Department of Neuro-Psychopharmacology, Maj Institute of Pharmacology, Polish Academy of Sciences, Smętna street 12, 31-343, Kraków, Poland.
Psychopharmacology (Berl). 2022 Nov;239(11):3633-3656. doi: 10.1007/s00213-022-06238-x. Epub 2022 Sep 30.
The pharmacological effects of antidepressants in modulating noradrenergic transmission as compared to serotonergic transmission in a rat model of Parkinson's disease under chronic L-DOPA therapy are insufficiently explored.
The aim of the present study was to investigate the effect of the tricyclic antidepressant desipramine administered chronically alone or jointly with L-DOPA, on motor behavior and monoamine metabolism in selected brain structures of rats with the unilateral 6-OHDA lesion.
The antiparkinsonian activities of L-DOPA and desipramine were assessed behaviorally using a rotation test and biochemically based on changes in the tissue concentrations of noradrenaline, dopamine and serotonin and their metabolites, evaluated separately for the ipsi- and contralateral motor (striatum, substantia nigra) and limbic (prefrontal cortex, hippocampus) structures of rat brain by HPLC method.
Desipramine administered alone did not induce rotational behavior, but in combination with L-DOPA, it increased the number of contralateral rotations more strongly than L-DOPA alone. Both L-DOPA and desipramine + L-DOPA significantly increased DA levels in the ipsilateral striatum, substantia nigra, prefrontal cortex and the ipsi- and contralateral hippocampus. The combined treatment also significantly increased noradrenaline content in the ipsi- and contralateral striatum, while L-DOPA alone decreased serotonin level on both sides of the hippocampus.
The performed analysis of the level of monoamines and their metabolites in the selected brain structures suggests that co-modulation of noradrenergic and dopaminergic transmission in Parkinson's disease by the combined therapy with desipramine + L-DOPA may have some positive implications for motor and psychiatric functions but further research is needed to exclude potential negative effects.
在慢性 L-DOPA 治疗的帕金森病大鼠模型中，与 5-羟色胺传递相比，抗抑郁药对去甲肾上腺素传递的药理学作用调节作用研究不足。
本研究旨在探讨三环类抗抑郁药地昔帕明单独或联合 L-DOPA 长期给药对单侧 6-羟基多巴胺损伤大鼠的运动行为和单胺代谢的影响。
通过旋转试验评估 L-DOPA 和地昔帕明的抗帕金森作用，并用 HPLC 法分别评估同侧（纹状体、黑质）和对侧（前额叶皮层、海马）脑区神经递质和代谢物浓度的变化来评估生物化学变化。
地昔帕明单独给药不会引起旋转行为，但与 L-DOPA 联合使用时，比 L-DOPA 单独使用更能增加对侧旋转次数。L-DOPA 和地昔帕明+L-DOPA 均可显著增加同侧纹状体、黑质、前额叶皮层和同侧及对侧海马中的 DA 水平。联合治疗还可显著增加同侧纹状体的去甲肾上腺素含量，而 L-DOPA 单独给药则会降低双侧海马的 5-羟色胺水平。
对选定脑区中单胺及其代谢物水平的分析表明，地昔帕明+L-DOPA 联合治疗对帕金森病患者的去甲肾上腺素能和多巴胺能传递进行共同调节，可能对运动和精神功能有一些积极影响，但需要进一步研究以排除潜在的负面影响。
