Piccart Elisabeth, Langlois Xavier, Vanhoof Greet, D'Hooge Rudi
Laboratory of Biological Psychology, Leuven Institute for Neuroscience & Disease (LIND), University of Leuven, Tiensestraat 102, BE-3000 Leuven, Belgium.
Janssen R&D, a division of Janssen Pharmaceutica NV, Beerse, Belgium.
Neuropharmacology. 2013 Dec;75:437-44. doi: 10.1016/j.neuropharm.2013.08.006. Epub 2013 Aug 22.
The pharmacological effect of the selective PDE10A inhibitor 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline succinic acid (MP-10) on aversively and appetitively motivated behavior in C57BL/6J mice was examined. MP-10 dose-dependently impaired performance on a highly demanding reward schedule during appetitive conditioning. The compound further affected cue-based, but not contextual aversive conditioning. Finally, dose-dependent impaired performance in an instrumentally conditioned reinforcement (ICR) task was found. This suggests that the observed behavioral effects of MP-10 can be at least partially ascribed to impaired incentive salience attribution. MP-10 administration dose-dependently enhanced striatal expression of the immediate early gene Zif268, which suggest that MP-10 affects the studied motivated behaviors by enhancing PDE10A-regulated striatal signaling. Striatal signaling thus appears to be crucial in processes that control reward-motivated behavior in general, and incentive salience attribution in particular. Continued research will prove valuable towards a better understanding of psychopathologies that affect reward-motivated behaviors, such as drug addiction and schizophrenia.
研究了选择性磷酸二酯酶10A（PDE10A）抑制剂2-[4-(1-甲基-4-吡啶-4-基-1H-吡唑-3-基)-苯氧基甲基]-喹啉琥珀酸（MP-10）对C57BL/6J小鼠厌恶和食欲驱动行为的药理作用。在食欲条件反射过程中，MP-10以剂量依赖的方式损害了在高要求奖励计划中的表现。该化合物进一步影响基于线索的厌恶条件反射，但不影响情境厌恶条件反射。最后发现，在工具性条件强化（ICR）任务中，MP-10的表现也呈剂量依赖性受损。这表明，观察到的MP-10的行为效应至少部分可归因于激励显著性归因受损。给予MP-10剂量依赖性地增强了即刻早期基因Zif268在纹状体中的表达，这表明MP-10通过增强PDE10A调节的纹状体信号传导来影响所研究的动机行为。因此，纹状体信号传导在一般控制奖励驱动行为，特别是激励显著性归因的过程中似乎至关重要。持续的研究对于更好地理解影响奖励驱动行为的精神病理学，如药物成瘾和精神分裂症，将具有重要价值。
