Individual Differences in Rate of Extinction and Relapse

Abstract

The current challenge in treating anxiety disorders is not how to reduce fear, but how to reduce relapse. In this thesis I aimed to gain insight into the processes underpinning relapse, which might further our treatment of anxiety disorders. Using a rodent model I first examined whether individual differences in the rate of extinction are associated with vulnerability to relapse (Chapter 3). I found that when tested under “mild” relapse conditions Slow Extinguishers showed relapse but Fast Extinguisher did not. Interestingly, it is not the case that Fast Extinguishers fail to ever exhibit relapse of fear following extinction training as both Fast and Slow Extinguishers showed comparable, high-levels of relapse when tested under “strong” relapse conditions. In other words, I found that Slow Extinguishers are more vulnerable to relapse than Fast Extinguishers. Next, I examined the molecular basis of these individual differences in rate of extinction (Chapter 4). I measured NR1, NR2A, NR2B, TrkB, pTrkB, BDNF, and cFos protein levels in the PFC, amygdala, and hippocampus, and, in general, there was a surprising lack of difference between Fast and Slow Extinguishers with most of these signals. However, there was some indication of a difference between Fast and Slow Extinguishers in NMDA receptor protein levels. To further explore this potential difference in NMDA receptors between Fast and Slow Extinguishers I then examined whether a partial NMDA receptor agonist, d-cycloserine (DCS), differentially affected relapse in the two conditions (Chapter 5). I consistently found that while DCS reduced relapse for Fast Extinguishers, it had minimal effects on reducing relapse for Slow Extinguishers. Individually, these Chapters address issues about reconciling mixed findings in the literature about relapse, the targeted delivery of relapse prevention strategies, methodological considerations of Western Blotting, and factors which influence the effectiveness of DCS in enhancing extinction/exposure therapy. Taken together, the experiments presented in this thesis highlight that there is value in considering individual differences and raise questions about how the processes involved in extinction might differ for Fast and Slow Extinguishers, the implications this might have for other tasks, and the importance of improving and developing strategies for relapse prevention.