Guimarães Rayanne Poletti, Ribeiro Danilo Leandro, Dos Santos Keila Bariotto, Talarico Carlos Henrique Zanello, Godoy Lívea Dornela, Padovan-Neto Fernando E
Department of Psychology, Faculty of Philosophy, Sciences and Letters of Ribeirão Preto, University of São Paulo, Ribeirão Preto 14040-901, SP, Brazil.
Pharmaceuticals (Basel). 2022 Jul 30;15(8):947. doi: 10.3390/ph15080947.
The facilitation of corticostriatal transmission is modulated by the pharmacological inhibition of striatal phosphodiesterase 10A (PDE10A). Since L-DOPA-induced dyskinesia is associated with abnormal corticostriatal transmission, we hypothesized that inhibition of PDE10A would modulate L-DOPA-induced dyskinesia (LID) by regulating corticostriatal activity. 6-OHDA-lesioned rats were chronically treated with L-DOPA for one week. After that, for two additional weeks, animals were treated with the PDE10A inhibitor PDM-042 (1 and 3 mg/kg) one hour before L-DOPA. Behavioral analyses were performed to quantify abnormal involuntary movements (AIMs) and to assess the antiparkinsonian effects of L-DOPA. Single-unit extracellular electrophysiological recordings were performed in vivo to characterize the responsiveness of MSNs to cortical stimulation. The low dose of PDM-042 had an antidyskinetic effect (i.e., attenuated peak-dose dyskinesia) and did not interfere with cortically evoked spike activity. Conversely, the high dose of PDM-042 did not affect peak-dose dyskinesia, prolonged AIMs, and increased cortically evoked spike activity. These data suggest that the facilitation of corticostriatal transmission is likely to contribute to the expression of AIMs. Therefore, cyclic nucleotide manipulation is an essential target in controlling LID.
纹状体磷酸二酯酶10A（PDE10A）的药理学抑制可调节皮质纹状体传递。由于左旋多巴诱导的运动障碍与异常的皮质纹状体传递有关，我们推测抑制PDE10A将通过调节皮质纹状体活动来调节左旋多巴诱导的运动障碍（LID）。用6-羟基多巴胺损毁大鼠，并对其进行为期一周的左旋多巴长期治疗。之后，在额外的两周时间里，在给予左旋多巴前一小时，给动物注射PDE10A抑制剂PDM-042（1和3毫克/千克）。进行行为分析以量化异常不自主运动（AIMs）并评估左旋多巴的抗帕金森病作用。在体内进行单单位细胞外电生理记录，以表征中型多棘神经元（MSNs）对皮质刺激的反应性。低剂量的PDM-042具有抗运动障碍作用（即减轻峰值剂量运动障碍），且不干扰皮质诱发的峰电位活动。相反，高剂量的PDM-042不影响峰值剂量运动障碍，延长了AIMs，并增加了皮质诱发的峰电位活动。这些数据表明，皮质纹状体传递的易化可能有助于AIMs的表达。因此，环核苷酸调控是控制LID的关键靶点。
