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The Journal of Neuroscience, September 27, 2006, 26(39):10051-10056; doi:10.1523/JNEUROSCI.2466-06.2006

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Behavioral/Systems/Cognitive
Reconsolidation and Extinction of Conditioned Fear: Inhibition and Potentiation

Jonathan L. C. Lee, Amy L. Milton, and Barry J. Everitt

Department of Experimental Psychology, University of Cambridge, Cambridge CB2 3EB, United Kingdom

Correspondence should be addressed to Jonathan L. C. Lee, Department of Experimental Psychology, University of Cambridge, Downing Street, Cambridge CB2 3EB, UK. Email: jlcl2{at}cam.ac.uk

NMDA receptors are important for the acquisition, reconsolidation, and extinction of memories. NMDA receptor antagonists impair these memory processes, whereas the partial agonist D-cycloserine (DCS) potentiates both learning and extinction. Here, we used DCS and the noncompetitive NMDA receptor antagonist (+)-5-methyl-10,11-dihydro-SH-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801) to investigate the effects of enhancing and blocking NMDA receptor-mediated glutamatergic transmission on the reconsolidation and extinction of a conditioned fear memory. Either long extinction training or short memory reactivation sessions were used to preferentially engage extinction and reconsolidation processes, respectively. MK-801 blocked extinction to maintain high levels of conditioned freezing, and DCS potentiated extinction to reduce freezing, when they were administered before a long extinction training session. However, the opposite behavioral outcome was observed when the brief memory reactivation session was used: MK-801 administration impaired, whereas DCS increased, freezing, likely reflecting impairment and enhancement of reconsolidation, respectively. Finally, by using localized intracerebral infusions, we showed that the basolateral amygdala is a primary locus of action of systemically administered DCS. Thus, intrabasolateral amygdala DCS potentiated both the extinction and the reconsolidation of fear conditioning, depending on the length of the extinction/memory reactivation session. Therefore, memory reconsolidation can be both disrupted and enhanced, and extinction can be both potentiated and impaired, either to reduce or increase conditioned fear. These results have important implications for the use of reconsolidation blockade and potentiation of extinction as treatment strategies for maladaptive memory disorders.

Key words: memory; reconsolidation; extinction; NMDA receptor; basolateral amygdala; rat

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Received April 25, 2006; revised July 31, 2006; accepted Aug. 28, 2006.

Correspondence should be addressed to Jonathan L. C. Lee, Department of Experimental Psychology, University of Cambridge, Downing Street, Cambridge CB2 3EB, UK. Email: jlcl2{at}cam.ac.uk

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