NMDA receptor-mediated processing in inferior frontal gyrus facilitates acquisition and extinction learning and strengthens renewal

While the renewal effect of extinction is considered to be invoked by attention to context during the extinction phase, there is also evidence that processing during initial learning (acquisition) may be important for later renewal. A noradrenergic agonist and a dopaminergic antagonist, administered before acquisition, did not affect renewal, however, the effects of NMDAergic neurotransmission in this regard are as yet unknown. In a previous study, administration of a single dose of the NMDA agonist d-cycloserine (DCS) before extinction learning facilitated extinction in the context of acquisition (AAA), but had no effect upon renewal. In the present fMRI study, DCS was administered prior to the initial acquisition of a predictive learning task, in order to investigate whether NMDA receptor (NMDAR) stimulation at this timepoint will modulate overall learning as well as the level of renewal, while increasing activation in the extinction- and renewal-relevant brain regions of inferior frontal gyrus (iFG) and hippocampus (HC). DCS facilitated acquisition, as well as extinction learning in the context of acquisition (AAA), and raised the level of ABA renewal. While BOLD activation during acquisition did not differ between treatment groups, activation in bilateral iFG showed a double dissociation during processing of AAA extinction trials, with DCS-mediated higher activation in right iFG and deactivation in left iFG. In contrast, placebo showed higher activation in left iFG and deactivation in right iFG. During the test (recall) phase, left iFG and right anterior hippocampus activation was increased in DCS participants who showed renewal, with activation in this region correlating with the ABA renewal level. The results demonstrate that NMDA receptor stimulation can facilitate both initial learning and extinction of associations, and in this way has an impact upon the resultant level of renewal. In particular NMDAergic processing in iFG appears relevant for the facilitation of AAA extinction and ABA recall in the test phase.