Facilitation of Extinction Retention and Reconsolidation Blockade in PTSD
About 6.4% of the U.S. population suffers from posttraumatic stress disorder (PTSD). Responses to evidence-based trauma-focused therapies for PTSD vary. This study tests whether allopregnanolone (Allo) treatment in individuals with refractory PTSD facilitates learning and memory processes underlying the efficacy of trauma-focused therapies for PTSD. Trauma-focused psychotherapies show general efficacy in PTSD. However, symptom improvement in response to such treatments can vary substantially among individuals with PTSD. Several factors may contribute to treatment response including neurobiological factors that impact brain capacities needed to reprocess trauma memories and consolidate reconfigured brain circuits during recovery. During trauma-focused therapies, activation of a threat-related memory renders the memory "labile" and engages two competing processes: extinction and reconsolidation. Extinction involves: a) activation of prefrontal cortical (PFC) inhibition of amygdala-mediated physiological and behavioral defense responses, and b) acquisition and consolidation of new learning (e.g., the conditioned threat stimulus or CS+ no longer signals threat in the new time-space context). At the molecular level, extinction involves both synaptic long-term potentiation (LTP) and long-term depression (LTD). Extinction thus improves function, but is not permanent, as amygdala-mediated defense responses may reemerge in a new context, upon re-exposure to the original threat, or with the passage of time. PTSD has been associated with deficits in both extinction learning and retention. Reconsolidation blockade also may contribute to PTSD recovery. Protein synthesis inhibitors (not safe/feasible in humans), beta-blockers, and protein kinase A (PKA) inhibitors can block reconsolidation (if given within an hour of brief threat memory reactivation),the the latter by disrupting phosphorylation of serine 845 residues on Glu-R1 AMPA receptors, thus limiting their synaptic incorporation-a prerequisite for memory reconsolidation. Thereafter, the former CS+-US association is "remembered", but amygdala-mediated defense responses are not co-activated by the CS+. Some, but not all human studies, have demonstrated propranolol-induced blockade of episodic and aversive memory reconsolidation, as well as PTSD symptom improvement in paradigms combining reconsolidation blockade and extinction.
Start: June 2021