Differential behavioral and molecular alterations upon protracted abstinence from cocaine versus morphine, nicotine, THC and alcohol

Addict Biol. 2017 Sep;22(5):1205-1217. doi: 10.1111/adb.12405. Epub 2016 Apr 28.


Unified theories of addiction are challenged by differing drug-seeking behaviors and neurobiological adaptations across drug classes, particularly for narcotics and psychostimulants. We previously showed that protracted abstinence to opiates leads to despair behavior and social withdrawal in mice, and we identified a transcriptional signature in the extended amygdala that was also present in animals abstinent from nicotine, Δ9-tetrahydrocannabinol (THC) and alcohol. Here we examined whether protracted abstinence to these four drugs would also share common behavioral features, and eventually differ from abstinence to the prototypic psychostimulant cocaine. We found similar reduced social recognition, increased motor stereotypies and increased anxiety with relevant c-fos response alterations in morphine, nicotine, THC and alcohol abstinent mice. Protracted abstinence to cocaine, however, led to strikingly distinct, mostly opposing adaptations at all levels, including behavioral responses, neuronal activation and gene expression. Together, these data further document the existence of common hallmarks for protracted abstinence to opiates, nicotine, THC and alcohol that develop within motivation/emotion brain circuits. In our model, however, these do not apply to cocaine, supporting the notion of unique mechanisms in psychostimulant abuse.

Keywords: extended amygdala; gene expression; social interaction.

Publication types

  • Comparative Study

MeSH terms

  • Alcohol Abstinence
  • Amygdala / metabolism*
  • Analgesics, Opioid / adverse effects*
  • Animals
  • Anxiety / psychology
  • Behavior, Animal*
  • Brain / metabolism
  • Cannabinoid Receptor Agonists / adverse effects*
  • Central Nervous System Depressants / adverse effects*
  • Cocaine / adverse effects
  • Dopamine Uptake Inhibitors / adverse effects*
  • Dronabinol / adverse effects
  • Drug-Seeking Behavior
  • Emotions
  • Ethanol / adverse effects
  • Male
  • Mice
  • Morphine / adverse effects
  • Motivation
  • Nicotine / adverse effects
  • Nicotinic Agonists / adverse effects*
  • Proto-Oncogene Proteins c-fos / metabolism
  • Social Behavior*
  • Stereotyped Behavior / physiology
  • Substance Withdrawal Syndrome / metabolism
  • Substance Withdrawal Syndrome / physiopathology*
  • Substance Withdrawal Syndrome / psychology


  • Analgesics, Opioid
  • Cannabinoid Receptor Agonists
  • Central Nervous System Depressants
  • Dopamine Uptake Inhibitors
  • Nicotinic Agonists
  • Proto-Oncogene Proteins c-fos
  • Ethanol
  • Nicotine
  • Morphine
  • Dronabinol
  • Cocaine