Aversion-resistant fentanyl self-administration in mice

Psychopharmacology (Berl). 2021 Mar;238(3):699-710. doi: 10.1007/s00213-020-05722-6. Epub 2020 Nov 23.


Rationale: Animal models of compulsive drug use that continues despite negative consequences can be used to investigate the neural mechanisms of addiction. However, models of punished or aversion-resistant opioid self-administration are notably lacking.

Objectives: We sought to develop an aversion-resistant, oral fentanyl self-administration paradigm.

Methods: In Experiment 1, C57BL/6J male and female, adult mice consumed fentanyl (10 μg/mL) in a two-bottle drinking in the dark task and escalating concentrations of quinine were added to the bottles. In Experiment 2, mice were trained to administer oral fentanyl (10 μg/mL) in an operant response task. Quinine was next added to the fentanyl solution in escalating concentrations. In Experiment 3, mice were trained to respond for oral fentanyl or fentanyl adulterated with 500 μM quinine on every session. In Experiment 4, mice were trained to respond for a 1% sucrose solution before introduction of quinine.

Results: Quinine reduced two-bottle choice consumption in males but not in females. Both sexes demonstrated the ability to detect the selected concentrations of quinine in fentanyl. In the operant chamber, mice responded robustly for oral fentanyl but introduction of quinine at any stage of training was insufficient to reduce responding. In contrast, quinine reduced responding for sucrose at concentrations above 250 μM.

Conclusions: Mice will respond for and consume oral fentanyl in both a two-bottle choice and an operant response task. Quinine is detectable in fentanyl but mice will continue to respond for and consume fentanyl with quinine in both paradigms. These data support the use of these models in behavioral studies of compulsive-like opioid use.

Keywords: Addiction; Compulsive; Mouse; Opioid; Quinine.

MeSH terms

  • Affect / drug effects
  • Analgesics, Opioid / administration & dosage*
  • Animals
  • Behavior, Addictive / psychology*
  • Choice Behavior / drug effects*
  • Conditioning, Operant / drug effects
  • Dose-Response Relationship, Drug
  • Drinking Behavior / physiology
  • Female
  • Fentanyl / administration & dosage*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Quinine / administration & dosage*
  • Self Administration
  • Sex Factors
  • Sucrose / administration & dosage*
  • Taste / drug effects


  • Analgesics, Opioid
  • Sucrose
  • Quinine
  • Fentanyl