Ariano M A, Engber T M, Susel Z, Chase T N
Department of Anatomy & Neurobiology, University of Vermont College of Medicine, Burlington 05405.
Exp Neurol. 1991 Apr;112(1):112-8. doi: 10.1016/0014-4886(91)90120-2.
Striatal dopamine deafferentation has previously been found to diminish D1 dopamine receptor clustering in association with striatal cyclic AMP-immunoreactive neurons. The administration of the dopamine precursor levodopa (L-DOPA) to animals with unilaterally placed 6-hydroxydopamine nigrostriatal tract lesions now appears to partially restore D1 dopamine receptor morphochemical organization in the deafferented striatum. Differences in the mode of levodopa delivery produced dissimilar D1 recovery patterns. The prodrug, L-DOPA methyl ester, was administered in combination with the peripheral aromatic amino acid decarboxylase inhibitor, benserazide, to achieve consistent plasma levels of the dopamine precursor. Continuous levodopa infusion (100 mg/kg/day, ip) led to a slight dorsomedial reassociation of D1 receptor binding sites with the postsynaptic cyclic AMP transduction system on the deafferented side. In contrast, intermittent levodopa therapy (50 mg/kg, ip, bid) produced a noticeable down regulation of the dopamine receptor system and also contributed to some region-specific recovery of the morphochemical pattern of D1 receptor binding site reaggregation with the postsynaptic cyclic AMP second messenger transduction system. These results suggest that exogenous levodopa replacement therapy desensitizes striatal D1 dopamine receptors. This was substantiated using image analysis of densitometric histograms. The down regulation of D1 receptors is dependent on the levodopa treatment regimen employed. Our findings provide a potential morphological basis for the behavioral desensitization shown previously in response to chronic, intermittent levodopa administration.
此前已发现，纹状体多巴胺去传入会减少与纹状体环磷酸腺苷免疫反应性神经元相关的D1多巴胺受体聚集。给单侧放置6-羟基多巴胺黑质纹状体束损伤的动物施用多巴胺前体左旋多巴（L-DOPA），现在似乎能部分恢复去传入纹状体中D1多巴胺受体的形态化学组织。左旋多巴给药方式的差异产生了不同的D1恢复模式。将前药L-多巴甲酯与外周芳香族氨基酸脱羧酶抑制剂苄丝肼联合使用，以实现多巴胺前体的血浆水平一致。持续输注左旋多巴（100mg/kg/天，腹腔注射）导致去传入侧D1受体结合位点与突触后环磷酸腺苷转导系统出现轻微的背内侧重新结合。相比之下，间歇性左旋多巴治疗（50mg/kg，腹腔注射，每日两次）导致多巴胺受体系统明显下调，也有助于D1受体结合位点与突触后环磷酸腺苷第二信使转导系统的形态化学模式在某些区域特异性恢复。这些结果表明，外源性左旋多巴替代疗法会使纹状体D1多巴胺受体脱敏。使用光密度直方图的图像分析证实了这一点。D1受体的下调取决于所采用的左旋多巴治疗方案。我们的研究结果为先前对慢性间歇性左旋多巴给药所表现出的行为脱敏提供了潜在的形态学基础。
