Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA, 23298-0613, USA; The Center for the Study for Tobacco Products, Virginia Commonwealth University, Richmond, VA, 23298-0613, USA.
Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA, 23298-0613, USA.
Neuropharmacology. 2019 Oct;157:107669. doi: 10.1016/j.neuropharm.2019.107669. Epub 2019 Jun 18.
Models to assess the addictive-like properties of nicotine in mice are limited. Therefore, we aimed to characterize and validate an addiction index by using an oral nicotine free-choice paradigm in mice. Adult C57BL/6J, DBA/2J, or genetically modified mice carrying deletions for nicotinic acetylcholine receptor (nAChR) subunits, (n = 8-10/sex/group) were given a choice of water or nicotine (10-960 μg/ml) solution using a two-bottle free-choice (2BC) paradigm. In general, oral nicotine intake and preference were higher in female mice compared to males. Absence of nicotine led to withdrawal, and intermittent access resulted in an escalation in consumption and greater nicotine withdrawal than continuous exposure. Additionally, oral nicotine consumption increased nucleus accumbens tyrosine hydroxylase levels. While β2 and α6 KO mice showed a significant decrease in nicotine intake, deletion of α5 nAChRs increased nicotine consumption at high concentrations. Deletion of the α7 subunit altered the observed sex difference in nicotine consumption, with females consuming less than males. The α4β2 partial agonist varenicline decreased oral nicotine consumption. Although addition of quinine to the nicotine solution lowered nicotine intake, mice primed with nicotine did not lower their intake after quinine addition. Nicotine deprivation followed by re-exposure showed increased nicotine consumption, and DBA/2J mice consumed less nicotine compared to C57BL/6J. We validated the mouse 2BC paradigm to study nicotine's addictive-like properties including nicotine intake, preference, withdrawal, and escalation of nicotine consumption during binge drinking or after reinstatement of a deprivation period.
用于评估尼古丁类成瘾性的小鼠模型有限。因此，我们旨在使用一种口腔尼古丁自由选择范式，在小鼠中建立并验证一个成瘾指数。成年 C57BL/6J、DBA/2J 或携带烟碱型乙酰胆碱受体 (nAChR) 亚单位缺失的基因改造小鼠（每组 8-10 只/性别）通过双瓶自由选择（2BC）范式，可选择饮水或尼古丁（10-960μg/ml）溶液。一般来说，与雄性小鼠相比，雌性小鼠的口腔尼古丁摄入量和偏好度更高。缺乏尼古丁会导致戒断，间歇性接触会导致摄入量增加和更大的尼古丁戒断，而持续暴露则不会。此外，口腔尼古丁的摄入会增加伏核酪氨酸羟化酶的水平。β2 和 α6 KO 小鼠的尼古丁摄入量明显减少，而α5 nAChR 的缺失则增加了高浓度的尼古丁摄入。α7 亚单位的缺失改变了观察到的尼古丁摄入中的性别差异，雌性的摄入量低于雄性。α4β2 部分激动剂伐尼克兰降低了口腔尼古丁的消耗。虽然在尼古丁溶液中添加奎宁会降低尼古丁的摄入，但经尼古丁预暴露的小鼠在添加奎宁后不会降低其摄入量。尼古丁剥夺后再暴露会导致尼古丁摄入量增加，与 C57BL/6J 相比，DBA/2J 小鼠的尼古丁摄入量更少。我们验证了小鼠 2BC 范式，以研究尼古丁的类成瘾特性，包括尼古丁摄入、偏好、戒断和 binge 饮酒期间或剥夺期后尼古丁摄入量的增加。
