title: Nucleus accumbens core mammalian target of rapamycin signaling pathway is critical for cue-induced reinstatement of cocaine seeking in rats.
abstract: Relapse to drug seeking was studied using a rodent model of reinstatement induced by exposure to drug-related cues. The mammalian target of rapamycin (mTOR), a serine/threonine protein kinase that regulates cell growth and survival by controlling translation in response to nutrients and growth factors, has been demonstrated to be involved in neuronal adaptations that underlie drug addiction and learning and memory. We investigated the potential role of the mTOR signaling pathway in relapse to cocaine seeking by using the cue-induced reinstatement model in self-administering rats. We found that exposure to a cocaine-related cue induced reinstatement to cocaine seeking and increased phosphorylation of p70s6 kinase (p70s6k) and ribosomal protein s6 (rps6), measures of mTOR activity, in the nucleus accumbens (NAc) core but not shell. Furthermore, inhibition of NAc core but not shell p70s6k and rps6 phosphorylation by rapamycin decreased cue-induced reinstatement of cocaine seeking. Finally, stimulation of NAc core p70s6k and rps6 phosphorylation by NMDA enhanced cue-induced reinstatement, an effect reversed by rapamycin pretreatment. Additionally, rapamycin infusion into the NAc core or shell did not alter ongoing cocaine self-administration or cue-induced reinstatement of sucrose seeking. These findings indicate that cue-induced reinstatement of cocaine seeking is mediated by activation of the mTOR signaling pathway in the NAc core.
authors.affiliation: National Institute on Drug Dependence, Peking University, Beijing 100191, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Wang
authors.forename: Yi-xiao
authors.initials: YX
authors.lastname: Luo
authors.forename: Ying-ying
authors.initials: YY
authors.lastname: He
authors.forename: Fang-qiong
authors.initials: FQ
authors.lastname: Li
authors.forename: Hai-shui
authors.initials: HS
authors.lastname: Shi
authors.forename: Li-fen
authors.initials: LF
authors.lastname: Xue
authors.forename: Yan-xue
authors.initials: YX
authors.lastname: Xue
authors.forename: Lin
authors.initials: L
authors.lastname: Lu
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D003042:Cocaine / Q000008:administration & dosage*; D003216:Conditioning, Operant / Q000502:physiology*; D003463:Cues; D005106:Exploratory Behavior / Q000502:physiology*; D005108:Extinction, Psychological / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D009714:Nucleus Accumbens / Q000187:drug effects / Q000502:physiology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012646:Self Administration; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D003042:Cocaine