Azam L, Chen Y, Leslie F M
Department of Biology, University of Utah, 257 South 1400 East, Salt Lake City, UT 84112, USA.
Neuroscience. 2007 Feb 23;144(4):1347-60. doi: 10.1016/j.neuroscience.2006.11.011. Epub 2006 Dec 29.
We have combined anatomical and functional methodologies to provide a comprehensive analysis of the properties of nicotinic acetylcholine receptors (nAChRs) on developing dopamine (DA) neurons of Sprague-Dawley rats. Double-labeling in situ hybridization was used to examine the expression of nAChR subunit mRNAs within developing midbrain DA neurons. As brain maturation progressed there was a change in the pattern of subunit mRNA expression within DA neurons, such that alpha3 and alpha4 subunits declined and alpha6 mRNA increased. Although there were strong similarities in subunit mRNA expression in substantia nigra (SNc) and ventral tegmental area (VTA), there was higher expression of alpha4 mRNA in SNc than VTA at gestational day (G) 15, and of alpha5, alpha6 and beta3 mRNAs during postnatal development. Using a superfusion neurotransmitter release paradigm to functionally characterize nicotine-stimulated release of [(3)H]DA from striatal slices, the properties of the nAChRs on DA terminals were also found to change with age. Functional nAChRs were detected on striatal terminals at G18. There was a decrease in maximal release in the first postnatal week, followed by an increase in nicotine efficacy and potency during the second and third postnatal weeks. In the transition from adolescence (postnatal days (P) 30 and 40) to adulthood, there was a complex pattern of functional maturation of nAChRs in ventral, but not dorsal, striatum. In males, but not females, there were significant changes in both nicotine potency and efficacy during this developmental period. These findings suggest that nAChRs may play critical functional roles throughout DA neuronal maturation.
我们结合了解剖学和功能方法，对斯普拉格-道利大鼠发育中的多巴胺（DA）神经元上烟碱型乙酰胆碱受体（nAChRs）的特性进行了全面分析。采用双标记原位杂交技术检测发育中的中脑DA神经元内nAChR亚基mRNA的表达。随着脑成熟的进展，DA神经元内亚基mRNA的表达模式发生了变化，α3和α4亚基减少，而α6 mRNA增加。虽然黑质（SNc）和腹侧被盖区（VTA）中亚基mRNA的表达有很强的相似性，但在妊娠第15天，SNc中α4 mRNA的表达高于VTA，在出生后发育过程中，α5、α6和β3 mRNA的表达也是如此。利用灌流神经递质释放模式从功能上表征尼古丁刺激纹状体切片中[³H]DA的释放，发现DA终末上nAChRs的特性也随年龄而变化。在第18天在纹状体终末检测到功能性nAChRs。出生后第一周最大释放量减少，随后在出生后第二周和第三周尼古丁的效力和效能增加。从青春期（出生后第30天和40天）到成年期的转变过程中，腹侧纹状体而非背侧纹状体中nAChRs的功能成熟模式复杂。在这个发育阶段，雄性而非雌性的尼古丁效力和效能都有显著变化。这些发现表明，nAChRs可能在整个DA神经元成熟过程中发挥关键的功能作用。
