Journal article
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 CAMKII alpha Levels
Neuropsychopharmacology (New York, N.Y.), Vol.39, pp.1694-1702
28/01/2014
PMID: 24469593
Metrics
10 Record Views
UN Sustainable Development Goals (SDGs)
This output has contributed to the advancement of the following goals:
Source: InCites
Abstract
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.
Details
- Title
- 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 CAMKII alpha Levels
- Creators
- Morgan H. James (Author) - University of Newcastle AustraliaRikki K Quinn (Author) - University of Newcastle AustraliaLin Kooi Ong (Author) - University of Newcastle AustraliaEmily M. Levi (Author) - University of Newcastle AustraliaJanine L. Charnley (Author) - University of Newcastle AustraliaDoug W. Smith (Author) - University of Newcastle AustraliaPhillip W. Dickson (Author) - University of Newcastle AustraliaChristopher V. Dayas (Corresponding Author) - University of Newcastle Australia
- Publication Details
- Neuropsychopharmacology (New York, N.Y.), Vol.39, pp.1694-1702
- Publisher
- Springer Nature
- Identifiers
- 991013086313402368
- Copyright
- (c) 2014 American College of Neuropsychopharmacology. All rights reserved 0893-133X/14.
- Academic Unit
- SCU College
- Language
- English
- Resource Type
- Journal article