title: Rapamycin reduces motivated responding for cocaine and alters GluA1 expression in the ventral but not dorsal striatum.
abstract: The mechanistic target of rapamycin complex 1 (mTORC1) regulates synaptic protein synthesis and therefore synaptic function and plasticity. A role for mTORC1 has recently been demonstrated for addiction-related behaviors. For example, central or intra-accumbal injections of the mTORC1 inhibitor rapamycin attenuates several indices of cocaine-seeking including progressive ratio (PR) responding and reinstatement. These behavioral effects are associated with decreased mTORC1 activity and synaptic protein translation in the nucleus accumbens (NAC) and point to a possible therapeutic role for rapamycin in the treatment of addiction. Currently, it is unclear whether similar behavioral and biochemical effects can be achieved by administering rapamycin systemically, which represents a more clinically-appropriate route of administration. Here, we assessed the effects of repeated, systemic administration of rapamycin (10mg/kg, i.p.) on PR responding for cocaine. We also assessed whether systemic rapamycin was associated with changes in measures of mTORC1 activity and GluA1 expression in the ventral and dorsal striatum. We report that systemic rapamycin treatment reduced PR breakpoints to levels comparable to intra-NAC rapamycin. Systemic rapamycin treatment also reduced phosphorylated p70S6K and GluA1 AMPARs within the NAC but not dorsal striatum. Thus, systemic administration of rapamycin is as effective at reducing drug seeking behavior and measures of mTORC1 activity compared to direct accumbal application and may therefore represent a possible therapeutic option in the treatment of addiction. Possible caveats of this treatment approach are discussed.
authors.affiliation: Brain Health Institute, Rutgers University, NJ, USA; 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.
authors.forename: Morgan H
authors.initials: MH
authors.lastname: James
authors.affiliation: 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.
authors.forename: Rikki K
authors.initials: RK
authors.lastname: Quinn
authors.affiliation: 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.
authors.forename: Lin Kooi
authors.initials: LK
authors.lastname: Ong
authors.affiliation: 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.
authors.forename: Emily M
authors.initials: EM
authors.lastname: Levi
authors.affiliation: 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.
authors.forename: Doug W
authors.initials: DW
authors.lastname: Smith
authors.affiliation: 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.
authors.forename: Phillip W
authors.initials: PW
authors.lastname: Dickson
authors.affiliation: 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. Electronic address: Christopher.Dayas@newcastle.edu.au.
authors.forename: Christopher V
authors.initials: CV
authors.lastname: Dayas
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003042:Cocaine / Q000494:pharmacology*; D058999:Drug-Seeking Behavior / Q000187:drug effects; D005108:Extinction, Psychological / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D009042:Motivation / Q000187:drug effects*; D046912:Multiprotein Complexes / Q000378:metabolism; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism*; D012646:Self Administration / Q000523:psychology; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D066328:Ventral Striatum / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology
chemical_list: D003042:Cocaine; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D018091:Receptors, AMPA; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases
keywords: Cocaine; Nucleus accumbens; Progressive ratio; Rapamycin; Striatum; mTOR