Laboratory of Behavioral and Molecular Neuroscience, Department of Molecular Therapeutics, The Scripps Research Institute - Scripps Florida, Jupiter, FL 33458, USA.
Biochem Pharmacol. 2011 Oct 15;82(8):984-95. doi: 10.1016/j.bcp.2011.06.026. Epub 2011 Jun 29.
Tobacco smoking is one of the leading causes of disease and premature death in the United States. Nicotine is considered the major reinforcing component in tobacco smoke responsible for tobacco addiction. Nicotine acts in the brain through the neuronal nicotinic acetylcholine receptors (nAChRs). The predominant nAChR subtypes in mammalian brain are those containing α4 and β2 subunits. The α4β2 nAChRs, particularly those located in the mesoaccumbens dopamine pathway, play a key role in regulating the reinforcing properties of nicotine. Considering that twelve mammalian nAChR subunits have been cloned, it is likely that nAChRs containing subunits in addition to, or other than, α4 and β2 also play a role in the tobacco smoking habit. Consistent with this possibility, human genome-wide association studies have shown that genetic variation in the CHRNA5-CHRNA3-CHRNB4 gene cluster located in chromosome region 15q25, which encode the α5, α3 and β4 nAChR subunits, respectively, increases vulnerability to tobacco addiction and smoking-related diseases. Most recently, α5-containing nAChRs located in the habenulo-interpeduncular tract were shown to limit intravenous nicotine self-administration behavior in rats and mice, suggesting that deficits in α5-containing nAChR signaling in the habenulo-interpeduncular tract increases vulnerability to the motivational properties of nicotine. Finally, evidence suggests that nAChRs may also play a prominent role in controlling consumption of addictive drugs other than nicotine, including cocaine, alcohol, opiates and cannabinoids. The aim of the present review is to discuss recent preclinical findings concerning the identity of the nAChR subtypes that regulate self-administration of nicotine and other drugs of abuse.
吸烟是美国疾病和早逝的主要原因之一。尼古丁被认为是导致烟草成瘾的主要强化成分。尼古丁通过神经元烟碱型乙酰胆碱受体（nAChRs）在大脑中发挥作用。哺乳动物大脑中的主要 nAChR 亚型是包含α4 和β2 亚基的那些。α4β2 nAChRs，特别是位于中脑伏隔核多巴胺通路中的那些，在调节尼古丁的强化特性方面发挥着关键作用。考虑到已经克隆了 12 种哺乳动物 nAChR 亚基，除了α4 和β2 之外，还包含其他亚基的 nAChRs 或包含其他亚基的 nAChRs 可能在吸烟习惯中发挥作用。这一可能性与人类全基因组关联研究结果一致，该研究表明位于染色体 15q25 区域的 CHRNA5-CHRNA3-CHRNB4 基因簇中的遗传变异，分别编码α5、α3 和β4 nAChR 亚基，增加了对烟草成瘾和与吸烟相关疾病的易感性。最近，研究表明位于缰核-脚间核束中的包含α5 的 nAChRs 限制了大鼠和小鼠的静脉内尼古丁自我给药行为，这表明缰核-脚间核束中包含α5 的 nAChR 信号传导缺陷增加了对尼古丁动机特性的易感性。最后，有证据表明 nAChRs 可能在控制除尼古丁以外的成瘾药物的消耗方面也发挥着重要作用，包括可卡因、酒精、阿片类药物和大麻素。本综述的目的是讨论最近关于调节尼古丁和其他滥用药物自我给药的 nAChR 亚型的身份的临床前发现。
