Naeff B, Schlumpf M, Lichtensteiger W
Institute of Pharmacology, University of Zürich, Switzerland.
Brain Res Dev Brain Res. 1992 Aug 21;68(2):163-74. doi: 10.1016/0165-3806(92)90058-5.
The ontogeny of high affinity nicotinic cholinergic binding sites was studied in Long-Evans rat brain by in vitro autoradiography, using [3H]nicotine (10 nM) and cold (-)nicotine bitartrate to assess specificity. The first binding sites become detectable in spinal cord and caudal medulla oblongata at gestational day (GD) 12. Until GD 14, labelling spreads throughout lower brainstem, mesencephalon and parts of diencephalon, with higher densities in ventral areas (including the area of developing mesencephalic dopamine neurons). Matrix zones remain unlabelled. Receptor sites appear in the cerebellar anlage by GD 15, and in caudal caudate-putamen by GD 16. During development from late gestational to early postnatal stages, labelling is reduced in many lower brainstem areas and increases in forebrain, in particular in neocortex. Receptor density remains high in thalamus. In neocortex, nicotinic receptor sites are first seen in the subplate layer by GD 20. Labelling of this zone remains prominent until PN 14, when an additional band of increased receptor density is seen in cortical layers III/IV which contain high receptor levels in adulthood. At PN 27, the pattern has become similar to the adult one. The development of [3H]nicotine-binding sites in individual brain regions, with a general caudo-rostral gradient, accompanies cell differentiation and early synapse formation, e.g., in neocortex. The ontogenetic pattern differs in detail from that of muscarinic-cholinergic binding sites. The early presence of binding sites provides a basis for specific actions of nicotine on the fetal brain. As a consequence of the ontogenetic changes, different brain structures become targets for the action of this drug at different stages of development.
通过体外放射自显影技术，利用[3H]尼古丁（10 nM）和冷的（-）酒石酸尼古丁来评估特异性，研究了Long-Evans大鼠脑中高亲和力烟碱型胆碱能结合位点的个体发生。在妊娠第12天，脊髓和延髓尾侧首次可检测到结合位点。直到妊娠第14天，标记物扩散至整个脑桥下部、中脑和部分间脑，腹侧区域（包括发育中的中脑多巴胺神经元区域）密度更高。基质区无标记。妊娠第15天，小脑原基出现受体位点，妊娠第16天，尾状核-壳核尾部出现受体位点。在从妊娠晚期到出生后早期的发育过程中，许多脑桥下部区域的标记减少，而前脑尤其是新皮质的标记增加。丘脑的受体密度仍然很高。在新皮质中，妊娠第20天在板下层首次见到烟碱型受体位点。该区域的标记一直很明显，直到出生后第14天，此时在成年期受体水平较高的皮质第III/IV层出现另一受体密度增加带。出生后第27天，模式已与成年期相似。例如在新皮质中，各个脑区[3H]尼古丁结合位点的发育呈现一般的尾-头梯度，伴随着细胞分化和早期突触形成。个体发生模式在细节上与毒蕈碱型胆碱能结合位点不同。结合位点的早期存在为尼古丁对胎儿脑的特异性作用提供了基础。由于个体发生的变化，不同脑结构在发育的不同阶段成为该药物作用的靶点。
