- Title
- 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
- Creator
- James, Morgan H.; Quinn, Rikki K.; Ong, Lin Kooi; Levi, Emily M.; Charnley, Janine L.; Smith, Doug W.; Dickson, Phillip W.; Dayas, Christopher V.
- Relation
- Neuropsychopharmacology Vol. 39, Issue 7, p. 1694-1702
- Publisher Link
- http://dx.doi.org/10.1038/npp.2014.16
- Publisher
- Nature Publishing Group
- Resource Type
- journal article
- Date
- 2014
- Description
- 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 Ca²⁺/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.
- Subject
- mechanistic target of rapamycin (mTOR); rapamycin; nucleus accumbens; GluA1; CAMKIIα; cocaine
- Identifier
- http://hdl.handle.net/1959.13/1304557
- Identifier
- uon:20866
- Identifier
- ISSN:1740-634X
- Language
- eng
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