mTORC I Inhibition in the Nucleus Accumbens 'Protects' Against the Expression of Drug Seeking and 'Relapse' and Is Associated with Reductions in GluAI AMPAR and CAMKIIα Levels
mTORC I Inhibition in the Nucleus Accumbens 'Protects' Against the Expression of Drug Seeking and 'Relapse' and Is Associated with Reductions in GluAI AMPAR and CAMKIIα Levels
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DOI：
10.1038/npp.2014.16
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发表时间：
2014-06-01
影响因子：
7.6
通讯作者：
Dayas, Christopher V.
中科院分区：
文献类型：
--
作者：
James, Morgan H.;Quinn, Rikki K.;Dayas, Christopher V.
The mechanistic target of rapamycin complex 1 (mTORC I) is necessary for synaptic plasticity, as it is critically involved in the translation of synaptic transmission-related proteins, such as Ca2+/Calmodulin-dependent kinase II alpha (CAMKII alpha) and AMPA receptor subunits (GluAs). Although recent studies have implicated mTORC I signaling in drug-motivated behavior, the ineffectiveness of rapamycin, an rnTORCI inhibitor, in suppressing cocaine self-administration has raised questions regarding the specific role of mTORC I in drug-related behaviors. Here, we examined mTORCI's role in three drug-related behaviors: cocaine taking, withdrawal, and reinstatement of cocaine seeking, by measuring indices of mTORCI 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 mTORC I activity in the nucleus accumbens (NAC). Intra-cerebroventricular rapamycin attenuated progressive ratio (PR) break points and reduced phospho-p70 ribosomal S6 kinase, GluAl AMPAR, and CAMKII alpha levels in the NAC shell (NACsh) and core (NACc). In a subsequent study, we treated rats with intra-NACsh infusions of rapamycin (2.5 mu g/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 mTORC I activity, total CAMKII alpha, and GluA I AMPAR levels in the NACsh. Together, these data highlight a role for mTORC I 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 mTORC I in the regulation of GluA I AMPARs and CAMKII alpha in the NACsh.
