Facilitation of Extinction Retention and Reconsolidation Blockade by IV Allopregnanolone in PTSD

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Trauma-focused psychotherapies show general efficacy in posttraumatic stress disorder (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 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 feasible in humans), beta-blockers, protein kinase A (PKA) inhibitors can block reconsolidation (if given within an hour of brief threat memory reactivation), 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+. In the proposed study, we aim to use a standard 3-day differential fear- conditioning paradigm to demonstrate facilitation of extinction retention (Expt. 1) and reconsolidation blockade (Expt. 2) by appropriately timed intravenous (IV) administration of allopregnanolone (Allo). Allo is a metabolite of progesterone that positively modulates GABA effects at GABAA receptors; sulfated metabolites of Allo antagonize NMDA receptors. Men and women with PTSD are at high risk for Allo deficiency, and low resting Allo has been associated with poor extinction retention. In contrast, administration of an Allo analog after brief reactivation of conditioned fear in Allo-deficient rodents has been shown to block reconsolidation. In Expts. 1 and 2 of the study, 128 men and women with PTSD will undergo differential fear conditioning (Day 1). On Day 2 of Expt. 1, IV Allo vs. placebo will be infused after extinction training to raise plasma Allo to resting levels associated with optimum extinction retention; extinction retention will be tested on Day 3. On Day 2 of Expt. 2, high dose IV Allo vs. placebo will be administered immediately after fear memory reactivation by a singe CS+, and reconsolidation blockade will be tested on Day 3. If this study is successful, Allo could potentially be administered to augment trauma-focused therapy in treatment refractory PTSD patients.