Abstract
The effectiveness of D-cycloserine (DCS) , an N-methyl-D-aspartate glutamate receptor partial agonist, and valproic acid (VPA) , a histone deacetylase inhibitor, in facilitating the extinction of conditioned fear has been explored in humans and animals. We confirmed whether DCS (100 mg) and VPA (400 mg) act in off-line fear extinction processes during sleep or waking, for further clinical application to anxiety disorders and posttraumatic stress disorder (PTSD). We performed two consecutive randomized, placebo controlled clinical trials in healthy humans. Visual cues and electric shocks were used as the conditioned stimulus (CS) and unconditioned stimulus (US), respectively. The off-line fear extinction effect was observed not in simple recall after the extinction of coupled CS-US, but was observed in the post-re-exposure phase after unexpected re-exposure to reinstatement CS-US coupling. In addition, VPA facilitated the off-line learning process of conditioned fear extinction during sleep, while DCS did during waking. These findings suggest that DCS and VPA might enhance exposure-based cognitive therapy for anxiety disorders and PTSD by reducing the vulnerability to reinstatement and preventing relapses of conditioned fear, and provide evidence for a peculiarity of the sleep-dependent off-line process for conditioned fear extinction.
