D-cycloserine facilitates procedural learning but not declarative learning in healthy humans: a randomized controlled trial of the effect of D-cycloserine and valproic acid on overnight properties in the performance of non-emotional memory tasks.

Although D-cycloserine (DCS), a partial agonist of the N-methyl-d-aspartate (NMDA) receptor, and valproic acid (VPA), a histone deacetylase inhibitor, have been investigated for their roles in the facilitation of emotional learning, the effects on non-emotional declarative and procedural learning have not been clarified. We performed a randomized, blind, placebo-controlled, 4-arm clinical trial to determine the effects of DCS and VPA on the overnight properties of declarative and procedural learning in 60 healthy adults. Subjects were orally administrated a placebo, 100 mg DCS, 400 mg VPA, or a combination of 100 mg DCS and 400 mg VPA before they performed declarative and procedural learning tasks. Subjects then had their performance retested the following day. We observed that DCS facilitated procedural but not declarative learning and that VPA did not contribute to learning. Surprisingly, however, VPA attenuated the enhancement effect of DCS when coadministered with it. These results suggest that DCS acts as an enhancer of hippocampus-independent learning and that VPA may have an extinguishing pharmacological effect on excitatory post-synaptic action potentials that NMDA receptors regulate within procedural learning.