Toward reconsolidation blockade as a novel treatment for PTSD

• Main Authors: Roger K. Pitman, Alain Brunet, Vadim Bolshakov, Karine Gamache, Karim Nader
• Format: Article
• Language: English
• Published: Taylor & Francis Group 2012-09-01
• Series: European Journal of Psychotraumatology
• Subjects: PTSD; mice; classical conditioning; reconsolidation blockade; systemic drugs

Rationale/statement of the problem : Animal research has challenged the permanency of memory by suggesting that reactivation (retrieval) of a specific memory may return it to a labile state from which it must be “re-consolidated” if it is to persist. Pharmacologically blocking reconsolidation offers the therapeutic possibility of weakening traumatic memories in post-traumatic stress disorder (PTSD). Methods : We have been testing the above hypothesis using systemic drugs approved for human use. In rats we employ classical conditioning consisting of pairing a tone CS with a shock US on Day 1 (acquisition), presenting the tone without shock on Day 2 (reactivation) followed by drug, and then re-presenting the CS alone on Days 3 and 10 (tests). We have also used slice electrophysiology to measure the increase in cortico- and thalamo-lateral amygdala synaptic efficacy as a result of the tone-shock association, and then decrement in this efficacy following reconsolidation blockade. In PTSD subjects, we have administered oral drug along with verbal or written narration of the traumatic event (reactivation) and subsequently measured the strength of the traumatic memory via psychophysiological recording during script-driven imagery, and/or symptom report. Results : In animal work, we have found that the antiglucocorticoid receptor mifepristone, the protein synthesis inhibitor rapamycin, and the alpha-2-adrenergic autoreceptor agonist clonidine all block partially reconsolidation of conditioned fear. Clonidine does so in a dose-dependent manner. Additionally, rapamycin reverses the synaptic enhancement described above, providing an underlying physiological basis for reconsolidation blockade. In humans, we have found that traumatic memory reactivation plus double-blind, placebo-controlled propranolol reduce physiologic responding during script-driven imagery, and that six weekly open-label propranolol plus memory reactivation sessions reduce PTSD symptoms to a similar degree as current cognitive behavioral treatments. A double-blind clinical trial is underway. Conclusion : The above results show progress toward a clinical application of reconsolidation blockade, but much more needs to be done before efficacy is demonstrated.