mTOR complex 1: a key player in neuroadaptations induced by drugs of abuse

J Neurochem. 2014 Jul;130(2):172-84. doi: 10.1111/jnc.12725. Epub 2014 Apr 19.

Abstract

The mammalian (or mechanistic) target of rapamycin (mTOR) complex 1 (mTORC1) is a serine and threonine kinase that regulates cell growth, survival, and proliferation. mTORC1 is a master controller of the translation of a subset of mRNAs. In the central nervous system mTORC1 plays a crucial role in mechanisms underlying learning and memory by controlling synaptic protein synthesis. Here, we review recent evidence suggesting that the mTORC1 signaling pathway promotes neuroadaptations following exposure to a diverse group of drugs of abuse including stimulants, cannabinoids, opiates, and alcohol. We further describe potential molecular mechanisms by which drug-induced mTORC1 activation may alter brain functions. Finally, we propose that mTORC1 is a focal point shared by drugs of abuse to mediate drug-related behaviors such as reward seeking and excessive drug intake, and offer future directions to decipher the contribution of the kinase to mechanisms underlying addiction. Recent studies suggesting that exposure to diverse classes of drugs of abuse as well as exposure to drug-associated memories lead to mTORC1 kinase activation in the limbic system. In turn, mTORC1 controls the onset and the maintenance of pathological neuroadaptions that underlie several features of drug addiction such as drug seeking and relapse. Therefore, we propose that targeting mTORC1 and its effectors is a promising strategy to treat drug disorders.

Keywords: addiction; alcohol; drugs of abuse; limbic system; mTOR; translation.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Adaptation, Physiological / drug effects*
  • Animals
  • Autophagy / drug effects
  • Behavior / drug effects
  • Humans
  • Illicit Drugs / pharmacology*
  • Immunosuppressive Agents
  • Mechanistic Target of Rapamycin Complex 1
  • Multiprotein Complexes / drug effects*
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / physiology*
  • Neurons / drug effects
  • Protein Biosynthesis / drug effects
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • Signal Transduction / genetics
  • Signal Transduction / physiology
  • Sirolimus
  • Substance-Related Disorders / genetics
  • Substance-Related Disorders / physiopathology
  • Substance-Related Disorders / psychology
  • Synaptic Transmission / drug effects
  • TOR Serine-Threonine Kinases / drug effects*
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / physiology*

Substances

  • Illicit Drugs
  • Immunosuppressive Agents
  • Multiprotein Complexes
  • RNA, Messenger
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Sirolimus