title: Role for mTOR signaling and neuronal activity in morphine-induced adaptations in ventral tegmental area dopamine neurons.
abstract: While the abuse of opiate drugs continues to rise, the neuroadaptations that occur with long-term drug exposure remain poorly understood. We describe here a series of chronic morphine-induced adaptations in ventral tegmental area (VTA) dopamine neurons, which are mediated via downregulation of AKT-mTORC2 (mammalian target of rapamycin complex-2). Chronic opiates decrease the size of VTA dopamine neurons in rodents, an effect seen in humans as well, and concomitantly increase the excitability of the cells but decrease dopamine output to target regions. Chronic morphine decreases mTORC2 activity, and overexpression of Rictor, a component of mTORC2, prevents morphine-induced changes in cell morphology and activity. Further, local knockout of Rictor in VTA decreases DA soma size and reduces rewarding responses to morphine, consistent with the hypothesis that these adaptations represent a mechanism of reward tolerance. Together, these findings demonstrate a novel role for AKT-mTORC2 signaling in mediating neuroadaptations to opiate drugs of abuse.
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Michelle S
authors.initials: MS
authors.lastname: Mazei-Robison
authors.forename: Ja Wook
authors.initials: JW
authors.lastname: Koo
authors.forename: Allyson K
authors.initials: AK
authors.lastname: Friedman
authors.forename: Carien S
authors.initials: CS
authors.lastname: Lansink
authors.forename: Alfred J
authors.initials: AJ
authors.lastname: Robison
authors.forename: Monika
authors.initials: M
authors.lastname: Vinish
authors.forename: Vaishnav
authors.initials: V
authors.lastname: Krishnan
authors.forename: Seyun
authors.initials: S
authors.lastname: Kim
authors.forename: Michael A
authors.initials: MA
authors.lastname: Siuta
authors.forename: Aurelio
authors.initials: A
authors.lastname: Galli
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Niswender
authors.forename: Raghu
authors.initials: R
authors.lastname: Appasani
authors.forename: Monika C
authors.initials: MC
authors.lastname: Horvath
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Neve
authors.forename: Paul F
authors.initials: PF
authors.lastname: Worley
authors.forename: Solomon H
authors.initials: SH
authors.lastname: Snyder
authors.forename: Yasmin L
authors.initials: YL
authors.lastname: Hurd
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Cheer
authors.forename: Ming-Hu
authors.initials: MH
authors.lastname: Han
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Russo
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Nestler
mesh_terms: D000222:Adaptation, Physiological / Q000187:drug effects / Q000502:physiology*; D000293:Adolescent; D000328:Adult; D000818:Animals; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000502:physiology*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D015534:Trans-Activators / Q000502:physiology*; D014157:Transcription Factors; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000502:physiology*; D055815:Young Adult
chemical_list: C504923:Crtc2 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D009020:Morphine