Effect of D-cycloserine and valproic acid on the extinction of reinstated fear-conditioned responses and habituation of fear conditioning in healthy humans: a randomized controlled trial

Abstract

Rationale: Although the effects of D: -cycloserine (DCS) and valproic acid (VPA) on the facilitation of the extinction of fear-conditioned memory have been elucidated in animals, these effects have not been clearly confirmed in humans.

Objective: This study aimed to determine the effect of DCS (100 mg) and VPA (400 mg) on the facilitation of the extinction and acquisition of fear-conditioned memory in humans.

Methods: We performed a randomized, blind, placebo-controlled, four-arm clinical trial in 60 healthy adults. Visual cues and electric shocks were used as the conditioned stimulus (CS) and unconditioned stimulus (US), respectively.

Results: The extinction or acquisition effect was not observed in the simple recall after the extinction or acquisition of coupled CS-US; however, the extinction and habituation effects but not the acquisition effects were presented after the unexpected re-exposure of coupled CS-US (reinstatement stimuli). Extinction and habituation effects were facilitated by either a single dose of DCS or VPA or a combination of DCS and VPA. However, we did not observe the expected synergistic effect of the combined treatment on the extinction or habituation of fear conditioning.

Conclusion: A single dose of DCS or VPA might enhance exposure-based cognitive therapy of anxiety disorders by reducing the vulnerability to reinstatement and preventing relapses of fear-conditioned responses.