Developing Memory Reconsolidation Blockers as Novel PTSD Treatments.

摘要

The original aim of this project was to develop pharmacologic interventions that, when presented together with traumatic memory reactivation, could serve as novel treatments for posttraumatic stress disorder (PTSD). Candidate drugs were tested in animals in a single-trial, fear conditioning paradigm. Some of those found promising were tested in human subjects with PTSD in a single reactivation session, psychophysiological experiment employing script-driven imagery. One drug, viz., propranolol, was tested in a randomized clinical trial (RCT) employing six traumatic memory reactivation sessions. Positive findings in rats included the following. Post-reactivation mifepristone (a glucocorticoid receptor antagonist) blocked the reconsolidation of a conditioned fear memory; propranolol (a beta-adrenergic blocker) prevented mifepristone s effect. Post-reactivation clonidine (an alpha-2-adrenergic agonist) also blocked the reconsolidation of a conditioned fear memory. Post-reactivation rapamycin, a protein synthesis inhibitor, also blocked the reconsolidation of a conditioned fear memory. This last effect was found to be exerted through a post-synaptic mechanism, in contrast to fear conditioning (memory consolidation), which was found to be exerted through a pre-synaptic mechanism. In humans with PTSD, we failed to find that mifepristone, with or without the N-methyl-D-aspartate (NMDA) partial agonist d-cycloserine, both administered prior to traumatic memory reactivation, reduced subsequent physiological responding during scriptdriven imagery of the traumatic event. Finally, in the context of a first, double-blind, placebo-controlled, RCT, we found that a series of six traumatic memory reactivation sessions plus propranolol was efficacious in reducing symptoms in chronic PTSD. This last finding represents a new, translational treatment for this disorder.