Stress-Induced Reinstatement of Drug Seeking: 20 Years of Progress

Neuropsychopharmacology. 2016 Jan;41(1):335-56. doi: 10.1038/npp.2015.142. Epub 2015 May 15.


In human addicts, drug relapse and craving are often provoked by stress. Since 1995, this clinical scenario has been studied using a rat model of stress-induced reinstatement of drug seeking. Here, we first discuss the generality of stress-induced reinstatement to different drugs of abuse, different stressors, and different behavioral procedures. We also discuss neuropharmacological mechanisms, and brain areas and circuits controlling stress-induced reinstatement of drug seeking. We conclude by discussing results from translational human laboratory studies and clinical trials that were inspired by results from rat studies on stress-induced reinstatement. Our main conclusions are (1) The phenomenon of stress-induced reinstatement, first shown with an intermittent footshock stressor in rats trained to self-administer heroin, generalizes to other abused drugs, including cocaine, methamphetamine, nicotine, and alcohol, and is also observed in the conditioned place preference model in rats and mice. This phenomenon, however, is stressor specific and not all stressors induce reinstatement of drug seeking. (2) Neuropharmacological studies indicate the involvement of corticotropin-releasing factor (CRF), noradrenaline, dopamine, glutamate, kappa/dynorphin, and several other peptide and neurotransmitter systems in stress-induced reinstatement. Neuropharmacology and circuitry studies indicate the involvement of CRF and noradrenaline transmission in bed nucleus of stria terminalis and central amygdala, and dopamine, CRF, kappa/dynorphin, and glutamate transmission in other components of the mesocorticolimbic dopamine system (ventral tegmental area, medial prefrontal cortex, orbitofrontal cortex, and nucleus accumbens). (3) Translational human laboratory studies and a recent clinical trial study show the efficacy of alpha-2 adrenoceptor agonists in decreasing stress-induced drug craving and stress-induced initial heroin lapse.

Publication types

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

MeSH terms

  • Animals
  • Behavior, Addictive / metabolism*
  • Behavior, Addictive / pathology
  • Behavior, Addictive / psychology
  • Brain / metabolism*
  • Brain / pathology
  • Conditioning, Psychological / physiology
  • Drug-Seeking Behavior / physiology*
  • Glucocorticoids / biosynthesis
  • Humans
  • Illicit Drugs / metabolism
  • Nerve Net / metabolism*
  • Nerve Net / pathology
  • Self Administration
  • Stress, Psychological / metabolism*
  • Stress, Psychological / pathology
  • Stress, Psychological / psychology


  • Glucocorticoids
  • Illicit Drugs