Cole D G, Growdon J H, DiFiglia M
Laboratory of Cellular Neurobiology, Massachusetts General Hospital, Charlestown 02129.
Exp Neurol. 1993 Apr;120(2):223-32. doi: 10.1006/exnr.1993.1057.
It is controversial whether levodopa (L-DOPA) therapy in the early stages of Parkinson's disease (PD) predisposes to later complications. Partial lesions of the substantia nigra (SN) in rat provide a model of the early stages of PD. We have investigated the potential effects of L-DOPA in early PD by analyzing its influence on the activity of the immediate early gene Fos in the partially lesioned rat. Fos has been used to examine neuronal response to a variety of stimuli in vivo, and L-DOPA is known to increase Fos-like immunoreactivity (FosLI) in striatal neurons after complete lesions of the SN. To determine its effects following partial lesions, we analyzed FosLI in rats given L-DOPA after partial (50-90%) and complete (> 90%) unilateral 6-hydroxydopamine lesions of the SN. Behavioral responses to intraperitoneal injections of apomorphine and amphetamine during life and cell counts of neurons in the SN with tyrosine hydroxylase-like immunoreactivity established the extent of nigral cell loss. FosLI was present in the striatum on the lesioned side predominantly laterally in rats with partial lesions and throughout in rats with complete lesions. Sections counterstained with toluidine blue revealed that only medium-sized striatal neurons displayed FosLI. Prominent FosLI was also found in the ipsilateral piriform cortex and amygdala in both groups and additionally in the ipsilateral zona incerta in the complete group. Therefore L-DOPA induces Fos in the striatum after partial as well as complete SN lesions. This result suggests that L-DOPA-induced Fos expression may occur in the early stages of PD and may not require dopamine receptor upregulation, which is believed to develop only in completely lesioned rats and in later stages of PD. The unexpected induction of Fos activity in brain regions besides the striatum suggests that L-DOPA therapy in patients with PD may have more widespread effects than previously anticipated. Since Fos is known to regulate gene transcription, potential alterations in its activity may contribute to the complications associated with L-DOPA therapy in PD.
左旋多巴（L-DOPA）治疗帕金森病（PD）早期是否会引发后期并发症存在争议。大鼠黑质（SN）部分损伤可提供PD早期的模型。我们通过分析L-DOPA对部分损伤大鼠即刻早期基因Fos活性的影响，研究了其在PD早期的潜在作用。Fos已被用于检测体内神经元对多种刺激的反应，并且已知在SN完全损伤后，L-DOPA可增加纹状体神经元中Fos样免疫反应性（FosLI）。为了确定其在部分损伤后的作用，我们分析了在SN单侧进行部分（50 - 90%）和完全（> 90%）6-羟基多巴胺损伤后给予L-DOPA的大鼠的FosLI。通过对腹腔注射阿扑吗啡和苯丙胺的行为反应以及对SN中具有酪氨酸羟化酶样免疫反应性的神经元进行细胞计数，确定了黑质细胞丢失的程度。在部分损伤的大鼠中，FosLI主要出现在损伤侧纹状体的外侧，而在完全损伤的大鼠中则遍布整个纹状体。用甲苯胺蓝复染的切片显示，只有中等大小的纹状体神经元显示出FosLI。在两组大鼠的同侧梨状皮质和杏仁核中也发现了显著的FosLI，在完全损伤组中还额外在同侧未定带中发现了FosLI。因此，在SN部分损伤以及完全损伤后，L-DOPA均可诱导纹状体中的Fos。这一结果表明，L-DOPA诱导的Fos表达可能发生在PD早期，并且可能不需要多巴胺受体上调，而多巴胺受体上调被认为仅在完全损伤的大鼠和PD后期才会出现。纹状体以外脑区Fos活性的意外诱导表明，PD患者的L-DOPA治疗可能具有比先前预期更广泛的影响。由于已知Fos可调节基因转录，其活性的潜在改变可能导致与PD中L-DOPA治疗相关的并发症。
