mTORC1 Inhibition in the Nucleus Accumbens ‘Protects’ Against the Expression of Drug Seeking and ‘Relapse’ and Is Associated with Reductions in GluA1 AMPAR and CAMKIIα Levels

• DOI: 10.1038/npp.2014.16
• Publication Date: 2014-01-28T10:53:16Z
• Authors: Morgan H James; Rikki K Quinn; Lin Kooi Ong; Emily M Levi; Janine L Charnley; Doug W Smith; Phillip W Dickson; Christopher V Dayas
• Keywords: 0301 basic medicine; 571; nucleus accumbens; GluAI; Drug-Seeking Behavior; cocaine; Self Administration; Mechanistic Target of Rapamycin Complex 1; Motor Activity; Nucleus Accumbens; Cocaine-Related Disorders; 03 medical and health sciences; Cocaine; Dopamine Uptake Inhibitors; mechanistic target of rapamycin (mTOR); Recurrence; Animals; Receptors, AMPA; Sirolimus; CAMKII alpha; rapamycin; TOR Serine-Threonine Kinases; Rats; CAMKIIα; Gene Expression Regulation; Multiprotein Complexes; Conditioning, Operant; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Reinforcement, Psychology; GluA1

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.