However, it does block reextinction when the extinction retention test occurs in a context different from that of initial acquisition and initial extinction,50 suggesting that NMDA receptor activation is required when extinction events are relatively novel but not when they are relatively familiar.50

On the other hand, novelty does not seem to matter for fear conditioning itself because disruption of the NMDA Inhibitors,research,lifescience,medical receptor blocks fear acquisition in both a novel and a familiar context.33,49 Effects of localized infusions of NMDA receptor antagonists prior to second extinction are more complex and are reviewed Inhibitors,research,lifescience,medical elsewhere (see ref 51). Role of D-cycloserine in fear extinction Because blockade of the NMDA receptor impairs extinction, we wondered whether enhancing the functioning of that receptor would enhance extinction. To test this we administered a compound called D-cycloserine (DCS) either systemically Inhibitors,research,lifescience,medical or directly into the rats’ amygdala prior to extinction training

and then tested retention of extinction the next day.52 DCS does not bind to the NMDA receptor itself, but to another receptor on the NMDA protein called the glycine regulatory site. Activation of Inhibitors,research,lifescience,medical this site improves the ability of the NMDA receptor protein to flux calcium which initiates a variety of intracellular events that are critical for extinction. As predicted, when DCS was given in combination with repeated exposure to the feared stimulus without a shock, extinction

retention was enhanced, when testing took place after DCS had worn off. This did not occur in control rats that received the drug alone, Inhibitors,research,lifescience,medical without extinction training. Based on these results, we concluded that the positive effects of the DCS else were specifically connected with extinction and did not result from a general dampening of fear expression. These effects have now been replicated in a large number of studies. Systemic administration of DCS either before52-61 or after54 extinction training facilitates extinction. Local infusion of DCS into the basolateral nucleus of the amygdala prior to52,62 or after54 fear extinction training mimics the effects of systemic administration. Chang and Maren63 recently Afatinib showed that although DCS infusions directly into infralimbic cortex did not facilitate extinction, these infusions did facilitate the subsequent reextinction of fear when animals were trained in a drug-free state.