Department of Physiology, School of Medicine, Babol University of Medical Sciences, Babol, Iran; Neuroscience Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran.
Neuroscience Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences, P.O. Box 19615-1178, Tehran, Iran.
Brain Res Bull. 2018 Sep;142:320-327. doi: 10.1016/j.brainresbull.2018.08.017. Epub 2018 Aug 28.
Brain reward and motivation circuit begin from the ventral tegmental area (VTA) that its dopaminergic terminals project to various regions of the brain including the nucleus accumbens (NAc). This reward circuit is influenced by drugs of abuse such as morphine and cannabinoid. The present study tried to investigate the role of the intra-accumbal CB1 receptor in the c-fos level and pCREB/CREB ratio in the NAc and the VTA during reinstatement phase of morphine-induced conditioned place preference (CPP) by western blotting. The present data reveals that intra-accumbal administration of CB1 agonist, WIN55,212-2 (0.5, 1 and 2 mM/0.5 μl DMSO) before/during extinction period of morphine-induced CPP, significantly decreased the NAc and the VTA c-fos protein level in the reinstatement phase; whereas the pre-reinstatement administration of the CB1 agonist, increased the c-fos protein level. Intra-accumbal administration of the CB1 agonist during the extinction period of morphine-induced CPP reduced the pCREB/CREB ratio in the NAc. Also, the present data show that intra-accumbal administration of CB1 antagonist, AM251 (15, 45 and 90 μM/0.5 μl DMSO) during/after extinction period of morphine-induced CPP affects the NAc and the VTA c-fos protein level in the reinstatement phase. Also, intra-NAc microinjection of AM251 during the extinction period reduced pCREB/CREB ratio in these regions. In conclusion, the results presented here provide compelling evidence of the modulation and involvement of the c-fos and the CREB molecules in the cannabinoid-opioid interaction of the brain reward system in the CPP paradigm.
脑奖赏和动机回路始于腹侧被盖区（VTA），其多巴胺能末梢投射到包括伏隔核（NAc）在内的大脑的各个区域。该奖赏回路受吗啡和大麻素等滥用药物的影响。本研究试图通过 Western blot 法研究内侧伏隔核内 CB1 受体在吗啡诱导的条件性位置偏爱（CPP）复燃阶段中 NAc 和 VTA 中 c-fos 水平和 pCREB/CREB 比值中的作用。本数据显示，内侧伏隔核内给予 CB1 激动剂 WIN55,212-2（0.5、1 和 2 mM/0.5 μl DMSO），在吗啡诱导的 CPP 消退期间/期间，显着降低了复燃阶段的 NAc 和 VTA c-fos 蛋白水平；而在复燃前给予 CB1 激动剂，则增加了 c-fos 蛋白水平。内侧伏隔核内给予 CB1 激动剂，在吗啡诱导的 CPP 消退期间降低了 NAc 中的 pCREB/CREB 比值。此外，本数据还显示，内侧伏隔核内给予 CB1 拮抗剂 AM251（15、45 和 90 μM/0.5 μl DMSO），在吗啡诱导的 CPP 消退期间/之后，影响了 NAc 和 VTA 中的 c-fos 蛋白水平在复燃阶段。此外，内侧伏隔核内给予 AM251 可在消退期间减少这些区域中的 pCREB/CREB 比值。总之，本研究结果提供了令人信服的证据，表明 c-fos 和 CREB 分子在 CPP 范式中脑奖赏系统中大麻素-阿片相互作用中的调节和参与。
