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

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. 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. 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. 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. 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.