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<p>Comorbidity between post-traumatic stress disorder (PTSD) and alcohol use is common and mutually-reinforcing, yet there are no pharmacological strategies that specifically target trauma-linked escalation of alcohol intake. We evaluated whether 3,4-methylenedioxymethamphetamine (MDMA), given in a therapy-adjunctive fashion (30 min before fear extinction), could facilitate extinction of conditioned fear and reduce alcohol consumption in a rat model that combines fear conditioning, binge-like alcohol access, abstinence, and re-exposure. Inbred alcohol-preferring (iP) and outbred Wistar rats of both sexes underwent auditory fear conditioning, voluntary ethanol drinking, and subsequently fear extinction after MDMA or vehicle administration, with drug-free extinction recall and alcohol consumption assessed thereafter. Fear conditioning increased voluntary alcohol intake only in iP rats, suggesting a genotype-related fear–alcohol contingency. MDMA acutely reduced freezing during extinction, but ultimately reshaped across-session freezing patterns in a strain- and sex-dependent manner. There were no lasting MDMA treatment effects on next-day drug-free recall. MDMA also altered on-drug fear-expression during extinction without affecting later recall in an iP rat cohort without prior alcohol exposure, indicating the effect is not secondary to drinking history. Critically, MDMA prevented the shock-related increase in alcohol consumption but only in iP rats. These data suggest MDMA’s most reliable action in this model is to disrupt trauma-linked escalation of alcohol intake in genetically- and experientially- vulnerable rats, rather than to globally enhance fear extinction.</p>

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MDMA alters fear extinction, and reduces alcohol consumption in inbred alcohol preferring iP rats but not outbred Wistar rats

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月27日

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  • Kade L. Huckstep,
  • Billi Newton,
  • Grace Bailey,
  • Annai Charlton,
  • Amy J. Pearl,
  • Xavier J. Maddern,
  • Robyn M. Brown,
  • Gavan P. McNally,
  • Dan I. Lubman,
  • Shalini Arunogiri,
  • Kirsten C. Morley,
  • Erin J. Campbell,
  • Andrew J. Lawrence,
  • Leigh C. Walker

摘要

Comorbidity between post-traumatic stress disorder (PTSD) and alcohol use is common and mutually-reinforcing, yet there are no pharmacological strategies that specifically target trauma-linked escalation of alcohol intake. We evaluated whether 3,4-methylenedioxymethamphetamine (MDMA), given in a therapy-adjunctive fashion (30 min before fear extinction), could facilitate extinction of conditioned fear and reduce alcohol consumption in a rat model that combines fear conditioning, binge-like alcohol access, abstinence, and re-exposure. Inbred alcohol-preferring (iP) and outbred Wistar rats of both sexes underwent auditory fear conditioning, voluntary ethanol drinking, and subsequently fear extinction after MDMA or vehicle administration, with drug-free extinction recall and alcohol consumption assessed thereafter. Fear conditioning increased voluntary alcohol intake only in iP rats, suggesting a genotype-related fear–alcohol contingency. MDMA acutely reduced freezing during extinction, but ultimately reshaped across-session freezing patterns in a strain- and sex-dependent manner. There were no lasting MDMA treatment effects on next-day drug-free recall. MDMA also altered on-drug fear-expression during extinction without affecting later recall in an iP rat cohort without prior alcohol exposure, indicating the effect is not secondary to drinking history. Critically, MDMA prevented the shock-related increase in alcohol consumption but only in iP rats. These data suggest MDMA’s most reliable action in this model is to disrupt trauma-linked escalation of alcohol intake in genetically- and experientially- vulnerable rats, rather than to globally enhance fear extinction.