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

Post-traumatic stress disorder and alcohol use often co-occur and worsen each other, but no medications specifically target trauma-driven increases in drinking. In rats predisposed to heavy alcohol use (inbred alcohol-preferring rats), a single dose of MDMA given before fear-extinction training prevented the rise in alcohol consumption that normally follows a stressful experience. MDMA did not improve long-term fear extinction memory in any group. The effect on drinking was specific to the genetically vulnerable rats and was not explained by prior alcohol history. MDMA's main benefit in this model was disrupting the link between trauma and escalated alcohol intake, not enhancing fear extinction.

Study at a glance

Abstract

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.