D-cycloserine facilitation of fear extinction and exposure-based therapy might rely on lower-level, automatic mechanisms.

Exposure-based therapy, a leading technique in the treatment of a range of anxiety disorders, is facilitated by D-cycloserine (DCS), a partial N-methyl-D-aspartate receptor agonist. This review discusses the potential mechanisms involved in this facilitation and its implications for developing theories of fear conditioning in humans. Basic research in rodents suggests that DCS acts by speeding up extinction. However, several laboratory-based investigations found that DCS had no effect on extinction in humans. This report proposes that these observations can be accounted for by a dual-model theory of fear conditioning in humans that engages two complementary defensive systems: a reflexive lower-order system independent of conscious awareness and a higher-order cognitive system associated with conscious awareness of danger and expectation. The DCS studies in animals seem to have explored lower-order conditioning mechanisms, whereas human studies have explored higher-order cognitive processes. These observations suggest that DCS might act preferentially on lower- rather than higher-order learning. This report presents evidence suggesting that, in humans, DCS might similarly affect lower-order learning during exposure-based therapy and, consequently, might be less effective during cognitive therapy (e.g., cognitive restructuring). Finally, it is recommended that extinction studies using DCS in humans be conducted with fear-relevant stimuli (e.g., snakes), short conditional stimulus-unconditioned stimulus intervals and intense unconditioned stimulus to promote lower-order conditioning processes.