Contribution of Dynorphin and Orexin Neuropeptide Systems to the Motivational Effects of Alcohol

Handb Exp Pharmacol. 2018;248:473-503. doi: 10.1007/164_2018_100.


Understanding the neural systems that drive alcohol motivation and are disrupted in alcohol use disorders is of critical importance in developing novel treatments. The dynorphin and orexin/hypocretin neuropeptide systems are particularly relevant with respect to alcohol use and misuse. Both systems are strongly associated with alcohol-seeking behaviors, particularly in cases of high levels of alcohol use as seen in dependence. Furthermore, both systems also play a role in stress and anxiety, indicating that disruption of these systems may underlie long-term homeostatic dysregulation seen in alcohol use disorders. These systems are also closely interrelated with one another - dynorphin/kappa opioid receptors and orexin/hypocretin receptors are found in similar regions and hypocretin/orexin neurons also express dynorphin - suggesting that these two systems may work together in the regulation of alcohol seeking and may be mutually disrupted in alcohol use disorders. This chapter reviews studies demonstrating a role for each of these systems in motivated behavior, with a focus on their roles in regulating alcohol-seeking and self-administration behaviors. Consideration is also given to evidence indicating that these neuropeptide systems may be viable targets for the development of potential treatments for alcohol use disorders.

Keywords: Alcohol; Dynorphin; Ethanol; Hypocretin; Kappa opioid receptor; Orexin.

MeSH terms

  • Alcoholism*
  • Dynorphins / physiology*
  • Ethanol / pharmacology*
  • Humans
  • Motivation*
  • Orexins / physiology*


  • Orexins
  • Ethanol
  • Dynorphins