Does Reconsolidation Occur in Humans: A Reply

Schiller and Phelps (2011) have provided a thoughtful and comprehensive review in the May issue of Frontiers in Behavioral Neurosciences entitled, “Does reconsolidation occur in humans? ” This scholarly paper captures many of the challenges in translating the animal research on reconsolidation to humans. We agree with their main argument that there is little published evidence in humans that meets one important reconsolidation criterion, namely, that the memory-weakening treatment should be administered after the memory reactivation, so as not to influence the preceding memory retrieval process. However, it is unclear whether pre-reactivation propranolol significantly hampers memory retrieval. On the basis of this uncertainty, Schiller and Phelps go on to suggest that the memory impairing effects of pre-reactivation propranolol (e.g., Kindt et al., 2009; Brunet et al., 2011) must be explained by some process other than reconsolidation. Such a conclusion appears illogical, because if propranolol does not impair retrieval sufficiently to preclude reconsolidation, then blockade of memory reconsolidation remains a viable explanation for pre-reactivation propranolol's memory-weakening action. Indeed, the ultimate evidence for successful memory retrieval is measured during reactivation (e.g., freezing behavior in rodent fear conditioning, GSR in human fear conditioning, etc.). Therefore, any impairment of retrieval should be detected. Moreover, as shown recently by Debiec et al. (2011) immediate post-retrieval beta-adrenergic receptor stimulation enhances reconsolidation of fear conditioning in the amygdala. In this scenario, administration of propranolol following memory retrieval (which results in arousal and noradrenergic stimulation) may be too late to be effective. So, a parsimonious explanation is that pre-reactivation propranolol did block reconsolidation to some extent in the above-mentioned studies. Pre-reactivation propranolol studies (and other studies with a similar design) ought to be pursued vigorously because, irrespective of how the memory impairing effect is obtained, they offer the prospect of a novel approach to treating mental disorders that have at their core an emotional, usually traumatic, memory. Although Schiller and Phelps acknowledge some of the challenges of blocking reconsolidation using pharmacological means in humans, it is important to note the reasons for this difficulty. In animals, reconsolidation (i.e., protein synthesis) is believed to begin 3–10 min after memory reactivation (Monfils et al., 2009). Most of it appears to take place within the first 2 h (Przybyslawski et al., 1999) and to be over by the sixth hour (Duvarci and Nader, 2004). Considering that oral propranolol takes about 90 min to reach its peak bioavailability in human blood (Marino, 1987); and considering that only a fraction of this drug will eventually cross the blood–brain barrier to be available to exert the necessary effect, protocols that use post-reactivation propranolol are vulnerable to yielding negative results because not enough protein synthesis will have been blocked by the time the drug reaches its full effect in the human brain. Since conducting our proof-of-concept study in posttraumatic stress disorder (PTSD; Brunet et al., 2008), which used post-reactivation propranolol, we have opted to use pre-reactivation propranolol in an attempt to develop what we hope will be a more potent therapeutic protocol (see Brunet et al., 2011). It is unfortunate that this type of protocol does not meet an important scientific criterion for studies that use it to be labeled as genuine “reconsolidation” studies, but this is the price to pay for conducting sound translational research in patients. Schiller et al. (2010) are to be commended for their efforts to devise a human protocol that circumvents the problems associated with pharmacological blockade of reconsolidation by incorporating new material into a destabilized old memory, rather than simply blocking its reconsolidation. However, they have yet to show that such an approach is sufficiently potent to help patients overcome their psychological symptoms stemming from a traumatic emotional memory.