Harden D G, Grace A A
Department of Neuroscience, University of Pittsburgh, Pennsylvania 15260, USA.
J Neurosci. 1995 Sep;15(9):6157-66. doi: 10.1523/JNEUROSCI.15-09-06157.1995.
The administration of L-dihydroxyphenylalanine (L-DOPA) to patients with Parkinson's disease is known to produce acute effects that include the reduction of rigidity as well as delayed therapeutic actions involving the resumption of complex motor behavior. In order to examine the potential role of dopamine (DA) cell activity in mediating these responses, the effects of acute and repeated L-DOPA administration on the electrophysiological activity of the residual dopamine (DA) neurons were examined in rats that had received partial 6-hydroxydopamine (6-OHDA)-induced DA lesions. DA cell activity was assessed along three dimensions: (1) the relative proportion of DA neurons exhibiting spontaneous spike firing, (2) their basal firing rate, and (3) their firing pattern. Following 6-OHDA-induced DA depletion, rats were treated for 1 month with saline or L-DOPA. In addition, rats from each group received either an acute injection of L-DOPA or saline on the day of recording. In rats receiving repeated saline treatment, the DA neurons recorded following acute L-DOPA administration were firing at significantly slower basal firing rates and exhibited less burst firing when compared to saline-pretreated rats given acute saline. In contrast, DA cells recorded from rats that had received repeated L-DOPA administration for 4 weeks followed by an acute saline injection did not exhibit any significant differences from DA cells of intact control rats with respect to basal firing rate or firing pattern; however, there was a substantial increase in the proportion of DA neurons exhibiting spontaneous spike firing after correcting for 6-OHDA-induced cell loss. In addition, in rats receiving repeated L-DOPA treatment, the DA cells recorded following acute administration of L-DOPA showed significantly less of a reduction in firing rate when compared to the cells recorded following acute L-DOPA in the saline treatment group. These results show that: (1) acute L-DOPA administration appears to exert its actions by DA autoreceptor stimulation, whereas (2) repeated L-DOPA administration increases the proportion of spontaneously active DA neurons in partially lesioned rats. As a result, repeated L-DOPA administration would be expected to cause an increase in spike-dependent DA release as a consequence of the greater proportion of DA cells showing spontaneous activity. This may be the major factor underlying the delayed therapeutic benefits of L-DOPA therapy in the treatment of Parkinson's disease.
已知给帕金森病患者服用L-二羟基苯丙氨酸（L-DOPA）会产生急性效应，包括减轻僵硬以及涉及恢复复杂运动行为的延迟治疗作用。为了研究多巴胺（DA）细胞活动在介导这些反应中的潜在作用，在接受部分6-羟基多巴胺（6-OHDA）诱导的DA损伤的大鼠中，研究了急性和重复给予L-DOPA对残余多巴胺（DA）神经元电生理活动的影响。从三个维度评估DA细胞活动：（1）表现出自发放电的DA神经元的相对比例，（2）它们的基础放电率，以及（3）它们的放电模式。在6-OHDA诱导DA耗竭后，大鼠用生理盐水或L-DOPA治疗1个月。此外，每组大鼠在记录当天接受一次急性L-DOPA或生理盐水注射。在接受重复生理盐水治疗的大鼠中，与给予急性生理盐水的生理盐水预处理大鼠相比，急性给予L-DOPA后记录的DA神经元基础放电率明显较慢，爆发性放电较少。相比之下，接受重复L-DOPA给药4周后再急性注射生理盐水的大鼠记录的DA细胞，在基础放电率或放电模式方面与完整对照大鼠的DA细胞没有任何显著差异；然而，在校正6-OHDA诱导的细胞损失后，表现出自发放电的DA神经元比例大幅增加。此外，在接受重复L-DOPA治疗的大鼠中，与生理盐水治疗组急性给予L-DOPA后记录的细胞相比，急性给予L-DOPA后记录的DA细胞放电率降低明显较少。这些结果表明：（1）急性给予L-DOPA似乎通过DA自身受体刺激发挥作用，而（2）重复给予L-DOPA会增加部分损伤大鼠中自发活动的DA神经元比例。因此，由于显示自发活动的DA细胞比例更高，预计重复给予L-DOPA会导致与动作电位相关的DA释放增加。这可能是L-DOPA治疗帕金森病延迟治疗益处的主要因素。
