Vecchia Débora Dalla, Kanazawa Luiz Kae Sales, Wendler Etiéli, de Almeida Soares Hocayen Palloma, Bruginski Estevan, Campos Francinete Ramos, Stern Cristina Aparecida Jark, Vital Maria Aparecida Barbato Frazão, Miyoshi Edmar, Wöhr Markus, Schwarting Rainer K W, Andreatini Roberto
Department of Pharmacology, Setor de Ciências Biológicas, Universidade Federal do Paraná, Centro Politécnico, C.P. 19031, 81540-990, Curitiba, PR, Brazil.
Biosciences and Mass Spectrometry Laboratory, Department of Pharmacy, Federal University of Paraná, Av. Pref. Lothário Meissner, 632, 80210-170, Curitiba, PR, Brazil.
Behav Brain Res. 2018 Apr 16;342:1-10. doi: 10.1016/j.bbr.2017.12.041. Epub 2018 Jan 4.
Parkinson's disease is a chronic neurodegenerative disorder characterized by cardinal motor features, such as bradykinesia, but also vocal deficits (e.g. difficulties to articulate words and to keep the tone of voice) and depression. In the present study, rats with bilateral 6-hydroxydopamine lesion of the substantia nigra pars compacta were evaluated for changes in the emission of 50-kHz ultrasonic vocalizations, gait impairment (catwalk test), and depressive-like behaviour (sucrose preference test). Furthermore, we evaluated the effect of repeated treatment (28 days) with ketamine (5, 10, and 15 mg/kg, ip, once per week) or imipramine (15 mg/kg, ip, daily). The lesion had prominent effects on the production of 50-kHz ultrasonic vocalizations (reduced call numbers, call durations, total calling time, and increased latency to start calling), led to gait impairment (increased run duration and stand of right forelimb) and induced anhedonia (reduced sucrose preference). Also, significant correlations between gait changes, sucrose preference, and ultrasonic calling were found, yet, except for run duration and sucrose preference, these correlations were low indicating that these associations are weak. Importantly, ketamine and imipramine reversed lesion-induced anhedonia and improved gait impairments, but neither drug improved ultrasonic calling. In conclusion, the substantia nigra lesion with 6-hydroxydopamine induced subtle motor and non-motor manifestations, reflecting key features of the wide clinical spectrum of early Parkinson's disease. Furthermore, the present results suggest a potential efficacy of ketamine on depression and gait alterations in Parkinson's disease.
帕金森病是一种慢性神经退行性疾病，其特征为主要运动症状，如运动迟缓，还包括发声缺陷（如言语表达困难和语调维持困难）以及抑郁。在本研究中，对双侧黑质致密部6-羟基多巴胺损伤的大鼠进行了评估，观察其50千赫兹超声发声、步态障碍（猫步试验）和抑郁样行为（蔗糖偏好试验）的变化。此外，我们评估了氯胺酮（5、10和15毫克/千克，腹腔注射，每周一次）或丙咪嗪（15毫克/千克，腹腔注射，每日一次）重复治疗（28天）的效果。该损伤对50千赫兹超声发声产生了显著影响（叫声数量减少、叫声持续时间缩短、总叫声时间减少以及开始叫声的潜伏期延长），导致步态障碍（奔跑持续时间增加和右前肢站立）并诱发快感缺失（蔗糖偏好降低）。此外，还发现步态变化、蔗糖偏好和超声发声之间存在显著相关性，然而，除了奔跑持续时间和蔗糖偏好外，这些相关性较低，表明这些关联较弱。重要的是，氯胺酮和丙咪嗪可逆转损伤诱导的快感缺失并改善步态障碍，但两种药物均未改善超声发声。总之，6-羟基多巴胺所致黑质损伤诱发了轻微的运动和非运动表现，反映了早期帕金森病广泛临床谱的关键特征。此外，目前的结果提示氯胺酮对帕金森病的抑郁和步态改变具有潜在疗效。
