。这种疗法有望成为一种帮助戒烟的新疗法。
Adequate treatment of tobacco addiction remains problematic. Part of the problem with treatment is a poor understanding of the pharmacologic aspects of nicotine contributing to addiction. In addition to activating nicotinic acetylcholine receptors, nicotine also desensitizes them. It is currently not known how much of each of nicotine's actions contribute to its particular behavioral effects. Sazetidine-A (saz-A) is a novel nicotinic receptor-desensitizing agent and partial agonist with high selectivity for alpha 4 beta 2 receptors. The current experiments were conducted to determine whether saz-A would reduce nicotine self-administration in rats and to characterize its ancillary effects. Adult male Sprague-Dawley rats were allowed to self-administer nicotine. After initial food pellet training followed by 10 sessions of nicotine self-administration training, the rats were administered saz-A (0.1-3 mg/kg s.c.) or the saline vehicle in a repeated-measures counterbalanced design. Saz-A at the 3 mg/kg dose significantly decreased nicotine self-administration relative to performance of the same rats after saline injections. In a second study, long-term administration of this dose of sazetidine-A over the course of 10 sessions significantly reduced nicotine self-administration with no apparent diminution of effect. Saz-A in this dose range had only modest effects on locomotor activity, without any overall decrease in activity over a 1-h-long session. Saz-A significantly reduced food self-administration, but this effect was smaller than its effect on nicotine self-administration. Saz-A, which is a selective alpha 4 beta 2-desensitizing agent and partial agonist, effectively reduces nicotine self-administration. This type of treatment holds promise for a new therapy to aid smoking cessation.