Evidence indicates that the biochemical and molecular mechanisms of depotentiation are opposite to those of long-term potentiation. For example, long-term potentiation is associated with membrane insertion of nonNMDA receptors.14 Depotentiation, by contrast, is associated with internalization of the same type of receptors (see ref 15). Po-Wu Gean and colleagues demonstrated that depotentiation occurs in the

amygdala.16,17 For example, depotentiation-inducing low-frequency stimulation of the amygdala in vivo 10 min after fear acquisition blocked the Inhibitors,research,lifescience,medical expression of conditioned fear 24 h later, an effect that could be interpreted as a mimicking of extinction.16 These findings are intriguing, but puzzling, because they would seem to offer no explanation of recovery Inhibitors,research,lifescience,medical of fear following extinction through reinstatement, Raf activity renewal, or spontaneous recovery. Although “new learning” and “unlearning” mechanisms of extinction are often presented as mutually exclusive possibilities, it has been acknowledged that both may occur to some extent, eg, ref 2. Interestingly, depotentiation is inducible more readily at short intervals following induction of longterm potentiation and does not seem to be inducible at all at intervals Inhibitors,research,lifescience,medical greater than about 1 h (see ref 18). In rodents, extinction studies typically do not use intervals between acquisition and extinction training of less than 24 h, although biochemical processes of extinction

were reported to be different when extinction training was conducted immediately following acquisition compared with 1 h or 3 h after extinction training.19 To test the hypothesis that extinction training given Inhibitors,research,lifescience,medical shortly after conditioning might “erase” the original fear memory, rats were fear conditioned and then given

extinction training either 10 min, 1 h, 24 h, or 3 days later.18 Consistent with an inhibitory learning mechanism Inhibitors,research,lifescience,medical of extinction, rats extinguished 24 or 72 h following acquisition exhibited moderate to strong reinstatement, renewal, and spontaneous recovery. By contrast, and consistent with an erasure mechanism, rats extinguished 10 min to 1 h after acquisition exhibited little or no reinstatement, renewal, or spontaneous recovery. These data support a model in which different neural mechanisms are recruited depending on the temporal delay of fear extinction. Based on these results, Dr Barbara Rolhbaum’s group at Emory has been testing whether a full out therapeutic dose of exposure therapy in the emergency room will lead to stronger fear extinction in traumatized individuals compared with delayed extinction, although the results are not yet fully in. Extinction training after memory recall may also “erase” fear memories Very similar results have been found when extinction training was carried out 10 min to 1 h after fear memory recall.20 Rats were trained to associate a tone with a footshock and then divided into five groups.