Mental Illness Research, Education and Clinical Center, Veterans Administration Puget Sound Health Care System Seattle, WA, USA ; Department of Psychiatry and Behavioral Sciences, University of Washington Seattle, WA, USA.
Front Pharmacol. 2012 Oct 22;3:184. doi: 10.3389/fphar.2012.00184. eCollection 2012.
Noradrenergic neurons in the locus coeruleus (LC) are significantly reduced in Parkinson's disease (PD) and the LC exhibits neuropathological changes early in the disease process. It has been suggested that a loss of LC neurons can enhance the susceptibility of dopaminergic neurons to damage. To determine if LC noradrenergic innervation protects dopaminergic neurons from damage, the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was administered to adult male C57Bl/6 mice 3 days after bilateral LC administration of 6-hydroxydopamine (6OHDA), a time when there is a significant reduction in LC neuronal number and innervation to forebrain regions. To assess if LC loss can affect dopaminergic loss four groups of animals were studied: control, 6OHDA, MPTP, and 6OHDA + MPTP; animals sacrificed 3 weeks after MPTP administration. The number of dopaminergic neurons in the substantia nigra (SN) and ventral tegmental area (VTA), and noradrenergic neurons in the LC were determined. Catecholamine levels in striatum were measured by high-pressure liquid chromatography. The loss of LC neurons did not affect the number of dopaminergic neurons in the SN and VTA compared to control; however, LC 6OHDA significantly reduced striatal dopamine (DA; 29% reduced) but not norepinephrine (NE) concentration. MPTP significantly reduced SN and VTA neuronal number and DA concentration in the striatum compared to control; however, there was not a correlation of striatal DA concentration with SN or VTA neuronal number. Administration of 6OHDA prior to MPTP did not enhance MPTP-induced damage despite an effect of LC loss on striatal DA concentration. However, the loss of LC neurons before MPTP resulted now in a correlation between SN and VTA neuronal number to striatal DA concentration. These results demonstrate that the loss of either LC or DA neurons can affect the function of each others systems, indicating the importance of both the noradrenergic and dopaminergic system in PD.
蓝斑核（LC）中的去甲肾上腺素能神经元在帕金森病（PD）中显著减少，并且 LC 在疾病过程的早期就表现出神经病理学变化。有人认为 LC 神经元的丧失可以增强多巴胺能神经元对损伤的易感性。为了确定 LC 去甲肾上腺素能神经支配是否能保护多巴胺能神经元免受损伤，将多巴胺神经毒素 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）给予成年雄性 C57Bl/6 小鼠，在双侧 LC 给予 6-羟多巴胺（6OHDA）后 3 天，此时 LC 神经元数量和对前脑区域的神经支配显著减少。为了评估 LC 丧失是否会影响多巴胺能神经元的丧失，研究了四组动物：对照组、6OHDA 组、MPTP 组和 6OHDA+MPTP 组；在 MPTP 给药后 3 周处死动物。通过高效液相色谱法测定黑质（SN）和腹侧被盖区（VTA）中的多巴胺能神经元数量和 LC 中的去甲肾上腺素能神经元数量。纹状体中的儿茶酚胺水平通过高压液相色谱法测量。与对照组相比，LC 神经元的丧失并不影响 SN 和 VTA 中的多巴胺能神经元数量；然而，LC 6OHDA 显著降低纹状体多巴胺（DA；减少 29%）但不降低去甲肾上腺素（NE）浓度。MPTP 显著降低 SN 和 VTA 神经元数量和纹状体中的 DA 浓度与对照组相比；然而，纹状体 DA 浓度与 SN 或 VTA 神经元数量之间没有相关性。尽管 LC 丧失对纹状体 DA 浓度有影响，但在给予 MPTP 之前给予 6OHDA 并不能增强 MPTP 诱导的损伤。然而，MPTP 之前 LC 神经元的丧失现在导致 SN 和 VTA 神经元数量与纹状体 DA 浓度之间存在相关性。这些结果表明，LC 或 DA 神经元的丧失都可以影响彼此系统的功能，表明去甲肾上腺素能和多巴胺能系统在 PD 中的重要性。
