Division of Pharmacology and Toxicology, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, FIN-00014 Helsinki, Finland.
Neurosci Lett. 2011 Mar 17;491(2):108-12. doi: 10.1016/j.neulet.2011.01.015. Epub 2011 Jan 11.
Neuronal changes induced by chronic nicotine in the brain dopaminergic circuits are thought to lead to compulsive nicotine use. When nicotine is given to mice chronically in their drinking water, its intake and effects mimic human smoking. Previously, we have reported that this treatment in mice induces several neurochemical and behavioural changes that are associated with nicotine addiction. Here we studied the effects of chronic oral nicotine treatment and nicotine treatment cessation on two well-characterised markers of neuronal plasticity, brain-derived neurotrophic factor (BDNF) and phosphorylated cAMP-responsive element-binding protein (pCREB), in several dopaminergic brain areas. BDNF levels were not altered by chronic nicotine treatment, but they were significantly increased in the nucleus accumbens (NAc) after 24h and 29 days of nicotine abstinence and in the ventral tegmental area (VTA) and substantia nigra after 29 days of nicotine abstinence. These findings suggest that nicotine abstinence promotes long-lasting neuroadaptations in dopaminergic neurocircuits by inducing BDNF production. Withdrawal from chronic nicotine treatment oppositely affected pCREB levels in the NAc and in the VTA. Thus, in the NAc, the pCREB levels were significantly elevated and in the VTA significantly decreased as compared with the pCREB levels during the nicotine treatment. These alterations could be compensatory and related to increased dopaminergic signalling during nicotine treatment. In conclusion, the current results suggest the involvement of BDNF- and CREB-related neuronal processes in nicotine-induced neurochemical, behavioural, and neuroplastic changes in dopaminergic neurocircuits.
慢性尼古丁在大脑多巴胺能回路中引起的神经元变化被认为导致强迫性使用尼古丁。当尼古丁在老鼠的饮用水中被长期给予时，其摄入和效果模拟了人类吸烟。以前，我们已经报道过这种在老鼠中的治疗方法会引起几种与尼古丁成瘾相关的神经化学和行为变化。在这里，我们研究了慢性口服尼古丁治疗和尼古丁治疗停止对两种经过充分表征的神经元可塑性标志物，脑源性神经营养因子（BDNF）和磷酸化 cAMP 反应元件结合蛋白（pCREB）在几个多巴胺能脑区的影响。慢性尼古丁处理并没有改变 BDNF 水平，但在 24 小时和 29 天的尼古丁戒断后，在伏隔核（NAc）中以及在 29 天的尼古丁戒断后，在腹侧被盖区（VTA）和黑质中，BDNF 水平显著增加。这些发现表明，尼古丁戒断通过诱导 BDNF 产生促进多巴胺能神经回路的持久神经适应。慢性尼古丁治疗的戒断对 NAc 和 VTA 中的 pCREB 水平产生了相反的影响。因此，与尼古丁处理期间的 pCREB 水平相比，在 NAc 中 pCREB 水平显著升高，而在 VTA 中 pCREB 水平显著降低。这些改变可能是代偿性的，与尼古丁处理期间多巴胺能信号的增加有关。总之，目前的结果表明，BDNF 和 CREB 相关的神经元过程参与了尼古丁诱导的多巴胺能神经回路中的神经化学、行为和神经可塑性变化。
