Chen J F, Aloyo V J, Qin Z H, Weiss B
Department of Pharmacology, Medical College of Pennsylvania, Philadelphia 19129.
Neurochem Int. 1994 Oct;25(4):355-66. doi: 10.1016/0197-0186(94)90143-0.
The consequences of irreversibly-inhibiting D2 dopaminergic receptors on the expression of D1 and D2 dopamine receptor mRNAs and proenkephalin mRNA and on the levels of mu- and delta-opioid receptors in rat striatum were studied following single or repeated administration of the irreversibly-acting D2 dopamine receptor antagonist, fluphenazine-N-mustard (FNM). The density of dopamine and opioid receptors was determined by receptor autoradiography and the levels of the mRNA for the D1 and D2 dopamine receptors and proenkephalin were measured by in situ hybridization histochemistry. Repeated treatment of rats with FNM for 6 days produced more than 80% inhibition of D2 dopamine receptors but less than 25% inhibition of D1 dopamine receptors. Repeated treatment with FNM also resulted in statistically significant increases in D2 dopamine receptor mRNA but decreases in D1 dopamine receptor mRNA. In contrast, acute treatment with FNM for 3 h had no significant effects on D1 or D2 dopamine receptor mRNAs in striatum. An examination of the effects of FNM on the opioid system showed that repeated treatment with FNM for 6 days produced more than a 2-fold increase in the expression of proenkephalin mRNA in striatum. This was accompanied by significant decreases in mu- and delta-opioid receptors in striatum, mainly by reducing the size of the patch compartment of striatum. Acute treatment with FNM for 3 h produced small increases in proenkephalin mRNA and mu-opioid receptors in striatum but had no significant effects on delta-opioid receptors. These results suggest that persistent inhibition of D2 dopamine receptors differentially regulates the expression of D1 and D2 dopamine receptor mRNA in striatum, and that the magnitude, duration and interval of inhibiting dopaminergic transmission may be important factors in regulating dopamine receptor mRNA expression. These results also suggest that D2 dopamine antagonists indirectly down-regulate opioid receptors by increasing the expression of proenkephalin mRNA, thereby increasing enkephalin which, in turn, decreases opioid receptors in striatum.
在单次或重复给予不可逆作用的D2多巴胺受体拮抗剂氟奋乃静氮芥（FNM）后，研究了不可逆抑制D2多巴胺受体对大鼠纹状体中D1和D2多巴胺受体mRNA、前脑啡肽mRNA表达以及μ-和δ-阿片受体水平的影响。通过受体放射自显影术测定多巴胺和阿片受体的密度，并用原位杂交组织化学法测量D1和D2多巴胺受体及前脑啡肽的mRNA水平。用FNM对大鼠进行重复处理6天可产生超过80%的D2多巴胺受体抑制，但对D1多巴胺受体的抑制小于25%。用FNM重复处理还导致D2多巴胺受体mRNA有统计学意义的增加，但D1多巴胺受体mRNA减少。相比之下，用FNM急性处理3小时对纹状体中的D1或D2多巴胺受体mRNA没有显著影响。对FNM对阿片系统影响的检查表明，用FNM重复处理6天可使纹状体中前脑啡肽mRNA的表达增加2倍以上。这伴随着纹状体中μ-和δ-阿片受体的显著减少，主要是通过减小纹状体的斑块区室大小。用FNM急性处理3小时可使纹状体中前脑啡肽mRNA和μ-阿片受体有小幅增加，但对δ-阿片受体没有显著影响。这些结果表明，持续抑制D2多巴胺受体可差异性调节纹状体中D1和D2多巴胺受体mRNA的表达，并且抑制多巴胺能传递的程度、持续时间和间隔可能是调节多巴胺受体mRNA表达的重要因素。这些结果还表明，D2多巴胺拮抗剂通过增加前脑啡肽mRNA的表达间接下调阿片受体，从而增加脑啡肽，进而减少纹状体中的阿片受体。
