Hennessy, Vanessa; (2025) Novel behavioural and psychopharmacological strategies for the prevention and treatment of aversive memories in men and women. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

This thesis explores the interaction between physiological stress responses and aversive memory performance following trauma, with a focus on epigenetic and molecular targets for novel interventions to attenuate intrusive, sensory-perceptual memories—a core symptom of post-traumatic stress disorder (PTSD) (Chapter 1, Section 1.1). Given that trauma exposure alone is not always sufficient for PTSD development, sex as a biological variable is considered as a key factor influencing stress responses and effectiveness of aversive memory modification strategies (Section 1.2). Research paradigms and methodologies employed in subsequent experimental chapters are outlined in Section 1.3. Chapter 2 examines novel psychopharmacological and behavioural strategies using a double-blind, randomised design (N=80; 40 women). The histone deacetylase inhibitor (HDACi) Sodium Valproate (400mg) or placebo was administered before retrieval + extinction or extinction alone of conditioned aversive (phobic) memory. HDACi facilitated (re)extinction but did not prevent the return of fear responses under challenge, with post-hoc analyses suggesting sex-dependent effects. Chapter 3 investigates the impact of post-trauma hydrocortisone (30mg) administration on intrusive memories in healthy men (N=60) and women (N=59). Hydrocortisone accelerated intrusion reduction over following week, with sex x baseline hormone interactions with hydrocortisone treatment modulating frequency effects. Chapter 4 explores mineralocorticoid receptor (MR) blockade using spironolactone (400mg) before analogue trauma in healthy men (N=78). While spironolactone had no effect on intrusion frequency, it significantly reduced the distress and vividness of intrusions. Notably, MR inhibition was testosterone-dependent with higher pre-stress levels resulting in reduced intrusion frequency, indicating a possible sex hormone interaction. Chapter 5 summarises these findings, integrating them within existing literature and discussing their clinical implications. Suggestions for future research are made aimed towards personalised psychiatric treatments and the development of empirically-based preventative strategies for stress-related disorders, targeting distressing, sensory-perceptual mnemonic symptoms.

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