Université de Bordeaux, 33076 Bordeaux Cedex, France; Centre National de la Recherche Scientifique (Unité Mixte de Recherche 5227), 33076 Bordeaux Cedex, France.
Neuroscience. 2010 Aug 11;169(1):158-70. doi: 10.1016/j.neuroscience.2010.04.061. Epub 2010 May 4.
Serotonin2C (5-HT(2C)) receptors act in the basal ganglia, a group of sub-cortical structures involved in motor behavior, where they are thought to modulate oral activity and participate in iatrogenic motor side-effects in Parkinson's disease and Schizophrenia. Whether abnormal movements initiated by 5-HT(2C) receptors are directly consequent to dysfunctions of the motor circuit is uncertain. In the present study, we combined behavioral, immunohistochemical and extracellular single-cell recordings approaches in rats to investigate the effect of the 5-HT(2C) agonist Ro-60-0175 respectively on orofacial dyskinesia, the expression of the marker of neuronal activity c-Fos in basal ganglia and the electrophysiological activity of substantia nigra pars reticulata (SNr) neuron connected to the orofacial motor cortex (OfMC) or the medial prefrontal cortex (mPFC). The results show that Ro-60-0175 (1 mg/kg) caused bouts of orofacial movements that were suppressed by the 5-HT(2C) antagonist SB-243213 (1 mg/kg). Ro-60-0175 (0.3, 1, 3 mg/kg) dose-dependently enhanced Fos expression in the striatum and the nucleus accumbens. At the highest dose, it enhanced Fos expression in the subthalamic nucleus, the SNr and the entopeduncular nucleus but not in the external globus pallidus. However, the effect of Ro-60-0175 was mainly associated with associative/limbic regions of basal ganglia whereas subregions of basal ganglia corresponding to sensorimotor territories were devoid of Fos labeling. Ro-60-0175 (1-3 mg/kg) did not affect the electrophysiological activity of SNr neurons connected to the OfMC nor their excitatory-inhibitory-excitatory responses to the OfMC electrical stimulation. Conversely, Ro-60-0175 (1 mg/kg) enhanced the late excitatory response of SNr neurons evoked by the mPFC electrical stimulation. These results suggest that oral dyskinesia induced by 5-HT(2C) agonists are not restricted to aberrant signalling in the orofacial motor circuit and demonstrate discrete modifications in associative territories.
5-羟色胺 2C（5-HT2C）受体在基底神经节中起作用，基底神经节是一组参与运动行为的皮质下结构，据认为它们可以调节口腔活动，并参与帕金森病和精神分裂症的医源性运动副作用。5-HT2C 受体引起的异常运动是否直接继发于运动回路的功能障碍尚不确定。在本研究中，我们结合行为学、免疫组织化学和细胞外单细胞记录方法，在大鼠中研究了 5-HT2C 激动剂 Ro-60-0175 对口腔运动障碍的影响，以及标记神经元活动的 c-Fos 在基底神经节中的表达，以及与口腔运动皮层（OfMC）或内侧前额叶皮层（mPFC）相连的黑质网状部（SNr）神经元的电生理活性。结果表明，Ro-60-0175（1mg/kg）引起口腔运动发作，5-HT2C 拮抗剂 SB-243213（1mg/kg）可抑制这些发作。Ro-60-0175（0.3、1、3mg/kg）剂量依赖性地增强纹状体和伏隔核中的 Fos 表达。在最高剂量下，它增强了丘脑底核、SNr 和动眼神经核团中的 Fos 表达，但不增强外苍白球中的 Fos 表达。然而，Ro-60-0175 的作用主要与基底神经节的联合/边缘区域有关，而与感觉运动区域对应的基底神经节亚区则没有 Fos 标记。Ro-60-0175（1-3mg/kg）不影响与 OfMC 相连的 SNr 神经元的电生理活性，也不影响它们对 OfMC 电刺激的兴奋性抑制-兴奋性反应。相反，Ro-60-0175（1mg/kg）增强了由 mPFC 电刺激引起的 SNr 神经元的晚期兴奋性反应。这些结果表明，5-HT2C 激动剂引起的口腔运动障碍不仅局限于口腔运动回路中的异常信号，而且还证明了联合区域的离散变化。
