The role of NMDA receptors in the extinction and re-extinction of Pavlovian fear conditioning

Abstract

The present thesis examined the role of N-methyl-D-apsartate receptors (NMDArs) in the extinction and re-extinction of Pavlovian fear conditioning in the rat. It is widely accepted that extinction is NMDAr-dependent, however, based on research showing that re-conditioning can be NMDAr-independent, it was hypothesised that extinction learning for the second time (i.e., re-extinction) might also be NMDAr-independent. The first series of experiments compared the effect of D-Cyloserine (DCS, a NMDAr partial agonist) on extinction and re-extinction of learned fear (Chapter 2). The results showed that DCS facilitated extinction but did not facilitate re-extinction of learned fear. This chapter also showed that the transition from NMDAr-dependent extinction to NMDAr-independent extinction is stimulus specific. That is, the first extinction session for any given CS is NMDAr-dependent even if the rat has received a previous cycle of fear conditioning and extinction training to a different CS. The second series of experiments continued investigating potential differences between extinction and re-extinction (Chapter 3). This series revealed that re-extinction like initial extinction, is context-specific and that the switch from NMDAr-dependent extinction to NMDAr-independent re-extinction is specific to the physical and temporal context. If re-extinction, to the same CS as initial extinction, occurs in the same temporal or physical context as initial extinction it is NMDAr-independent. However, if re-extinction occurs in a different physical or temporal context as initial extinction, re-extinction is NMDAr-dependent. The third series of experiments compared the effect of DCS on extinction that occurred immediately or after a delay following fear conditioning (Chapter 4). This series of experiments revealed that a recent aversive experience, such as footshock or fear conditioning, reduced the efficacy of DCS in facilitating the extinction of learned fear. Taken together the results reported in this thesis question the involvement of NMDArs in extinction under all circumstances and reveal a number of factors that can influence the NMDAr-dependency of extinction. Both the theoretical and clinical implications of these findings were discussed.