The NMDA agonist D-cycloserine facilitates fear memory consolidation in humans

Abstract

Animal research suggests that the consolidation of fear and extinction memories depends on N-methyl D-aspartate (NMDA)-type glutamate receptors. Using a fear conditioning and extinction paradigm in healthy normal volunteers, we show that postlearning administration of the NMDA partial agonist D-cycloserine (DCS) facilitates fear memory consolidation, evidenced behaviorally by enhanced skin conductance responses, relative to placebo, for presentations of a conditioned stimulus (CS) at a memory test performed 72 h later. DCS also enhanced CS-evoked neural responses in a posterior hippocampus/collateral sulcus region and in the medial prefrontal cortex at test. Our data suggest a role for NMDA receptors in regulating fear memory consolidation in humans.

Figure 1.

Fear and extinction recall paradigm. On day 1, subjects (n = 31 healthy female volunteers) were fear conditioned to a CS+ (a face) through multiple pairings with an UCS (electric shock) in context A (conditioning context, block A1). Fear responses were then extinguished in context B (extinction context, block B1) through multiple CS+ presentations in the absence of the UCS. To ascertain retention of fear memories until a recall test 72 h later (see below), conditioning was repeated in a further block (A2). As a control for nonassociative effects, we also employed a nonpredictive CS− (a face of opposite gender) that was never paired with the UCS and presented intermixed with the CS+. Contexts were defined by screen color and auditory input. It was assumed that this procedure would create a CS-associated fear memory. Based on an earlier study by our group (Kalisch et al. 2006a), it was also assumed that the procedure would create an (extinction) context-dependent extinction memory. Learning was followed by administration of either placebo (n = 16) or 500-mg DCS (n = 15). On day 2 (72 h later), CSs were presented in both contexts A and B to test for CS-evoked fear and extinction memory recall, respectively. To this purpose, each context was presented 16 times in alternating order. Recall of fear memory in context A on day 2 was facilitated by additionally presenting 1 unpaired shock at the beginning of each context A block, thus again firmly associating context A with the UCS. The task was a speeded gender decision task in response to the face stimuli. Gender of faces and conditioning and extinction contexts were counterbalanced between groups. The design was randomized, double blind, and between subject. Flash denotes electric shock.

Figure 2.

SCRs showing facilitated fear memory consolidation by DCS. (a) Day 1: Significantly larger SCRs to the CS+ than to the CS− during late fear conditioning in context A indicate learning of the CS+−UCS contingency (fear memory) in context A on day 1. A reversal of the conditioning effect during late extinction in context B indicates learning of the CS+−noUCS contingency (extinction memory) in context B. (b) Day 2: SCRs to the CS+ in the conditioning context were again significantly larger than to the CS− on day 2, but only in those subjects receiving DCS after learning on day 1. A similar effect was apparent in the extinction context, that is, there was no evidence for extinction memory recall. Scale: z scores (unit: standard deviations [SDs]). *P < 0.05, (*)P < 0.1, 1-tailed t-test versus 0.

Figure 3.

Effects of postlearning DCS on fMRI correlates of recall of fear memory on day 2. Activations associated with recall of fear memory on day 2 in left posterior hippocampus/collateral sulcus (x = −34, y = −32, z = −16) (a) and right MPFC/ACC (x = 2, y = 46, z = 34) (b) were larger in the DCS than in the placebo group. Images show the parametric contrast (CS+ > CS−)_DCS > (CS+ > CS−)_placebo, display threshold P ≤ 0.01. Hair cross denotes activation peak surviving SVC at P ≤ 0.05. Activations are superimposed on the mean structural image. The bar graphs show average contrast estimates for the parametric CS+ > CS− contrasts in both groups and contexts.