Procognitive impact of ciproxifan (a histaminergic H3 receptor antagonist) on contextual memory retrieval after acute stress

Summary Aim Although cognitive deficits commonly co‐occur with stress‐related emotional disorders, effect of procognitive drugs such as histaminergic H3 receptor antagonists are scarcely studied on memory retrieval in stress condition. Methods Experiment 1. Memory of two successive spatial discriminations (D1 then D2) 24 hours after learning was studied in a four‐hole board in mice. H3 receptor antagonist ciproxifan (ip 3 mg/kg) and acute stress (three electric footshocks; 0.9 mA; 15 ms) were administered 30 and 15 minutes respectively before memory retrieval test. Fos immunostaining was performed to evaluate the neural activity of several brain areas. Experiment 2. Effects of ciproxifan and acute stress were evaluated on anxiety‐like behavior in the elevated plus maze and glucocorticoid activity using plasma corticosterone assay. Results Experiment 1. Ciproxifan increased memory retrieval of D2 in nonstress condition and of D1 in stress one. Ciproxifan mitigated the stress‐induced increase of Fos expression in the prelimbic and infralimbic cortex, the central and basolateral amygdala and the CA1 of dorsal hippocampus. Experiment 2. Ciproxifan dampened the stress‐induced anxiety‐like behavior and plasma corticosterone increase. Conclusion Ciproxifan improved contextual memory retrieval both in stress and nonstress conditions without exacerbating behavioral and endocrine responses to stress. Overall, these data suggest potential usefulness of H3 receptor antagonists as cognitive enhancer both in nonstress and stress conditions.