Li Yong, Jiao Qian, Du Xixun, Bi Mingxia, Han Shuaishuai, Jiao Lingling, Jiang Hong
Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines, Physiology, Qingdao University Medical College, Qingdao University, Qingdao, China.
Front Cell Neurosci. 2018 Aug 8;12:241. doi: 10.3389/fncel.2018.00241. eCollection 2018.
Parkinson's disease (PD) is characterized not only by typical motor symptoms, but also by nonmotor symptoms in the early stages. In addition to the loss of dopaminergic (DAergic) neurons, progressive degenerations of noradrenergic (NA) and serotonergic (5-HT) neurons were also observed. However, the respective effects and interactions of these monoamine depletions on certain nonmotor symptoms are still largely unknown. In the present study, we performed selective depletions of NA, 5-HT and DA in mice by intraperitioneal injection of N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4), 4-chloro-L-phenylalanine (pCPA) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), respectively. DSP-4 led to a 34% decrease in the number of NAergic neurons in the locus coeruleus, and MPTP led to a 30% decrease in the number of DAergic neurons in the substantia nigra. Although there was no obvious change in the number of 5-HTergic neurons in the dorsal raphe nucleus after pCPA treatment, the levels of 5-HT and its metabolite in the frontal cortex and hippocampus were reduced, respectively. Locomotor activity deficit was induced by DA depletion and a decrease in traveled distance was potentiated by additional NA depletion. Despair-associated depressive-like behavior could be observed in every group. Anxiety states emerged only from the combined depletion of two or three monoamines. However, combined depletion of the three monoamines dramatically induced anhedonia, and it could also aggravate the depressive-like and anxiety behavior. Furthermore, NA depletion significantly reduced spatial learning and memory ability, which was not enhanced by additional 5-HT or DA depletion. Our data highlighted the interactive role of NA, 5-HT and DA in the motor, emotional and cognitive deficits, providing new insight into the complex orchestration of impaired monoaminergic systems that related to the pathology of PD.
帕金森病（PD）不仅以典型的运动症状为特征，在疾病早期还伴有非运动症状。除了多巴胺能（DAergic）神经元的丧失外，还观察到去甲肾上腺素能（NA）和5-羟色胺能（5-HT）神经元的进行性退化。然而，这些单胺耗竭对某些非运动症状的各自影响及相互作用仍 largely 未知。在本研究中，我们通过腹腔注射 N-(2-氯乙基)-N-乙基-2-溴苄胺盐酸盐（DSP-4）、4-氯-L-苯丙氨酸（pCPA）和 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）分别在小鼠中选择性耗竭 NA、5-HT 和 DA。DSP-4 导致蓝斑中 NAergic 神经元数量减少 34%，MPTP 导致黑质中 DAergic 神经元数量减少 30%。虽然 pCPA 处理后背缝核中 5-HTergic 神经元数量无明显变化，但额叶皮质和海马中 5-HT 及其代谢产物水平分别降低。DA 耗竭诱导运动活动缺陷，额外的 NA 耗竭会增强行进距离的减少。每组均观察到与绝望相关的抑郁样行为。焦虑状态仅在两种或三种单胺联合耗竭时出现。然而，三种单胺联合耗竭显著诱导快感缺失，并且还会加重抑郁样和焦虑行为。此外，NA 耗竭显著降低空间学习和记忆能力，额外的 5-HT 或 DA 耗竭并未增强这种能力。我们的数据突出了 NA、5-HT 和 DA 在运动、情绪和认知缺陷中的相互作用，为与 PD 病理相关的受损单胺能系统的复杂协调提供了新的见解。
