Sex-dependent opposite effects of a tropomyosin-related kinase B receptor (TrkB) agonist 7,8-dihydroxyflavone on cued fear extinction in mice

Pharmacological Enhancement of Extinction Retention in Non-stressed Adolescent Rats but Not Those Exposed to Chronic Corticosterone

“…However, 7,8-DHF administration had no impact in chronically stressed adolescent rats (i.e., those implanted with a 7-day-release corticosterone pellet; Analysis 2). These results contrast with those of Andero et al (2011) and Tohyama et al (2020) that 7,8-DHF enhanced within-session extinction in non-stressed adult mice and those exposed to immobilization stress. The possibility of a species difference is supported by the consistency of our results with reports that genetic antagonism of TrkB-mediated signaling in the amygdala of rats impairs the retention of fear extinction whilst leaving the acquisition of extinction intact ( Chhatwal et al, 2006 ).…”

“…Future work may also seek to extend the present work in male adolescent rats by testing whether 7,8-DHF enhances fear extinction consolidation in adolescent females and whether chronic stress interferes with such an effect. Not only are fluctuations in estradiol levels across the rodent estrous cycle associated with varying effectiveness of extinction in adolescent female rats ( Perry et al, 2020 ) but 7,8-DHF was reported to hinder extinction learning in adult female mice ( Tohyama et al, 2020 ), or exert no influence on extinction learning, retention, or renewal ( Baker-Andresen et al, 2013 ). Those effects in females are in stark contrast to the enhancement of fear extinction in male adult mice ( Andero et al, 2011 ; Tohyama et al, 2020 ) and adolescent male rats (non-stressed) reported in the current study.…”

“…Not only are fluctuations in estradiol levels across the rodent estrous cycle associated with varying effectiveness of extinction in adolescent female rats ( Perry et al, 2020 ) but 7,8-DHF was reported to hinder extinction learning in adult female mice ( Tohyama et al, 2020 ), or exert no influence on extinction learning, retention, or renewal ( Baker-Andresen et al, 2013 ). Those effects in females are in stark contrast to the enhancement of fear extinction in male adult mice ( Andero et al, 2011 ; Tohyama et al, 2020 ) and adolescent male rats (non-stressed) reported in the current study. Whilst age-dependent effects are possible, the possibility of sex-specific effects of 7,8-DHF on fear extinction requires addressing.…”

“…Therefore, here we examined the potential of an alternative pharmacological adjunct, 7,8-dihydroxyflavone (7,8-DHF), to improve fear extinction retention in adolescent rats exposed to chronic corticosterone. This adjunct was chosen based on a report that the administration of 7,8-DHF prior to extinction enhanced cued fear extinction in male mice ( Tohyama et al, 2020 ), as well as a study which found that administration of 7,8-DHF prior to extinction reduced fear responses during extinction training in both non-stressed adult mice as well as those exposed to immobilization stress prior to fear conditioning ( Andero et al, 2011 ). The non-stressed mice given 7,8-DHF also exhibited less relapse (i.e., reinstatement) of extinguished fear, compared to those given an injection of the vehicle.…”

7,8-Dihydroxyflavone and Neuropsychiatric Disorders: A Translational Perspective from the Mechanism to Drug Development

“…Due to the difficulty of fear, memory extinction is a typical feature of post-traumatic stress disorder (PTSD); however, currently, there is a lack of effective treatment drugs for PTSD [ 158 - 160 ]. Studies have shown that 7,8-DHF can improve the fear memory deficit or accelerate the extinction of fear memory, which indicates that 7,8-DHF is likely to be a candidate drug for the treatment of PTSD [ 161 - 165 ].…”