Gan Lu, Falzone Tomas L, Zhang Kehong, Rubinstein Marcelo, Baldessarini Ross J, Tarazi Frank I
Mailman Research Center, McLean Division of Massachusetts General Hospital, Belmont, MA 02478, USA.
J Mol Neurosci. 2004;22(3):167-78. doi: 10.1385/JMN:22:3:167.
Expression of dopamine ([DA] D1 and D2) and glutamate ([Glu], (N-methyl-d-aspartic acid [NMDA], alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA], and kanaic acid [KA]) receptor types were analyzed autoradiographically in forebrain regions of D4 receptor knockout mice and their wild-type controls. Selective radioligand binding to D4 receptors was virtually absent in D4 receptor knockout mouse brain in contrast to significant specific D4 binding in forebrain tissue of wild-type controls. Labeling of D1 receptors was significantly increased in nucleus accumbens (NAc; 39%) and caudate putamen (CPu; 42%) of D4-knockout mice vs wild-type controls. In addition, NMDA receptor labeling was significantly increased in NAc (31%), CPu (40%), and hippocampal CA1 (21%) and CA3 (25%) regions of D4 knockouts vs wild-type controls. No changes in D2, AMPA or KA receptors were found. The findings suggest that D1, D4, and NMDA receptors might interact functionally and that developmental absence of D4 receptors might trigger compensatory mechanisms that enhance expression of D1 receptors in NAc and CPu, and NMDA receptors in NAc, CPu, and hippocampus. The findings also encourage cautious interpretation of results in knockout mice with targeted absence of specific genes, as complex adaptive changes not directly related to the missing gene might contribute to physiological and behavioral responses.
采用放射自显影法分析了D4受体基因敲除小鼠及其野生型对照前脑区域中多巴胺（[DA] D1和D2）和谷氨酸（[Glu]，N-甲基-D-天冬氨酸[NMDA]、α-氨基-3-羟基-5-甲基-4-异恶唑丙酸[AMPA]和海人藻酸[KA]）受体类型的表达。与野生型对照前脑组织中显著的特异性D4结合相比，D4受体基因敲除小鼠脑内几乎不存在与D4受体的选择性放射性配体结合。与野生型对照相比，D4基因敲除小鼠伏隔核（NAc；39%）和尾壳核（CPu；42%）中D1受体的标记显著增加。此外，与野生型对照相比，D4基因敲除小鼠的NAc（31%）、CPu（40%）、海马CA1区（21%）和CA3区（25%）中NMDA受体标记显著增加。未发现D2、AMPA或KA受体有变化。这些发现表明，D1、D4和NMDA受体可能在功能上相互作用，并且D4受体的发育缺失可能触发补偿机制，增强NAc和CPu中D1受体以及NAc、CPu和海马中NMDA受体的表达。这些发现还促使人们谨慎解读特定基因靶向缺失的基因敲除小鼠的实验结果，因为与缺失基因无直接关系的复杂适应性变化可能会影响生理和行为反应。
