Gutiérrez-Cuesta Javier, Burokas Aurelijus, Mancino Samantha, Kummer Sami, Martín-García Elena, Maldonado Rafael
Departament de Ciencies Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.
Neuropsychopharmacology. 2014 Dec;39(13):2974-88. doi: 10.1038/npp.2014.149. Epub 2014 Jun 19.
The repeated cycles of cessation of consumption and relapse remain the major clinical concern in treating drug addiction. The endogenous opioid system is a crucial component of the reward circuit that participates in the adaptive changes leading to relapse in the addictive processes. We have used genetically modified mice to evaluate the involvement of μ-opioid receptor (MOR) and δ-opioid receptor (DOR) and their main endogenous ligands, the enkephalins derived from proenkephalin (PENK) and prodynorphin (PDYN), in the reinstatement of cocaine-seeking behavior. Constitutive knockout mice of MOR, DOR, PENK, and PDYN, and their wild-type littermates were trained to self-administer cocaine or to seek for palatable food, followed by a period of extinction and finally tested on a cue-induced reinstatement of seeking behavior. The four lines of knockout mice acquired operant cocaine self-administration behavior, although DOR and PENK knockout mice showed less motivation for cocaine than wild-type littermates. Moreover, cue-induced relapse was significantly decreased in MOR and DOR knockout mice. In contrast, PDYN knockout mice showed a slower extinction and increased relapse than wild-type littermates. C-Fos expression analysis revealed differential activation in brain areas related with memory and reward in these knockout mice. No differences were found in any of the four genotypes in operant responding to obtain palatable food, indicating that the changes revealed in knockout mice were not due to unspecific deficit in operant performance. Our results indicate that MOR, DOR, and PDYN have a differential role in cue-induced reinstatement of cocaine-seeking behavior.
药物消费的戒断和复发的反复循环仍然是治疗药物成瘾的主要临床关注点。内源性阿片系统是奖赏回路的关键组成部分，参与导致成瘾过程中复发的适应性变化。我们使用基因改造小鼠来评估μ-阿片受体（MOR）和δ-阿片受体（DOR）及其主要内源性配体——源自前脑啡肽（PENK）和前强啡肽（PDYN）的脑啡肽——在可卡因觅求行为恢复中的作用。对MOR、DOR、PENK和PDYN的组成型敲除小鼠及其野生型同窝小鼠进行训练，使其自我给药可卡因或觅求美味食物，随后进行一段时间的消退训练，最后测试线索诱导的觅求行为恢复情况。这四组敲除小鼠均获得了操作性可卡因自我给药行为，尽管DOR和PENK敲除小鼠对可卡因的动机低于野生型同窝小鼠。此外，MOR和DOR敲除小鼠中线索诱导的复发显著减少。相比之下，PDYN敲除小鼠的消退速度较慢，复发率高于野生型同窝小鼠。C-Fos表达分析揭示了这些敲除小鼠中与记忆和奖赏相关脑区的不同激活情况。在获取美味食物的操作性反应中，四种基因型均未发现差异，这表明敲除小鼠中揭示的变化并非由于操作性表现的非特异性缺陷所致。我们的结果表明，MOR、DOR和PDYN在线索诱导的可卡因觅求行为恢复中具有不同作用。
