d-cycloserine does not facilitate fear extinction by reducing conditioned stimulus processing or promoting conditioned inhibition to contextual cues

Abstract

The NMDA receptor partial agonist D-cycloserine (DCS) enhances the extinction of learned fear in rats and exposure therapy in humans with anxiety disorders. Despite these benefits, little is known about the mechanisms by which DCS promotes the loss of fear. The present study examined whether DCS augments extinction retention (1) through reductions in conditioned stimulus (CS) processing or (2) by promoting the development of conditioned inhibition to contextual cues. Rats administered DCS prior to extinction showed enhanced long-term extinction retention (Experiments 3 and 4). The same nonreinforced CS procedure used in extinction also reduced freezing at test when presented as pre-exposure before conditioning, demonstrating latent inhibition (Experiment 1). DCS administered shortly prior to pre-exposure had no effect on latent inhibition using parameters which produced weak (Experiment 2) or strong (Experiment 3) expression of latent inhibition. Therefore, DCS facilitated learning involving CS-alone exposures, but only when these exposures occurred after (extinction) and not before (latent inhibition) conditioning. We also used a retardation test procedure to examine whether the extinction context gained inhibitory properties for rats given DCS prior to extinction. With three different footshock intensities, there was no evidence that DCS promoted accrual of associative inhibition to the extinction context (Experiment 4). The present findings demonstrate that DCS does not facilitate extinction by reducing CS processing or causing the extinction context to become a conditioned inhibitor. Investigations into the mechanisms underlying the augmentation of extinction by DCS are valuable for understanding how fear can be inhibited.

Opposing effects of d-cycloserine on fear despite a common extinction duration: Interactions between brain regions and behavior

“…Under this model, DCS enhances inhibitory learning to the context, but allows extinction to remain vulnerable to behavioral manipulations that affect the context memory, including the contextual renewal and reconditioning effects. In a direct test of the context inhibition idea, Baker et al (2012) found that DCS promoted extinction, but the extinction context could be conditioned just as readily as a control context; i.e., there was no evidence for a retardation of acquisition effect that is often used as evidence for inhibition.…”

Optimizing treatments for anxiety by age and genetics

“…One such treatment is that of d-cycloserine (DCS), a glutamate receptor modulator, which has been shown to enhance long-term fear extinction in both adolescent and adult rats. 23,38 Comparable results have been shown with selective serotonin reuptake inhibitors, which, when administered chronically in combination with extinction training, prevent the return of fear memory in mice. 39,40 These results are promising, but nonpharmacological treatments may be optimal or preferred for treating the developing brain.…”

“…As an example, pharmacological treatments have been shown to enhance fear regulation. One such treatment is that of d ‐cycloserine (DCS), a glutamate receptor modulator, which has been shown to enhance long‐term fear extinction in both adolescent and adult rats . Comparable results have been shown with selective serotonin reuptake inhibitors, which, when administered chronically in combination with extinction training, prevent the return of fear memory in mice .…”

Psychological and neural mechanisms of experimental extinction: A selective review

“…This leaves open the possibility for manipulations that facilitate extinction, for example, to do so by affecting the development of inhibition to context rather than what is assumed, namely, the development of inhibition to the CS or occasion setting to the context. In a recent study by Baker, McNally, and Richardson (2012), such a design was used and while d-cycloserine was shown to facilitate the extinction of conditioned freezing to a CS, this study went further than others by testing whether the extinction context had developed enhanced inhibitory learning in d-cycloserine-treated animals. The results, unfortunately, are somewhat equivocal on this point because although the extinction context in drug-treated animals was no slower than in controls at acquiring fear of its own, a more traditional summation test for conditioned inhibition was not performed.…”