Cognitive flexibility is the ability to switch strategic responses adaptively in changing environments. Cognitive rigidity imposed by neural circuit adaptations during nicotine abstinence may foster maladaptive nicotine taking in addicts. We systematically examined the effects of spontaneous withdrawal in mice exposed to either nicotine (6.3 or 18 mg/kg/day) or saline for 14 days on cognitive flexibility using an operant strategy set-shifting task. Because frontostriatal circuits are critical for cognitive flexibility and brain-derived neurotrophic factor (BDNF) modulates glutamate plasticity in these circuits, we also explored the effects of nicotine withdrawal on these neurochemical substrates. Mice undergoing nicotine withdrawal required more trials to attain strategy-switching criterion. Error analysis show that animals withdrawn from both nicotine doses committed higher perseverative errors, which correlated with measures of anxiety. However, animals treated with the higher nicotine dose also displayed more strategy maintenance errors that remained independent of negative affect. BDNF mRNA expression increased in the medial prefrontal cortex (mPFC) following nicotine withdrawal. Surprisingly, BDNF protein declined in mPFC but was elevated in dorsal striatum (DS). DS BDNF protein positively correlated with perseverative and maintenance errors, suggesting mPFC-DS overflow of BDNF during withdrawal. BDNF-evoked glutamate release and synapsin phosphorylation was attenuated within DS synapses, but enhanced in the nucleus accumbens, suggesting a dichotomous role of BDNF signaling in striatal regions. Taken together, these data suggest that spontaneous nicotine withdrawal impairs distinct components of cognitive set-shifting and these deficits may be linked to BDNF-mediated alterations in glutamate signaling dynamics in discrete frontostriatal circuits.

认知灵活性是指在不断变化的环境中适应性地转换战略响应的能力。尼古丁戒断期间神经回路适应引起的认知僵硬可能会促使成瘾者吸收不良适应性尼古丁。我们系统地研究了使用操作策略策略转移任务对暴露于尼古丁（6.3或18 mg / kg /天）或生理盐水14天的小鼠自发戒断对认知灵活性的影响。因为前额窦回路对于认知灵活性至关重要，并且脑源性神经营养因子（BDNF）调节这些回路中的谷氨酸可塑性，所以我们还探讨了尼古丁戒断对这些神经化学底物的影响。接受尼古丁戒断的小鼠需要更多试验才能达到策略转换标准。误差分析表明，从两种尼古丁剂量中撤出的动物的持续性误差较高，这与焦虑程度相关。但是，用较高烟碱剂量治疗的动物也显示出更多的策略维持错误，而这些错误仍与负面影响无关。尼古丁戒断后，内侧前额叶皮层（mPFC）中的BDNF mRNA表达增加。令人惊讶的是，BDNF蛋白在mPFC中下降，但在背侧纹状体（DS）中升高。DS BDNF蛋白与持久性和维持性错误呈正相关，提示停药期间BDNF的mPFC-DS溢出。BDNF引起的谷氨酸释放和突触蛋白磷酸化在DS突触中减弱，但在伏隔核中增强，表明纹状体区域中BDNF信号的二分作用。在一起