Male and female rats show opiate withdrawal-induced place aversion and extinction in a Y-maze paradigm

Behav Brain Res. 2023 Feb 2:437:114122. doi: 10.1016/j.bbr.2022.114122. Epub 2022 Sep 26.


Gender differences have been observed in the vulnerability to drug abuse and in the different stages of the addictive process. In opiate dependence, differences between sexes have been shown in humans and laboratory animals in various phases of opiate addiction, especially in withdrawal-associated negative affective states. Using a Y-maze conditioned place aversion paradigm, we investigated potential sex differences in the expression and extinction of the aversive memory of precipitated opiate withdrawal state in morphine-dependent rats. No significant difference between sexes was observed in the occurrence of withdrawal signs following naloxone injection during conditioning. Moreover, opiate withdrawal memory expression and extinction following repeated testing was demonstrated in both male and female rats, with no significant differences between sexes. Finally, we report spontaneous recovery following extinction of opiate withdrawal memory. Altogether these data provide further evidence that persistent withdrawal-related memories may be strong drivers of opiate dependence, and demonstrate that both males and females can be used in experimental rodent cohorts to better understand opiate-related effects, reward, aversive state of withdrawal, abstinence and relapse.

Keywords: Opiate dependence; Place aversion; Recovery; Sex variable; Withdrawal aversive state.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics, Opioid / pharmacology
  • Animals
  • Avoidance Learning
  • Female
  • Humans
  • Male
  • Morphine / pharmacology
  • Morphine Dependence* / metabolism
  • Naloxone / pharmacology
  • Narcotic Antagonists / pharmacology
  • Opiate Alkaloids*
  • Opioid-Related Disorders*
  • Rats
  • Substance Withdrawal Syndrome* / metabolism


  • Opiate Alkaloids
  • Naloxone
  • Analgesics, Opioid
  • Morphine
  • Narcotic Antagonists