The glutamate homeostasis hypothesis of addiction

Nat Rev Neurosci. 2009 Aug;10(8):561-72. doi: 10.1038/nrn2515. Epub 2009 Jul 1.


Addiction is associated with neuroplasticity in the corticostriatal brain circuitry that is important for guiding adaptive behaviour. The hierarchy of corticostriatal information processing that normally permits the prefrontal cortex to regulate reinforcement-seeking behaviours is impaired by chronic drug use. A failure of the prefrontal cortex to control drug-seeking behaviours can be linked to an enduring imbalance between synaptic and non-synaptic glutamate, termed glutamate homeostasis. The imbalance in glutamate homeostasis engenders changes in neuroplasticity that impair communication between the prefrontal cortex and the nucleus accumbens. Some of these pathological changes are amenable to new glutamate- and neuroplasticity-based pharmacotherapies for treating addiction.

Publication types

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

MeSH terms

  • Animals
  • Glutamic Acid / metabolism*
  • Homeostasis / physiology*
  • Humans
  • Models, Biological*
  • Nerve Net / metabolism
  • Neural Pathways / metabolism
  • Nucleus Accumbens / metabolism
  • Nucleus Accumbens / pathology
  • Prefrontal Cortex / metabolism
  • Prefrontal Cortex / pathology
  • Substance-Related Disorders / metabolism*
  • Substance-Related Disorders / pathology


  • Glutamic Acid