Role of the primary motor cortex in L-Dopa-induced dyskinesia and its modulation by 5-HT1A receptor stimulation.
Role of the primary motor cortex in L-Dopa-induced dyskinesia and its modulation by 5-HT1A receptor stimulation.
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DOI：
10.1016/j.neuropharm.2011.05.021
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发表时间：
2011-09
影响因子：
4.7
通讯作者：
Bishop C
中科院分区：
文献类型：
--
作者：
Ostock CY;Dupre KB;Jaunarajs KL;Walters H;George J;Krolewski D;Walker PD;Bishop C
虽然5-羟色胺5-HT 1A受体（5-HT 1AR）激动剂通过使基底神经节神经回路的活动正常化来减少L-DOPA诱导的运动障碍（LID），但最近的证据表明，初级运动皮层（M1）内的假定5-HT 1AR也可能起作用。为了更好地描述这种可能的机制，首先使用c-fos免疫组织化学来确定全身给予完全5-HT 1AR激动剂±8-OH-DPAT对具有单侧内侧前脑束（MFB）多巴胺（DA）损伤的大鼠的M1和前额叶皮质（PFC）内L-DOPA诱导的立即早期基因表达的影响。接下来，为了确定直接刺激M1内的5-HT 1AR是否会减弱LID的发作，在M1微量输注±8-OH-DPAT（联合或不联合）后，测试了具有MFB病变的大鼠是否存在L-DOPA诱导的异常不自主运动（AIM）和旋转。5-HT 1AR拮抗剂WAY 100635。最后，在运动障碍高峰时将±8-OH-DPAT输注到M1中，以确定5-HT 1AR刺激是否减弱已建立的L-DOPA诱导的AIM和旋转。虽然在PFC内未观察到治疗效应，但全身±8-OH-DPAT抑制了M1内L-DOPA诱导的c-fos。M1内5-HT 1AR刺激减少了AIM的发作，WAY 100635逆转了这种作用，表明了受体特异性作用。最后，在运动障碍高峰期向M1连续输注±8-OH-DPAT可减轻L-DOPA诱导的AIM。总的来说，这些发现支持M1在LID中的不可或缺的作用及其通过局部5-HT 1AR的调节。
While serotonin 5-HT1A receptor (5-HT1AR) agonists reduce L-DOPA-induced dyskinesias (LID) by normalizing activity in the basal ganglia neurocircuitry, recent evidence suggests putative 5-HT1AR within the primary motor cortex (M1) may also contribute. To better characterize this possible mechanism, c-fos immunohistochemistry was first used to determine the effects of systemic administration of the full 5-HT1AR agonist ±8-OH-DPAT on L-DOPA-induced immediate early gene expression within M1 and the prefrontal cortex (PFC) of rats with unilateral medial forebrain bundle (MFB) dopamine (DA) lesions. Next, in order to determine if direct stimulation of 5-HT1AR within M1 attenuates the onset of LID, rats with MFB lesions were tested for L-DOPA-induced abnormal involuntary movements (AIMs) and rotations following M1 microinfusions of ±8-OH-DPAT with or without co-administration of the 5-HT1AR antagonist WAY100635. Finally, ±8-OH-DPAT was infused into M1 at peak dyskinesia to determine if 5-HT1AR stimulation attenuates established L-DOPA-induced AIMs and rotations. While no treatment effects were seen within the PFC, systemic ±8-OH-DPAT suppressed L-DOPA-induced c-fos within M1. Intra-M1 5-HT1AR stimulation diminished the onset of AIMs and this effect was reversed by WAY100635 indicating receptor specific effects. Finally, continuous infusion of ±8-OH-DPAT into M1 at peak dyskinesia alleviated L-DOPA-induced AIMs. Collectively, these findings support an integral role for M1 in LID and its modulation by local 5-HT1AR.