Weiss B, Davidkova G, Zhou L W, Zhang S P, Morabito M
Department of Pharmacology, MCP-Hahnemann School of Medicine, Allegheny University of the Health Sciences, Philadelphia, PA 19129, USA.
Neurochem Int. 1997 Oct;31(4):571-80. doi: 10.1016/s0197-0186(97)00025-9.
Drugs currently used to treat disorders of dopamine-mediated behaviors in the central nervous system are non-selective in that they interact not only with more than one isoform of dopamine receptor but also with receptors for other neurotransmitters. A new strategy to inhibit the actions of individual dopamine receptor subtypes is to inhibit the synthesis of the receptors through the use of oligonucleotides antisense to the transcripts encoding the different receptors. Earlier studies showed that oligodeoxynucleotides antisense to the D1 or D2 dopamine receptor messenger RNAs specifically inhibited the biological actions mediated by these individual isoforms of the dopamine receptor. However, these actions were relatively short-lasting. To determine whether one can achieve long-lasting inhibition of dopamine responses, while still taking advantage of the highly selective nature of an antisense strategy, an expression vector was employed that generates antisense RNA to the transcript encoding the D2 dopamine receptor. A single intrastriatal injection of this vector generated an antisense RNA to the D2 dopamine receptor, selectively reduced the levels of D2 dopamine receptors, and caused selective, long-term inhibition of behaviors mediated by D2 dopamine agonists. Such an antisense RNA strategy may find use in studying the function of dopaminergic receptors and in disorders associated with dopaminergic hyperactivity.
目前用于治疗中枢神经系统中多巴胺介导行为紊乱的药物是非选择性的，因为它们不仅与多种多巴胺受体亚型相互作用，还与其他神经递质的受体相互作用。抑制单个多巴胺受体亚型作用的一种新策略是通过使用与编码不同受体的转录本互补的寡核苷酸来抑制受体的合成。早期研究表明，与D1或D2多巴胺受体信使核糖核酸互补的寡脱氧核苷酸能特异性抑制这些多巴胺受体亚型介导的生物学作用。然而，这些作用持续时间相对较短。为了确定是否能在利用反义策略高度选择性的同时实现对多巴胺反应的长期抑制，使用了一种表达载体，该载体可产生与编码D2多巴胺受体的转录本互补的反义RNA。向纹状体内单次注射这种载体可产生与D2多巴胺受体互补的反义RNA，选择性降低D2多巴胺受体水平，并导致由D2多巴胺激动剂介导的行为受到选择性长期抑制。这种反义RNA策略可能在研究多巴胺能受体的功能以及与多巴胺能功能亢进相关的疾病中得到应用。
