Context-related extinction learning and renewal in humans is mediated by hippocampal and prefrontal regions. Renewal is defined as the reoccurrence of an extinguished response if the contexts present during extinction learning and recall differ. Animal studies implicate hippocampal γ-aminobutyric acid (GABA) A receptors in extinction and renewal. However, human studies on GABAergic mechanisms in extinction learning are lacking. In this fMRI study, we therefore investigated the role of the GABAergic system in context-related extinction learning and renewal. Participants treated with the GABA A agonist lorazepam prior to extinction learning were impaired in encoding changed associations during extinction learning, regardless of context, and in retrieving extinction associations during recall. In contrast, retrieval of associations learned during acquisition was largely unaffected, which led to reduced genuine renewal, since acquisition associations were retrieved context-independently. These deficits, which were presumably due to weak encoding of extinction associations, were related to altered BOLD activation in regions relevant for context processing and retrieval, as well as response selection: reduced activation in bilateral PFC and hippocampus during extinction learning and recall, and increased ventromedial/orbitofrontal cortex activation during recall. Our findings indicate that the GABergic system is involved in context-related extinction learning and recall in humans, by modulating hippocampus-based context processing and PFC-based processing of changed associations and subsequent response selection.

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A distributed network including prefrontal and hippocampal regions is involved in context-related extinction learning as well as in renewal. Renewal describes the recovery of an extinguished response if the context of extinction differs from the context of recall. Animal studies have demonstrated that prefrontal, but not hippocampal N-methyl-D-aspartate receptor (NMDAR) antagonism disrupted extinction learning and processing of task context. However, human studies of NMDAR in extinction learning are lacking, while NMDAR antagonism yielded contradictory results in other learning tasks. This fMRI study investigated the role of NMDAR for human behavioral and brain activation correlates of extinction and renewal. Healthy volunteers received a single dose of the NMDAR antagonist memantine prior to extinction of previously acquired stimulus-outcome associations presented in either identical or novel contexts. We observed better, and partly faster, extinction learning in participants receiving the NMDAR antagonist compared to placebo. However, memantine did not affect renewal. In both extinction and recall, the memantine group showed a deactivation in extinction-related brain regions, particularly in the prefrontal cortex, while hippocampal activity was increased. This higher hippocampal activation was in turn associated with the participants' body mass index (BMI) and extinction errors. Our results demonstrate potentially dose-related enhancing effects of memantine and highlight involvement of hippocampal NMDAR in context-related extinction learning.