Forget Benoît, Hamon Michel, Thiébot Marie-Hélène
INSERM U.677 (ex. U.288), Faculté de Médecine Pitié-Salpêtrière, 91 Boulevard de l'Hôpital, 75634, Paris Cedex 13, France.
Psychopharmacology (Berl). 2005 Oct;181(4):722-34. doi: 10.1007/s00213-005-0015-6. Epub 2005 Sep 29.
The endocannabinoid system plays a role in mediating the appetitive value of a variety of reinforcing compounds, either natural rewards or drugs of abuse, but little is known about its involvement in the incentive properties of nicotine.
The objective of the study is to evaluate whether activation of CB1 cannabinoid receptors is necessary for the establishment and the short- and long-term expression of nicotine-induced conditioned place preference (CPP). This was studied in rats subjected to an unbiased, one-compartment place conditioning procedure, using the selective CB1 receptor antagonist, rimonabant, as a pharmacological tool.
Wistar rats, given previous experience with nicotine in their home cage, were subjected to eight alternating nicotine (0.006-0.6 mg/kg s.c.) and saline pairings with distinct floor textures in an open field and given a test session, with no nicotine injection, in the open field whose floor was covered by two quadrants of the saline-paired texture and two quadrants of the nicotine-paired texture. Rimonabant (0.3-3 mg/kg i.p.) was administered 30 min before each nicotine (0.06 mg/kg) pairing to assess its effect on the establishment of nicotine-CPP. To study the effects of CB1 receptor blockade on short- and long-term expression of nicotine-CPP, rimonabant was administered as a single injection 30 min before the test session, conducted either 24 h, 3 weeks or 12 weeks after the last conditioning session.
Rats developed reliable and robust CPP to the 0.06- and 0.125-mg/kg doses of nicotine. Once established, CPP persisted for at least 12 weeks without additional exposure to nicotine and the test apparatus. Pre-pairing injections of rimonabant (3 mg/kg, but not lower doses) prevented the acquisition of nicotine-CPP, and a single pretest administration of rimonabant (3 mg/kg) abolished the expression of nicotine-CPP when the test session took place 24 h after the last conditioning session. However, rimonabant (3 mg/kg) did not antagonize the expression of nicotine-CPP when the test session was conducted 3 or 12 weeks after the acquisition phase.
The endocannabinoids are a necessary component in both the perception by rats of the motivational value of nicotine and the short-term capacity of nicotine-paired conditioned stimuli to elicit approach behaviour. In contrast, the acute blockade of CB1 receptors no longer impairs the long-term control of behaviour by nicotine-associated environmental cues. These data provide support to the notion that the blockade of CB1 receptors can oppose tobacco dependence, withdrawal and even relapse, though the time window of efficacy and/or the schedule of administration remain to be established.
内源性大麻素系统在介导多种强化化合物(包括天然奖赏或滥用药物)的奖赏价值方面发挥作用,但关于其在尼古丁的激励特性中的作用知之甚少。
本研究的目的是评估CB1大麻素受体的激活对于尼古丁诱导的条件性位置偏爱(CPP)的建立以及短期和长期表达是否必要。使用选择性CB1受体拮抗剂利莫那班作为药理学工具,在接受无偏倚的单室位置条件反射程序的大鼠中进行了此项研究。
曾在其饲养笼中接触过尼古丁的Wistar大鼠,在开放场中接受八次交替的尼古丁(0.006 - 0.6毫克/千克皮下注射)和生理盐水配对,每次配对的地面纹理不同,并在开放场中进行一次测试,测试场地面由两个与生理盐水配对纹理的象限和两个与尼古丁配对纹理的象限覆盖,且不注射尼古丁。在每次尼古丁(0.06毫克/千克)配对前30分钟给予利莫那班(0.3 - 3毫克/千克腹腔注射),以评估其对尼古丁-CPP建立的影响。为了研究CB1受体阻断对尼古丁-CPP短期和长期表达的影响,在最后一次条件反射训练后24小时、3周或12周进行测试前30分钟,单次注射利莫那班。
大鼠对0.06毫克/千克和0.125毫克/千克剂量的尼古丁产生了可靠且强烈的CPP。一旦建立,CPP在没有额外接触尼古丁和测试装置的情况下持续至少12周。预配对注射利莫那班(3毫克/千克,但较低剂量无效)可阻止尼古丁-CPP的获得,当测试在最后一次条件反射训练后24小时进行时,单次测试前给予利莫那班(3毫克/千克)可消除尼古丁-CPP的表达。然而,当测试在获得阶段后3周或12周进行时,利莫那班(3毫克/千克)并未拮抗尼古丁-CPP的表达。
内源性大麻素在大鼠对尼古丁动机价值的感知以及尼古丁配对条件刺激引发接近行为的短期能力方面都是必要成分。相比之下,CB1受体的急性阻断不再损害尼古丁相关环境线索对行为的长期控制。这些数据支持了这样一种观点,即阻断CB1受体可以对抗烟草依赖、戒断甚至复发,尽管疗效的时间窗口和/或给药方案仍有待确定。