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.
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.
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.
Morgan H
MH
James
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.
Rikki K
RK
Quinn
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.
Lin Kooi
LK
Ong
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.
Emily M
EM
Levi
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.
Janine L
JL
Charnley
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.
Doug W
DW
Smith
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.
Phillip W
PW
Dickson
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.
Christopher V
CV
Dayas
D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D003042:Cocaine / Q000009:adverse effects; D019970:Cocaine-Related Disorders / Q000517:prevention & control; D003216:Conditioning, Operant / Q000187:drug effects; D018765:Dopamine Uptake Inhibitors / Q000009:adverse effects; D058999:Drug-Seeking Behavior / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D000076222:Mechanistic Target of Rapamycin Complex 1; D009043:Motor Activity; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009714:Nucleus Accumbens / Q000187:drug effects*; D051381:Rats; D018091:Receptors, AMPA / Q000378:metabolism*; D012008:Recurrence; D012054:Reinforcement, Psychology; D012646:Self Administration; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D003042:Cocaine; D018765:Dopamine Uptake Inhibitors; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D018091:Receptors, AMPA; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases