Abstract
SummaryAimAlthough 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.ConclusionCiproxifan 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.
Highlights
The histamine H3 receptor is a central inhibitory autoreceptor located on histaminergic nerve terminals that are found mainly on cholinergic and dopaminergic neurons
We investigated the effects of an acute stress on memory in a contextual serial spatial discrimination task (CSD) where stress is not directly associated with the memory task
We previously showed that memory of the first discrimination involved the dorsal hippocampus in nonstress condition, whereas memory of the second discrimination involved the prefrontal cortex and the amygdala in stress condition.[43,44]
Summary
The histamine H3 receptor is a central inhibitory autoreceptor located on histaminergic nerve terminals that are found mainly on cholinergic and dopaminergic neurons. Cognitive deficits often show anxiety disorders[22] and stress impairs hippocampus‐dependent memory retrieval.[23] The deleterious effect of stress on cognitive functions is observed in stress‐related disorders such as anxiety and depression.[24,25,26] In such context, histaminergic system is a relevant target because histamine is an indicator of stress response[27,28,29,30,31,32] since stress is a potent activator of histamine neurons in the tuberomammillary nucleus of the hypothalamus.[33] A consensus view is that histamine antagonists have more impact in tasks having an anxiety component.[34] For example, it has been found that ciproxifan prevented the deleterious effects of chronic stress exposure in spatial memory.[35] In contrast, central administration of histamine can increase plasma corticosterone via its action on hypothalamic neuropeptides[36] and promotes anxiety‐like behavior.[37,38,39,40] Research efforts are needed to determine emotional impact of H3R antagonists at procognitive dose. This second experiment was designed to determine if the 3 mg/kg procognitive dose of ciproxifan could be dissociated from its emotional impact
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