Higa K K, Grim A, Kamenski M E, van Enkhuizen J, Zhou X, Li K, Naviaux J C, Wang L, Naviaux R K, Geyer M A, Markou A, Young J W
Department of Psychiatry, University of California San Diego, 9500 Gilman Drive MC 0804, La Jolla, CA, 92093-0804, USA.
Research Service, VA San Diego Healthcare System, 3350 La Jolla Village Drive, San Diego, CA, 92037, USA.
Psychopharmacology (Berl). 2017 May;234(9-10):1573-1586. doi: 10.1007/s00213-017-4572-2. Epub 2017 Feb 28.
Smoking is the leading cause of preventable death in the USA, but quit attempts result in withdrawal-induced cognitive dysfunction and predicts relapse. Greater understanding of the neural mechanism(s) underlying these cognitive deficits is required to develop targeted treatments to aid quit attempts.
We examined nicotine withdrawal-induced inattention in mice lacking the α7 nicotinic acetylcholine receptor (nAChR) using the five-choice continuous performance test (5C-CPT).
Mice were trained in the 5C-CPT prior to osmotic minipump implantation containing saline or nicotine. Experiment 1 used 40 mg kg day nicotine treatment and tested C57BL/6 mice 4, 28, and 52 h after pump removal. Experiment 2 used 14 and 40 mg kg day nicotine treatment in α7 nAChR knockout (KO) and wildtype (WT) littermates tested 4 h after pump removal. Subsets of WT mice were killed before and after pump removal to assess changes in receptor expression associated with nicotine administration and withdrawal.
Nicotine withdrawal impaired attention in the 5C-CPT, driven by response inhibition and target detection deficits. The overall attentional deficit was absent in α7 nAChR KO mice despite response disinhibition in these mice. Synaptosomal glutamate mGluR5 and dopamine D receptor expression were reduced during chronic nicotine but increased during withdrawal, potentially contributing to cognitive deficits.
The α7 nAChR may underlie nicotine withdrawal-induced deficits in target detection but is not required for response disinhibition deficits. Alterations to the glutamatergic and dopaminergic pathways may also contribute to withdrawal-induced attentional deficits, providing novel targets to alleviate the cognitive symptoms of withdrawal during quit attempts.
吸烟是美国可预防死亡的首要原因，但戒烟尝试会导致戒断引起的认知功能障碍，并预示着复吸。需要更深入了解这些认知缺陷背后的神经机制，以开发针对性治疗方法来辅助戒烟尝试。
我们使用五选择连续操作测试（5C-CPT），研究缺乏α7烟碱型乙酰胆碱受体（nAChR）的小鼠中尼古丁戒断引起的注意力不集中。
在植入含生理盐水或尼古丁的渗透微型泵之前，小鼠接受5C-CPT训练。实验1使用40mg/kg/天的尼古丁治疗，并在移除泵后4、28和52小时对C57BL/6小鼠进行测试。实验2在α7 nAChR基因敲除（KO）和野生型（WT）同窝小鼠中使用14和40mg/kg/天的尼古丁治疗，并在移除泵后4小时进行测试。WT小鼠的亚组在移除泵前后处死，以评估与尼古丁给药和戒断相关的受体表达变化。
尼古丁戒断损害了5C-CPT中的注意力，这是由反应抑制和目标检测缺陷驱动的。尽管α7 nAChR KO小鼠存在反应去抑制，但总体注意力缺陷并不存在。慢性尼古丁给药期间，突触体谷氨酸代谢型谷氨酸受体5（mGluR5）和多巴胺D受体表达降低，但戒断期间增加，这可能导致认知缺陷。
α7 nAChR可能是尼古丁戒断引起的目标检测缺陷的基础，但不是反应去抑制缺陷所必需的。谷氨酸能和多巴胺能途径的改变也可能导致戒断引起的注意力缺陷，为减轻戒烟尝试期间戒断的认知症状提供了新的靶点。
