Assessing nicotine dependence using an oral nicotine free-choice paradigm in mice
Assessing nicotine dependence using an oral nicotine free-choice paradigm in mice
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DOI：
10.1016/j.neuropharm.2019.107669
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发表时间：
2019-10-01
影响因子：
4.7
通讯作者：
Damaj, M. Imad
中科院分区：
文献类型：
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作者：
Bagdas, Deniz;Diester, Clare M.;Damaj, M. Imad
在老鼠身上评估尼古丁的成瘾特性的模型是有限的。因此，我们的目的是通过在小鼠身上使用口服尼古丁自由选择范式来表征和验证成瘾指数。成年C57BL/6J、DBA/2J或携带尼古丁乙酰胆碱受体(NAChR)亚单位缺失的转基因小鼠(n=8-10/性别/组)使用两瓶自由选择(2BC)范式选择水或尼古丁(10-960微克/毫升)溶液。总体而言，雌性小鼠的口服尼古丁摄入量和偏好高于雄性小鼠。缺乏尼古丁会导致戒断，间歇性接触会导致消费量上升，比持续接触尼古丁的戒断程度更大。此外，口服尼古丁的摄入增加了伏隔核酪氨酸羟基酶的水平。虽然β2和α6 KO小鼠的尼古丁摄入量显著减少，但α5 nAChRs的缺失增加了高浓度下的尼古丁摄入量。α7亚单位的缺失改变了观察到的尼古丁摄入量的性别差异，女性的尼古丁摄入量低于男性。α4β2部分激动剂varenicline减少了口服尼古丁的摄入量。尽管在尼古丁溶液中添加奎宁会降低尼古丁的摄入量，但服用尼古丁的小鼠在奎宁添加后并不会减少尼古丁的摄入量。尼古丁剥夺后再次暴露显示尼古丁消费量增加，与C57BL/6J相比，DBA/2J小鼠尼古丁消费量减少。我们验证了小鼠2BC范式，以研究尼古丁的成瘾性质，包括尼古丁摄取、偏好、戒断，以及在酗酒或恢复剥夺期间尼古丁消费的升级。
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 mu g/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 beta 2 and alpha 6 KO mice showed a significant decrease in nicotine intake, deletion of alpha 5 nAChRs increased nicotine consumption at high concentrations. Deletion of the alpha 7 subunit altered the observed sex difference in nicotine consumption, with females consuming less than males. The alpha 4 beta 2 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.