Hippocampal learning is thought to induce metaplasticity, which can facilitate subsequent learning. Administered at single low doses, the N -methyl- d -aspartate-type glutamate receptor antagonist memantine predominantly blocks α7 nicotinic acetylcholine receptors (α7 nAChRs). Placebo-controlled administration of a single low dose of memantine in a pharmaco-fMRI experiment may thus help characterize the role of α7 nAChRs in hippocampal metaplasticity. We hypothesized that if α7 nAChRs contribute to learning-induced metaplasticity in the hippocampus, blockade of these receptors with low-dose memantine would selectively interfere with a facilitation of subsequent learning without impairing hippocampal learning per se. To specifically test this hypothesis, we devised a randomized controlled trial in which healthy volunteers were administered a 20-mg single oral dose of memantine or placebo and scanned on three subsequent runs of a hippocampal learning task. Our results indicate no discrepancies in behavioral learning between low-dose memantine- and placebo-treated participants in the first and second run of this task. In the third run, however, only the placebo-treated group showed facilitated behavioral learning, an effect paralleled by decreased neural responses in the hippocampal cornu ammonis region. Our findings suggest that blockade of α7 nAChRs selectively interfered with a learning-induced facilitation of subsequent learning while leaving unimpaired hippocampal learning per se. Taken together, our results provide support for a relevant contribution of α7 nAChRs to learning-associated metaplasticity in the hippocampus.

The nucleus accumbens is critical for reward-guided learning and decision-making. It is thought to “gate” the flow of a diverse range of information (e.g., rewarding, aversive, and novel events) from limbic afferents to basal ganglia outputs. Gating and information encoding may be achieved via cross-frequency coupling, in which bursts of high-frequency activity occur preferentially during specific phases of slower oscillations. We examined whether the human nucleus accumbens engages such a mechanism by recording electrophysiological activity directly from the accumbens of human patients undergoing deep brain stimulation surgery. Oscillatory activity in the gamma (40–80 Hz) frequency range was synchronized with the phase of simultaneous alpha (8–12 Hz) waves. Further, losing and winning small amounts of money elicited relatively increased gamma oscillation power prior to and following alpha troughs, respectively. Gamma–alpha synchronization may reflect an electrophysiological gating mechanism in the human nucleus accumbens, and the phase differences in gamma–alpha coupling may reflect a reward information coding scheme similar to phase coding.