Tepper J M, Sun B C, Martin L P, Creese I
Center for Molecular and Behavioral Neuroscience, Aidekman Research Center, Program in Cellular and Molecular Biodynamics, Rutgers, The State University of New Jersey, Newark, New Jersey 07102, USA.
J Neurosci. 1997 Apr 1;17(7):2519-30. doi: 10.1523/JNEUROSCI.17-07-02519.1997.
Two different 19-mer antisense oligodeoxynucleotides complementary to the initial coding regions of dopamine D2 or D3 receptor mRNA were infused unilaterally into the substantia nigra of rats for 3-6 d to suppress synthesis of D2 and/or D3 receptors on substantia nigra dopaminergic neurons, thereby producing specific reductions of D2 and/or D3 receptors. Autoradiographic receptor binding revealed that D2 and D3 antisense oligodeoxynucleotides specifically and significantly reduced D2 or D3 binding in the ipsilateral substantia nigra, respectively, without affecting dopamine receptor binding in the neostriatum. Either D2 or D3 antisense oligodeoxynucleotides greatly attenuated the ability of apomorphine to inhibit dopaminergic neurons in vivo, an effect that was potentiated by simultaneous administration of D2 and D3 antisenses. Despite these effects, neither the rate nor the pattern of spontaneous activity of antisense-treated nigrostriatal neurons differed from those in the control groups. The proportion of antidromic responses consisting of full spikes from antisense-treated rats was significantly greater, and the mean antidromic threshold was significantly lower than in controls, indicating that autoreceptor knockdown increased both somatodendritic and terminal excitability. These data demonstrate that selective reduction of specific dopamine receptor subtypes by antisense infusion can be effected in vivo, and that nigrostriatal neurons express both D2 and D3 autoreceptors at their somatodendritic and axon terminal regions. Although the somatodendritic and terminal autoreceptors modulate dendritic and terminal excitability, respectively, the interaction of endogenously released dopamine with somatodendritic autoreceptors does not appear to exert a significant effect on spontaneous activity in anesthetized rats.
将两条分别与多巴胺D2或D3受体mRNA初始编码区互补的19聚体反义寡脱氧核苷酸单侧注入大鼠黑质，持续3 - 6天，以抑制黑质多巴胺能神经元上D2和/或D3受体的合成，从而特异性降低D2和/或D3受体。放射自显影受体结合显示，D2和D3反义寡脱氧核苷酸分别特异性且显著降低同侧黑质中的D2或D3结合，而不影响新纹状体中的多巴胺受体结合。D2或D3反义寡脱氧核苷酸均可大大减弱阿扑吗啡在体内抑制多巴胺能神经元的能力，同时给予D2和D3反义寡核苷酸可增强此效应。尽管有这些作用，但反义处理的黑质纹状体神经元的自发活动速率和模式与对照组均无差异。反义处理大鼠的由全峰电位组成的逆向反应比例显著更高，且平均逆向阈值显著低于对照组，表明自身受体敲低增加了树突体和终末的兴奋性。这些数据表明，通过反义注入可在体内选择性降低特定多巴胺受体亚型，且黑质纹状体神经元在其树突体和轴突终末区域均表达D2和D3自身受体。虽然树突体和终末自身受体分别调节树突和终末的兴奋性，但内源性释放的多巴胺与树突体自身受体的相互作用似乎对麻醉大鼠的自发活动没有显著影响。
