Department of Pharmacology, Setor de Ciências Biológicas, Universidade Federal do Paraná, Centro Politécnico, C.P. 19031, 81531-980, Curitiba, PR, Brazil; Uniandrade, Centro Universitário Campos de Andrade, Santa Quiteria, 80310-310, Curitiba, PR, Brazil.
Department of Pharmacology, Setor de Ciências Biológicas, Universidade Federal do Paraná, Centro Politécnico, C.P. 19031, 81531-980, Curitiba, PR, Brazil.
Brain Res Bull. 2021 Mar;168:63-73. doi: 10.1016/j.brainresbull.2020.12.011. Epub 2020 Dec 31.
The most common features of Parkinson's disease (PD) are motor impairments, but many patients also present depression and memory impairment. Ketamine, an N-methyl-d-aspartate (NMDA) receptor antagonist, has been shown to be effective in patients with treatment-resistant major depression. Thus, the present study evaluated the action of ketamine on memory impairment and depressive-like behavior in an animal model of PD. Male Wistar rats received a bilateral infusion of 6 μg/side 6-hydroxydopamine (6-OHDA) into the substantia nigra pars compacta (SNc). Short-term memory was evaluated by the social recognition test, and depressive-like behaviors were evaluated by the sucrose preference and forced swimming tests (FST). Drug treatments included vehicle (i.p., once a week); ketamine (5, 10 and 15 mg/kg, i.p., once a week); and imipramine (20 mg/kg, i.p., daily). The treatments were administered 21 days after the SNc lesion and lasted for 28 days. The SNc lesion impaired short-term social memory, and all ketamine doses reversed the memory impairment and anhedonia (reduction of sucrose preference) induced by 6-OHDA. In the FST, 6-OHDA increased immobility, and all doses of ketamine and imipramine reversed this effect. The anti-immobility effect of ketamine was associated with an increase in swimming but not in climbing, suggesting a serotonergic effect. Ketamine and imipramine did not reverse the 6-OHDA-induced reduction in tyrosine hydroxylase immunohistochemistry in the SNc. In conclusion, ketamine reversed depressive-like behaviors and short-term memory impairment in rats with SNc bilateral lesions, indicating a promising profile for its use in PD patients.
帕金森病（PD）最常见的特征是运动障碍，但许多患者也存在抑郁和记忆障碍。氯胺酮是一种 N-甲基-D-天冬氨酸（NMDA）受体拮抗剂，已被证明对治疗抵抗性重度抑郁症患者有效。因此，本研究评估了氯胺酮在 PD 动物模型中对记忆障碍和抑郁样行为的作用。雄性 Wistar 大鼠接受双侧立体定向注射 6μg/侧 6-羟多巴胺（6-OHDA）至黑质致密部（SNc）。通过社会识别测试评估短期记忆，通过蔗糖偏好和强迫游泳测试（FST）评估抑郁样行为。药物治疗包括载体（ip，每周一次）；氯胺酮（5、10 和 15mg/kg，ip，每周一次）；和丙咪嗪（20mg/kg，ip，每天）。在 SNc 损伤后 21 天开始给药，持续 28 天。SNc 损伤损害短期社会记忆，所有氯胺酮剂量均可逆转 6-OHDA 引起的记忆障碍和快感缺失（蔗糖偏好降低）。在 FST 中，6-OHDA 增加不动性，所有剂量的氯胺酮和丙咪嗪均可逆转这种作用。氯胺酮的抗不动性作用与游泳增加有关，但与攀爬无关，提示其具有血清素能作用。氯胺酮和丙咪嗪并未逆转 6-OHDA 诱导的 SNc 中酪氨酸羟化酶免疫组织化学减少。总之，氯胺酮逆转了双侧 SNc 损伤大鼠的抑郁样行为和短期记忆障碍，表明其在 PD 患者中的应用具有广阔前景。
