Carvalho Miguel M, Campos Filipa L, Marques Mariana, Soares-Cunha Carina, Kokras Nikolaos, Dalla Christina, Leite-Almeida Hugo, Sousa Nuno, Salgado António J
Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus de GualtarBraga, Portugal.
ICVS/3B's, PT Government Associate LaboratoryGuimarães, Portugal.
Front Behav Neurosci. 2017 Aug 8;11:145. doi: 10.3389/fnbeh.2017.00145. eCollection 2017.
The use of dopamine replacement therapies (DRT) in the treatment of Parkinson's disease (PD) can lead to the development of dopamine dysregulation syndrome (DDS) and impulse control disorders (ICD), behavioral disturbances characterized by compulsive DRT self-medication and development of impulsive behaviors. However, the mechanisms behind these disturbances are poorly understood. In animal models of PD, the assessment of the rewarding properties of levodopa (LD), one of the most common drugs used in PD, has produced conflicting results, and its ability to promote increased impulsivity is still understudied. Moreover, it is unclear whether acute and chronic LD therapy differently affects reward and impulsivity. In this study we aimed at assessing, in an animal model of PD with bilateral mesostriatal and mesocorticolimbic degeneration, the behavioral effects of LD therapy regarding reward and impulsivity. Animals with either sham or 6-hydroxydopamine (6-OHDA)-induced bilateral lesions in the (SNc) and ventral tegmental area (VTA) were exposed to acute and chronic LD treatment. We used the conditioned place preference (CPP) paradigm to evaluate the rewarding effects of LD, whereas impulsive behavior was measured with the variable delay-to-signal (VDS) task. Correlation analyses between behavioral measurements of reward or impulsivity and lesion extent in SNc/VTA were performed to pinpoint possible anatomical links of LD-induced behavioral changes. We show that LD, particularly when administered chronically, caused the development of impulsive-like behaviors in 6-OHDA-lesioned animals in the VDS. However, neither acute or chronic LD administration had rewarding effects in 6-OHDA-lesioned animals in the CPP. Our results show that in a bilateral rat model of PD, LD leads to the development of impulsive behaviors, strengthening the association between DRT and DDS/ICD in PD.
多巴胺替代疗法（DRT）用于治疗帕金森病（PD）时，可能会导致多巴胺调节障碍综合征（DDS）和冲动控制障碍（ICD）的发生，这些行为障碍的特征是强迫性DRT自我用药和冲动行为的出现。然而，这些障碍背后的机制仍知之甚少。在PD动物模型中，对左旋多巴（LD）（PD最常用药物之一）的奖赏特性评估产生了相互矛盾的结果，其促进冲动性增加的能力仍未得到充分研究。此外，尚不清楚急性和慢性LD治疗对奖赏和冲动性的影响是否不同。在本研究中，我们旨在评估在双侧中脑纹状体和中脑皮质边缘系统变性的PD动物模型中，LD治疗对奖赏和冲动性的行为影响。在黑质致密部（SNc）和腹侧被盖区（VTA）有假手术或6-羟基多巴胺（6-OHDA）诱导的双侧损伤的动物接受急性和慢性LD治疗。我们使用条件性位置偏爱（CPP）范式评估LD的奖赏作用，而冲动行为则通过可变信号延迟（VDS）任务进行测量。对奖赏或冲动性的行为测量与SNc/VTA损伤程度之间进行相关性分析，以确定LD诱导行为变化的可能解剖学联系。我们发现，LD，特别是长期给药时，会导致6-OHDA损伤动物在VDS中出现类似冲动的行为。然而，急性或慢性LD给药在6-OHDA损伤动物的CPP中均没有奖赏作用。我们的结果表明，在双侧PD大鼠模型中，LD会导致冲动行为的出现，加强了PD中DRT与DDS/ICD之间的关联。
