Developing Memory Reconsolidation Blockers as Novel PTSD Treatments

Abstract

Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information So far this project has published the original finding that the anti-progesterone and glucocorticoid receptor antagonist mifepristone, when administered systemically, reduces reconsolidation of a cue-conditioned fear response in rats, and that the beta-adrenergic blocker propranolol blocks this mifepristone effect. We have produced the original discovery that alpha-2-adrenergic agonist clonidine also reduces reconsolidation of a cue-conditioned fear response in rats in a dose-dependent manner. We have produced the original discovery that the mammalian target of rapamycin (mTOR) kinase-dependent signaling mediates stabilization of fear conditioning-produced synaptic strengthening in the conditioned stimulus pathways following memory recall in rats, thus providing a postretrieval memory update mechanism. We have achieved steady progress in the implementation of two randomized, double-blind, placebo-controlled studies in humans: one of post-reactivation mifepristone's ability to reduce psychophysiologic responding during traumatic imagery in trauma-exposed subjects, and the other of six sessions of post-reactivation propranolol for the treatment of PTSD. The blinds for these human studies have not yet been broken.

A neuroscience-based analysis of impacts of disaster memory on economic valuation.

“…R. Anderson & Bower, 1972; Lohnas et al, 2011; Melton, 1967; Siegel & Kahana, 2014). The idea that a reminder entails a recall of memory and a restorage of that memory provides an interesting model of posttraumatic stress disorder, which is marked by intrusive memories (Elzinga & Bremner, 2002; Nadel & Jacobs, 1996; Pitman, 2011; Verfaellie & Vasterling, 2009; Yehuda & LeDoux, 2007), potentially arising from individual discrete highly salient events (Hamner et al, 1999). In order to model the effect of intrusive memories, we applied reminders at regular intervals (every 50 timesteps, every 100 timesteps, every 200 timesteps).…”

Effects of Prereactivation Propranolol on Cocaine Craving Elicited by Imagery Script/Cue Sets in Opioid-dependent Polydrug Users

“…When similarly high doses of propranolol were tested in post-combat PTSD under double-blind conditions—and using only one reactivation session—they were no more effective than propranolol given in a no-reactivation control condition (Pitman 2011). …”

“…With a few exceptions (Kroes, Strange, et al, 2010; Saladin, Gray, et al, 2013), human studies of propranolol and memory have begun to include such a condition (Pitman 2011; Schwabe, Nader, et al, 2012) to strengthen a reconsolidation-based interpretation of the findings. Also, we administered propranolol before reactivation (so peak plasma levels would coincide with cue exposure), rather than immediately afterward.…”

“…Also, we administered propranolol before reactivation (so peak plasma levels would coincide with cue exposure), rather than immediately afterward. With some exceptions (Pitman 2011; Brunet, Poundja, et al, 2012; Schwabe, Nader, et al, 2012; Sevenster, Beckers, et al, 2012), the trend in human reconsolidation studies has been to administer propranolol after memory reactivation (Pitman 2011; Soeter and Kindt 2012; Saladin, Gray, et al, 2013) to help rule out drug effects on retrieval. These limitations would have impeded interpretation of a beneficial effect of propranolol if we had detected one.…”