Vidal Benjamin, Levigoureux Elise, Chaib Sarah, Bouillot Caroline, Billard Thierry, Newman-Tancredi Adrian, Zimmer Luc
Lyon Neuroscience Research Center, Université de Lyon, Université Claude Bernard Lyon 1, CNRS, INSERM, Lyon, France.
Hospices Civils de Lyon, Lyon, France.
J Parkinsons Dis. 2021;11(3):1257-1269. doi: 10.3233/JPD-212580.
The gold-standard treatment for Parkinson's disease is L-DOPA, which in the long term often leads to levodopa-induced dyskinesia. Serotonergic neurons are partially responsible for this, by converting L-DOPA into dopamine leading to its uncontrolled release as a "false neurotransmitter". The stimulation of 5-HT1A receptors can reduce involuntary movements but this mechanism is poorly understood.
This study aimed to investigate the functionality of 5-HT1A receptors using positron emission tomography in hemiparkinsonian rats with or without dyskinesia induced by 3-weeks daily treatment with L-DOPA. Imaging sessions were performed "off" L-DOPA.
Each rat underwent a positron emission tomography scan with [18F]F13640, a 5-HT1AR agonist which labels receptors in a high affinity state for agonists, or with [18F]MPPF, a 5-HT1AR antagonist which labels all the receptors.
There were decreases of [18F]MPPF binding in hemiparkinsonian rats in cortical areas. In dyskinetic animals, changes were slighter but also found in other regions. In hemiparkinsonian rats, [18F]F13640 uptake was decreased bilaterally in the globus pallidus and thalamus. On the non-lesioned side, binding was increased in the insula, the hippocampus and the amygdala. In dyskinetic animals, [18F]F13640 binding was strongly increased in cortical and limbic areas, especially in the non-lesioned side.
These data suggest that agonist and antagonist 5-HT1A receptor-binding sites are differently modified in Parkinson's disease and levodopa-induced dyskinesia. In particular, these observations suggest a substantial involvement of the functional state of 5-HT1AR in levodopa-induced dyskinesia and emphasize the need to characterize this state using agonist radiotracers in physiological and pathological conditions.
帕金森病的金标准治疗药物是左旋多巴，但长期使用往往会导致左旋多巴诱导的运动障碍。血清素能神经元对此负有部分责任，它们将左旋多巴转化为多巴胺，导致其作为“假神经递质”不受控制地释放。5-HT1A受体的刺激可以减少不自主运动，但这种机制尚不清楚。
本研究旨在使用正电子发射断层扫描技术，研究在每日用左旋多巴治疗3周诱导或未诱导运动障碍的偏侧帕金森病大鼠中5-HT1A受体的功能。成像实验在停用左旋多巴的情况下进行。
每只大鼠接受一次正电子发射断层扫描，使用[18F]F13640（一种5-HT1AR激动剂，以高亲和力状态标记受体）或[18F]MPPF（一种5-HT1AR拮抗剂，标记所有受体）。
偏侧帕金森病大鼠皮质区域的[18F]MPPF结合减少。在运动障碍动物中，变化较小，但在其他区域也有发现。在偏侧帕金森病大鼠中，双侧苍白球和丘脑的[18F]F13640摄取减少。在未损伤侧，岛叶、海马体和杏仁核的结合增加。在运动障碍动物中，皮质和边缘区域的[18F]F13640结合强烈增加，尤其是在未损伤侧。
这些数据表明，激动剂和拮抗剂5-HT1A受体结合位点在帕金森病和左旋多巴诱导的运动障碍中发生了不同的改变。特别是，这些观察结果表明5-HT1AR的功能状态在左旋多巴诱导的运动障碍中起重要作用，并强调需要在生理和病理条件下使用激动剂放射性示踪剂来表征这种状态。
