Department of Pharmaceutical Sciences, College of Pharmacy, South Dakota State University, Box 2202C, Avera Health and Science Center (SAV 265), Brookings, SD 57007, USA.
Alcohol. 2013 Jun;47(4):299-307. doi: 10.1016/j.alcohol.2013.02.003. Epub 2013 Apr 17.
Chronic administration of ethanol induces persistent accumulation of ΔFosB, an important transcription factor, in the midbrain dopamine system. This process underlies the progression to addiction. Previously, we have shown that cytisine, a neuronal nicotinic acetylcholine receptor (nAChR) partial agonist, reduces various ethanol-drinking behaviors and ethanol-induced striatal dopamine function. However, the effects of cytisine on chronic ethanol drinking and ethanol-induced up-regulation of striatal ΔFosB are not known. Therefore, we examined the effects of cytisine on chronic voluntary ethanol consumption and associated striatal ΔFosB up-regulation in C57BL/6J mice using behavioral and biochemical methods. Following the chronic voluntary consumption of 15% (v/v) ethanol under a 24-h two-bottle choice intermittent access (IA; 3 sessions/week) or continuous access (CA; 24 h/d and 7 d/week) paradigm, mice received repeated intraperitoneal injections of saline or cytisine (0.5 or 3.0 mg/kg). Ethanol and water intake were monitored for 24 h post-treatment. Pretreatment with cytisine (0.5 or 1.5 mg/kg) significantly reduced ethanol consumption and preference in both paradigms at 2 h and 24 h post-treatment. The ΔFosB levels in the ventral and dorsal striatum were determined by Western blotting 18-24 h after the last point of ethanol access. In addition, cytisine (0.5 mg/kg) significantly attenuated up-regulation of ΔFosB in the ventral and dorsal striatum following chronic ethanol consumption in IA and CA paradigms. The results indicate that cytisine modulates chronic voluntary ethanol consumption and reduces ethanol-induced up-regulation of striatal ΔFosB. Further, the data suggest a critical role of nAChRs in chronic ethanol-induced neurochemical adaptations associated with ethanol addiction.
慢性给予乙醇会导致中脑多巴胺系统中ΔFosB 的持续积累，ΔFosB 是一种重要的转录因子。这个过程是成瘾进展的基础。此前，我们已经表明，烟碱（一种神经元烟碱型乙酰胆碱受体（nAChR）部分激动剂）可减少各种乙醇饮用行为和乙醇诱导的纹状体多巴胺功能。然而，烟碱对慢性乙醇饮用和乙醇诱导的纹状体ΔFosB 上调的影响尚不清楚。因此，我们使用行为和生化方法，研究了烟碱对 C57BL/6J 小鼠慢性自愿性乙醇消耗和相关纹状体ΔFosB 上调的影响。在 24 小时双瓶选择间歇性摄入（IA；每周 3 次）或连续摄入（CA；24 小时/天和 7 天/周）范式下，慢性自愿摄入 15%（v/v）乙醇后，小鼠接受了盐水或烟碱（0.5 或 3.0mg/kg）的重复腹腔注射。在治疗后 24 小时监测乙醇和水的摄入量。在治疗后 2 小时和 24 小时，烟碱（0.5 或 1.5mg/kg）预处理显著减少了两种范式中的乙醇消耗和偏好。在最后一次接触乙醇后的 18-24 小时，通过 Western 印迹测定腹侧和背侧纹状体中的 ΔFosB 水平。此外，烟碱（0.5mg/kg）在 IA 和 CA 范式下，显著减弱了慢性乙醇摄入后腹侧和背侧纹状体中 ΔFosB 的上调。结果表明，烟碱调节慢性自愿性乙醇消耗，并减少乙醇诱导的纹状体 ΔFosB 上调。此外，数据表明 nAChR 在与乙醇成瘾相关的慢性乙醇诱导的神经化学适应中起着关键作用。
