Desai Rajeev I, Bergman Jack
Preclinical Pharmacology Laboratory, Department of Psychiatry, McLean Hospital/Harvard Medical School, Belmont, MA, USA.
Neuropsychopharmacology. 2015 Aug;40(9):2207-16. doi: 10.1038/npp.2015.64. Epub 2015 Mar 6.
A key feature of addiction to nicotine likely resides in its ability to produce subjective effects that, in turn, may be reflected in its discriminative-stimulus properties. Vaccination against such effects of nicotine offers an intriguing therapeutic approach for smoking cessation, but a reliably effective and immunologically safe vaccine remains to be identified. Here we report on the ability of SEL-068, a nanoparticle-based vaccine that targets nicotine, to modify the discriminative-stimulus effects of nicotine in a primate species. Results indicate that squirrel monkeys vaccinated with SEL-068 failed to acquire 0.1 mg/kg nicotine discrimination but readily learned to discriminate 0.001 mg/kg of the nicotinic full agonist (+)-epibatidine ((+)-EPI). After (+)-EPI training, doses of nicotine ⩾ 0.32 mg/kg, which produced behaviorally adverse actions, still failed to substitute for the (+)-EPI training stimulus in immunized monkeys, whereas (+)-EPI and the partial agonist varenicline engendered, respectively, complete and partial substitution in all monkeys with potency comparable to their potency in non-immunized subjects. In other subjects, nicotine was trained as a discriminative-stimulus and then replaced by (+)-EPI. Subsequent vaccination with SEL-068 led to a threefold and long-lasting (>30 weeks) decrease in the potency of nicotine but not (+)-EPI or varenicline. Collectively, our results show that SEL-068 can block the development of nicotine discrimination and attenuate nicotine's effects in nicotine-experienced monkeys without altering the discriminative-stimulus properties of other nicotinic drugs. The difference in the vaccine's effects in naive and nicotine-experienced subjects provides important insight into the conditions under which immunotherapy may be effective in combating nicotine addiction.
对尼古丁成瘾的一个关键特征可能在于其产生主观效应的能力，而这些主观效应反过来可能体现在其辨别刺激特性上。针对尼古丁此类效应的疫苗接种为戒烟提供了一种引人关注的治疗方法，但一种可靠有效的且免疫安全的疫苗仍有待确定。在此，我们报告了SEL-068（一种靶向尼古丁的纳米颗粒疫苗）改变灵长类动物中尼古丁辨别刺激效应的能力。结果表明，接种SEL-068的松鼠猴未能学会辨别0.1毫克/千克的尼古丁，但很容易学会辨别0.001毫克/千克的烟碱型完全激动剂（+）-依博加因（（+）-EPI）。在（+）-EPI训练后，剂量⩾0.32毫克/千克的尼古丁（会产生行为上的不良作用）在免疫的猴子中仍无法替代（+）-EPI训练刺激，而（+）-EPI和部分激动剂伐尼克兰在所有猴子中分别产生了完全和部分替代，其效力与它们在未免疫受试者中的效力相当。在其他实验对象中，尼古丁被训练为辨别刺激，然后被（+）-EPI替代。随后用SEL-068进行疫苗接种导致尼古丁的效力降低了三倍且持续时间长（>30周），但（+）-EPI或伐尼克兰的效力未受影响。总体而言，我们的结果表明，SEL-068可以阻断尼古丁辨别能力的发展，并减弱尼古丁在有尼古丁使用经验的猴子中的作用，而不会改变其他烟碱型药物的辨别刺激特性。疫苗在未接触过尼古丁和有尼古丁使用经验的实验对象中的效应差异，为免疫疗法在对抗尼古丁成瘾方面可能有效的条件提供了重要见解。
