Strömberg I, Kehr J, Andbjer B, Fuxe K
Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Exp Neurol. 2000 Jul;164(1):154-65. doi: 10.1006/exnr.2000.7421.
Grafting of ventral mesencephalic tissue in Parkinson's disease results in a partial dopaminergic reinnervation of host brain and dopamine agonist-induced rotational behavior is not completely reversed. To study a possible malfunction of the grafts, extracellular recordings with local applications of quinpirole were utilized and the neurophysiological results showed that a normalization of the upregulated dopamine D2 receptor supersensitivity occurred in reinnervated areas of the host striatum as well as in noninnervated areas remote from the graft innervation. Furthermore, the inhibitory effects on striatal nerve cell firing rate by the D1 receptor agonist SKF 81297 were not different in noninnervated or reinnervated areas of the striatum compared to the control side as seen from the dose-response curves. However, spontaneous striatal neuronal firing was significantly upregulated in noninnervated areas, while it was normalized in areas reached by graft-derived nerve fibers. Dual-probe microdialysis studying potassium-evoked glutamate release revealed that there was no difference in extracellular glutamate levels measured within or lateral to graft dopamine reinnervation. Thus, the upregulated spontaneous activity was not due to a difference in extracellular glutamate levels. The remaining rotational behavior seen after grafting was studied and recordings were performed in the striatum following systemic injection of the D1/D2 agonist apomorphine. The results revealed that apomorphine at the dose used to elicit turning behavior (0.05 mg/kg) still affected striatal neurons in noninnervated areas, while no effect was detected in reinnervated areas and in the intact side. However, a lower dose of apomorphine (0.005 mg/kg) showed no effects on striatal firing in graft reinnervated striata but only after dopamine depletion. In conclusion, the D2 supersensitivity is downregulated in graft-reinnervated striatum as well as in striatal areas lateral to the reinnervation when using selective D2 agonists, but the downregulation is not completely normalized when studying combined effects of D1/D2 agonists. Furthermore, the striatal neurons were firing significantly faster in noninnervated areas compared to reinnervated areas of graft-reinnervated striatum, which was most likely not due to changes in the glutamatergic input.
帕金森病患者移植腹侧中脑组织可使宿主脑部分多巴胺能神经再支配，且多巴胺激动剂诱导的旋转行为并未完全逆转。为研究移植组织可能存在的功能异常，采用局部应用喹吡罗的细胞外记录法，神经生理学结果显示，宿主纹状体再支配区域以及远离移植神经支配的未支配区域中，上调的多巴胺D2受体超敏反应均恢复正常。此外，从剂量反应曲线来看，与对照侧相比，纹状体未支配或再支配区域中，D1受体激动剂SKF 81297对纹状体神经细胞放电率的抑制作用并无差异。然而，未支配区域的纹状体神经元自发放电显著上调，而移植神经纤维所及区域的自发放电则恢复正常。双探针微透析研究钾离子诱发的谷氨酸释放发现，在移植多巴胺再支配区域内或其外侧测得的细胞外谷氨酸水平并无差异。因此，自发放电上调并非由细胞外谷氨酸水平差异所致。研究了移植后剩余的旋转行为，并在全身注射D1/D2激动剂阿扑吗啡后对纹状体进行记录。结果显示，用于引发旋转行为的剂量（0.05 mg/kg）的阿扑吗啡仍会影响未支配区域的纹状体神经元，而在再支配区域和完整侧未检测到影响。然而，较低剂量的阿扑吗啡（0.005 mg/kg）仅在多巴胺耗竭后才对移植再支配的纹状体的放电无影响。总之，使用选择性D2激动剂时，移植再支配的纹状体以及再支配区域外侧的纹状体区域中，D2超敏反应下调，但研究D1/D2激动剂的联合作用时，下调并未完全恢复正常。此外，与移植再支配纹状体的再支配区域相比，未支配区域的纹状体神经元放电明显更快，这很可能不是由于谷氨酸能输入的变化所致。
