James Morgan H, Quinn Rikki K, Ong Lin Kooi, Levi Emily M, Charnley Janine L, Smith Doug W, Dickson Phillip W, Dayas Christopher V
Neurobiology of Addiction Laboratory, School of Biomedical Sciences and Pharmacy and the Centre for Translational Neuroscience and Mental Health Research, University of Newcastle and the Hunter Medical Research Institute, Newcastle, NSW, Australia.
Neuropsychopharmacology. 2014 Jun;39(7):1694-702. doi: 10.1038/npp.2014.16. Epub 2014 Jan 28.
The mechanistic target of rapamycin complex 1 (mTORC1) is necessary for synaptic plasticity, as it is critically involved in the translation of synaptic transmission-related proteins, such as Ca(2+)/Calmodulin-dependent kinase II alpha (CAMKIIα) and AMPA receptor subunits (GluAs). Although recent studies have implicated mTORC1 signaling in drug-motivated behavior, the ineffectiveness of rapamycin, an mTORC1 inhibitor, in suppressing cocaine self-administration has raised questions regarding the specific role of mTORC1 in drug-related behaviors. Here, we examined mTORC1's role in three drug-related behaviors: cocaine taking, withdrawal, and reinstatement of cocaine seeking, by measuring indices of mTORC1 activity and assessing the effect of intra-cerebroventricular rapamycin on these behaviors in rats. We found that withdrawal from cocaine self-administration increased indices of mTORC1 activity in the nucleus accumbens (NAC). Intra-cerebroventricular rapamycin attenuated progressive ratio (PR) break points and reduced phospho-p70 ribosomal S6 kinase, GluA1 AMPAR, and CAMKIIα levels in the NAC shell (NACsh) and core (NACc). In a subsequent study, we treated rats with intra-NACsh infusions of rapamycin (2.5 μg/side/day for 5 days) during cocaine self-administration and then tracked the expression of addiction-relevant behaviors through to withdrawal and extinction. Rapamycin reduced drug seeking in signaled non-drug-available periods, PR responding, and cue-induced reinstatement, with these effects linked to reduced mTORC1 activity, total CAMKIIα, and GluA1 AMPAR levels in the NACsh. Together, these data highlight a role for mTORC1 in the neural processes that control the expression and maintenance of drug reward, including protracted relapse vulnerability. These effects appear to involve a role for mTORC1 in the regulation of GluA1 AMPARs and CAMKIIα in the NACsh.
雷帕霉素靶蛋白复合物1（mTORC1）对于突触可塑性是必需的，因为它在与突触传递相关的蛋白质（如钙/钙调蛋白依赖性激酶IIα（CAMKIIα）和AMPA受体亚基（GluAs））的翻译过程中起着关键作用。尽管最近的研究表明mTORC1信号传导与药物驱动行为有关，但mTORC1抑制剂雷帕霉素在抑制可卡因自我给药方面无效，这引发了关于mTORC1在药物相关行为中具体作用的疑问。在此，我们通过测量mTORC1活性指标并评估脑室内注射雷帕霉素对大鼠这些行为的影响，研究了mTORC1在三种与药物相关行为中的作用：可卡因摄取、戒断和可卡因寻求行为的恢复。我们发现，停止可卡因自我给药会增加伏隔核（NAC）中mTORC1活性指标。脑室内注射雷帕霉素可减弱渐进比率（PR）断点，并降低伏隔核壳（NACsh）和核心（NACc）中磷酸化p70核糖体S6激酶、GluA1 AMPAR和CAMKIIα的水平。在随后的一项研究中，我们在可卡因自我给药期间对大鼠进行脑室内注射雷帕霉素（2.5μg/侧/天，共5天），然后追踪成瘾相关行为直至戒断和消退的表达情况。雷帕霉素减少了有信号提示的无药期的觅药行为、PR反应和线索诱导的复吸，这些作用与NACsh中mTORC1活性、总CAMKIIα和GluA1 AMPAR水平降低有关。总之，这些数据突出了mTORC1在控制药物奖赏表达和维持的神经过程中的作用，包括长期复发易感性。这些作用似乎涉及mTORC1在调节NACsh中GluA1 AMPAR和CAMKIIα方面的作用。
