Institute of Pharmacology, Polish Academy of Sciences, Department of Neuro-Psychopharmacology, 31-343, Kraków, Smętna Street 12, Poland.
Institute of Pharmacology, Polish Academy of Sciences, Department of Neuro-Psychopharmacology, 31-343, Kraków, Smętna Street 12, Poland.
Neurochem Int. 2018 Dec;121:125-139. doi: 10.1016/j.neuint.2018.10.004. Epub 2018 Oct 2.
Antidepressant drugs are recommended for the treatment of Parkinson's disease (PD)-associated depression but their role in the modulation of L-DOPA-induced behavioral and neurochemical markers is poorly explored. The aim of the present study was to examine the impact of the tricyclic antidepressant amitriptyline and L-DOPA, administered chronically alone or in combination, on rotational behavior, monoamine levels and binding of radioligands to their transporters in the dopaminergic brain structures of unilaterally 6-OHDA-lesioned rats. Binding of [H]nisoxetine to noradrenaline transporter (NET), [H]GBR 12,935 to dopamine transporter (DAT) and [H]citalopram to serotonin transporter (SERT) were analyzed by autoradiography. Amitriptyline administered alone did not induce rotational behavior but in combination with L-DOPA increased the number of contralateral rotations much more strongly than L-DOPA alone. The combined treatment also significantly increased the tissue dopamine (DA) content in the ipsilateral striatum and substantia nigra (SN) vs. L-DOPA alone. 6-OHDA-mediated lesion of nigrostriatal DA neurons drastically reduced DAT and NET bindings in the ipsilateral striatum. In the ipsilateral SN, DAT binding decreased while NET binding rose. SERT binding increased significantly mainly in the SN. Amitriptyline administered alone or jointly with L-DOPA had no effect on DAT binding on the lesioned side, significantly decreased SERT binding in the striatum and SN while NET binding only in the SN. Since in the DA-denervated striatum, SERT is mainly responsible for reuptake of L-DOPA-derived DA while in the SN, SERT and NET are involved, the inhibition of these transporters by antidepressant drugs may improve dopaminergic transmission and consequently motor behavior.
抗抑郁药被推荐用于治疗帕金森病（PD）相关的抑郁症，但它们在调节 L-DOPA 诱导的行为和神经化学标志物方面的作用尚未得到充分探索。本研究旨在探讨三环类抗抑郁药阿米替林和 L-DOPA 单独或联合长期给药对单侧 6-OHDA 损伤大鼠多巴胺能脑结构中转录行为、单胺水平和放射性配体与转运体结合的影响。通过放射自显影分析[H]nisoxetine 与去甲肾上腺素转运体（NET）、[H]GBR 12,935 与多巴胺转运体（DAT）和[H]citalopram 与 5-羟色胺转运体（SERT）的结合。阿米替林单独给药不会引起旋转行为，但与 L-DOPA 联合给药时，与单独给予 L-DOPA 相比，更强烈地增加了对侧旋转的次数。联合治疗还显著增加了同侧纹状体和黑质（SN）中的组织多巴胺（DA）含量，而单独给予 L-DOPA 则没有。6-OHDA 介导的黑质纹状体 DA 神经元损伤使同侧纹状体中的 DAT 和 NET 结合显著减少。在同侧 SN 中，DAT 结合减少，而 NET 结合增加。SERT 结合显著增加，主要在 SN 中。阿米替林单独或与 L-DOPA 联合给药对损伤侧的 DAT 结合没有影响，显著降低了纹状体和 SN 中的 SERT 结合，而仅在 SN 中降低了 NET 结合。由于在 DA 去神经纹状体中，SERT 主要负责摄取 L-DOPA 衍生的 DA，而在 SN 中，SERT 和 NET 参与其中，因此抗抑郁药对这些转运体的抑制可能改善多巴胺能传递，并因此改善运动行为。
