Murphy R Logan, Locklear Laura L, Niaz M Haris, Walton Rebecca L, Hudson Alexandra D, Fryxell Karl J
School of Systems Biology, and the Interdisciplinary Program in Neurosciences, George Mason University, Mail Stop 1J1, Institute of Advanced Biomedical Research Building, 10920 George Mason Circle, Manassas, VA, 20110, USA.
Department of Physiology and Biophysics, University of Washington, Seattle, WA, USA.
Psychopharmacology (Berl). 2021 Dec;238(12):3477-3497. doi: 10.1007/s00213-021-05966-w. Epub 2021 Sep 7.
Cd81 -/- (knockout) mice have previously been reported to have reduced cocaine preference and increased striatal dopamine content and dopamine turnover, but normal learning and memory in the Morris water maze. The effects of Cd81 on other behaviors and drugs of abuse have not been investigated.
We measured the effects of Cd81 -/- in a modified two-bottle choice test for nicotine, as well as in somatic signs of nicotine withdrawal, four tests of affective behavior, and tyrosine hydroxylase gene expression assays.
We found that Cd81 loss-of-function significantly increased voluntary nicotine consumption and somatic signs of nicotine withdrawal. Nicotine consumption of Cd81 -/- female mice increased for 3 weeks and then remained relatively stable for the next 5 weeks, suggesting that their nicotine consumption continued to be limited by aversion to higher nicotine doses. Cd81 -/- also produced a dramatic and significant increase in struggling in the forced swim test and a significant increase in the time spent in the light chamber of the light/dark box. The elevated plus maze and the tail suspension test did not show a main effect of genotype. Therefore, we conclude that Cd81 did not have an overall effect on anxiety- or depression-like behavior. Tyrosine hydroxylase mRNA levels were unchanged.
Cd81 knockouts have a strongly increased nicotine preference, plus a proactive response to specific stressful situations. Together with reports of increased striatal dopamine content and anecdotal reports of increased aggressiveness, these provide intriguing parallels to some aspects of post-traumatic stress disorder.
此前有报道称，Cd81基因敲除小鼠对可卡因的偏好降低，纹状体多巴胺含量和多巴胺周转率增加，但在莫里斯水迷宫实验中的学习和记忆能力正常。尚未研究Cd81对其他行为和滥用药物的影响。
我们在改良的两瓶选择尼古丁测试中测量了Cd81基因敲除的影响，以及尼古丁戒断的躯体症状、四项情感行为测试和酪氨酸羟化酶基因表达分析。
我们发现Cd81功能丧失显著增加了自愿尼古丁摄入量和尼古丁戒断的躯体症状。Cd81基因敲除雌性小鼠的尼古丁摄入量在3周内增加，然后在接下来的5周内保持相对稳定，这表明它们的尼古丁摄入量继续受到对高剂量尼古丁厌恶的限制。Cd81基因敲除还导致强迫游泳测试中的挣扎行为显著增加，以及在明暗箱实验中在明室停留的时间显著增加。高架十字迷宫和悬尾实验未显示出基因型的主要影响。因此，我们得出结论，Cd8基因对焦虑或抑郁样行为没有总体影响。酪氨酸羟化酶mRNA水平未发生变化。
Cd81基因敲除小鼠对尼古丁的偏好大幅增加，并且对特定应激情况有主动反应。再加上纹状体多巴胺含量增加的报道以及攻击性增加的轶事报道，这些与创伤后应激障碍的某些方面存在有趣的相似之处。
