Behavioural therapy based on distraction alleviates impaired fear extinction in male serotonin transporter knockout rats

Background: The biological susceptibility model posits that some individuals, by genetic predisposition, are highly sensitive to environmental stimuli. Exposure to adverse stimuli leads to negative outcomes, and better outcomes follow favourable stimuli. Recent studies indicate that individuals carrying the low-activity (short; s) variant of the serotonin transporter (5-HTT)-linked polymorphic region (5-HTTLPR) show an enhanced vulnerability to posttraumatic stress disorder (PTSD). Simultaneously, they respond poorly to exposure therapy, the first-line treatment to enhance fear extinction in individuals with PTSD. Given that s-allele carriers also show improved adaptive responding when exposed to positive stimuli, we hypothesized that this trait could be used to offset impaired fear extinction. Methods: We explored this hypothesis preclinically using wild-type and 5-HTT knockout (5-HTT-/-) male rats (n = 36) that share behavioural similarities with 5-HTTLPR s-allele carriers. Subsequent to cued fear conditioning, animals were tested for short-(1 and 2 days postconditioning) and long-term (6 days postconditioning) fear extinction in the absence or presence of a secondary distracting stimulus predicting the delivery of sucrose pellets. Results: Introducing a secondary stimulus predicting sucrose pellets that distracts attention away from the fear-predicting stimulus led to a long-lasting improvement of impaired fear extinction in 5-HTT-/- male rats. Limitations: The context-dependency of the efficacy of the distraction therapy was not tested. In addition, it remains to be clarified whether the positive valence of the distracting stimulus is critical for the distraction of attention or whether a neutral and/or novel stimulus can induce similar effects. Finally, although of lesser importance from a therapeutic perspective, underlying mechanisms remain to be elucidated. Conclusion: These data indicate that positive environmental stimuli can be used to offset heightened responses to negative stimuli, particularly in individuals characterized by inherited 5-HTT downregulation and high sensitivity to environmental stimuli.