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.

An N-methyl-D-aspartate receptor agonist facilitates sleep-independent synaptic plasticity associated with working memory capacity enhancement.

Working memory (WM) capacity improvement is impacted by sleep, and possibly by N-methyl-D-aspartate (NMDA) agonists such as D-cycloserine (DCS), which also affects procedural skill performance. However, the mechanisms behind these relationships are not well understood. In order to investigate the neural basis underlying relationships between WM skill learning and sleep, DCS, and both sleep and DCS together, we evaluated training-retest performances in the n-back task among healthy subjects who were given either a placebo or DCS before the task training, and then followed task training sessions either with wakefulness or sleep. DCS facilitated WM capacity enhancement only occurring after a period of wakefulness, rather than sleep, indicating that WM capacity enhancement is affected by a cellular heterogeneity in synaptic plasticity between time spent awake and time spent asleep. These findings may contribute to development, anti-aging processes, and rehabilitation of higher cognition.