Role for mTOR signaling and neuronal activity in morphine-induced adaptations in ventral tegmental area dopamine neurons.

Mazei-Robison MS, Koo JW, Friedman AK, Lansink CS, Robison AJ, Vinish M, Krishnan V, Kim S, Siuta MA, Galli A, Niswender KD, Appasani R, Horvath MC, Neve RL, Worley PF, Snyder SH, Hurd YL, Cheer JF, Han MH, Russo SJ, Nestler EJ
Neuron. 2011 72 (6): 977-90

PMID: 22196333 · PMCID: PMC3246191 · DOI:10.1016/j.neuron.2011.10.012

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.

Copyright © 2011 Elsevier Inc. All rights reserved.

MeSH Terms (19)

Adaptation, Physiological Adolescent Adult Animals Dopaminergic Neurons Female Humans Male Mice Mice, Inbred C57BL Morphine Neurons Rats Rats, Sprague-Dawley Signal Transduction Trans-Activators Transcription Factors Ventral Tegmental Area Young Adult

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