Behavioral Neuroscience Program, Department of Psychology, Binghamton University, Binghamton, NY 13902-6000, USA.
Neuropharmacology. 2011 Sep;61(4):753-60. doi: 10.1016/j.neuropharm.2011.05.021. Epub 2011 May 27.
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 coadministration 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.
虽然 5-羟色胺 5-HT1A 受体（5-HT1AR）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-多巴诱导的运动障碍（LID），但最近的证据表明，初级运动皮层（M1）中的假定 5-HT1AR 也可能有贡献。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系统给予全 5-HT1AR 激动剂±8-OH-DPAT 对单侧内侧前脑束（MFB）多巴胺（DA）损伤大鼠 M1 和前额叶皮层（PFC）中 L-多巴诱导的即时早期基因表达的影响。接下来，为了确定是否直接刺激 M1 中的 5-HT1AR 可以减轻 LID 的发作，在 MFB 损伤大鼠中测试了 M1 微输注±8-OH-DPAT 对 L-多巴诱导的异常不自主运动（AIMs）和旋转的影响，同时给予或不给予 5-HT1AR 拮抗剂 WAY100635。最后，将±8-OH-DPAT 输注到 M1 中的峰值运动障碍中，以确定 5-HT1AR 刺激是否减轻已建立的 L-多巴诱导的 AIMs 和旋转。虽然在 PFC 中没有观察到治疗作用，但全身给予±8-OH-DPAT 可抑制 M1 中 L-多巴诱导的 c-fos。M1 内的 5-HT1AR 刺激可减少 AIMs 的发作，而 WAY100635 则可逆转这种作用，表明具有受体特异性作用。最后，在峰值运动障碍时将±8-OH-DPAT 持续输注到 M1 中可减轻 L-多巴诱导的 AIMs。总之，这些发现支持 M1 在 LID 中的整体作用及其通过局部 5-HT1AR 进行的调节。
