Role of H3-Receptor-Mediated Signaling in Anxiety and Cognition in Wild-Type and Apoe–/– Mice

Abstract

Increasing evidence supports a role for histamine as a neurotransmitter and neuromodulator in emotion and cognition. The H 3 receptor was first characterized as an autoreceptor that modulates histamine release and synthesis via negative feedback. Mice deficient in apoE (Apoe -/-) have been used to define the role of apoE in brain function. In the present study, we investigated the possible role of histamine H 3 -receptor-mediated signaling in anxiety and cognition in mice Apoe -/-and wild-type mice. H 3 antagonists increased measures of anxiety in wild-type, but not Apoe -/-, mice. In contrast, H 3 antagonists similarly impaired object recognition in wild-type and Apoe -/-mice. In Apoe -/-mice, reduced negative feedback via H 3 receptors could contribute to increased signaling of H 1 receptors. Apoe -/-mice showed higher sensitivity to the anxiety-reducing effects of the H 1 receptor antagonist mepyramine than wild-type mice. These effects were dissociated from effects of mepyramine on the HPA axis. Compared to saline controls, mepyramine reduced plasma ACTH and corticosterone levels in wild-type, but not Apoe -/-, mice. These data support a role for apoE in H 3 receptor signaling. H 3 antagonists were proposed as a treatment for cognitive disorders such as Alzheimer's disease, which is associated with increased anxiety and cognitive impairments. As H 3 antagonists increase measures of anxiety and impair object recognition in wild-type mice, the use of H 3 antagonists in cognitive disorders may be counterproductive and should be carefully evaluated.

Modulation of behavior by the histaminergic system: Lessons from HDC-, H3R- and H4R-deficient mice

“…In contrast to these results, H 3 R antagonists increased anxiety in wild-type mice in the elevated plus-maze (Bongers et al, 2004). This demonstrates that the results from pharmacologic and knockout approaches are not always compatible.…”

“…We could not find any information on the behavioral effect of novelty on Hrh3 −/− mice in the published literature, and there are no behavioral data available on H 4 R-deficient mice. However, administration of H 3 R antagonists to wild-type mice eliminated the ability to discriminate between novel and familiar objects (Bongers et al, 2004).…”

Histamine neuronal system as a therapeutic target for the treatment of cognitive disorders

“…Certainly, such a model is clinically very relevant, as deficits are genetic in origin and do not require pharmacological or surgical intervention. Although another report provided some contrasting data, as H 3 R antagonists/inverse agonists impaired object recognition in wild-type and Apoe -/-mice [74], these findings may be relevant to predict the potential of H 3 R antagonists/inverse agonists in ameliorating cognitive dysfunctions in humans [67]. In this regard, the presence of […”

Regional Differential Effects of the Novel Histamine H3 Receptor Antagonist 6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide hydrochloride (GSK189254) on Histamine Release in the Central Nervous System of Freely Moving Rats

“…Alternative strategies are being actively pursued, and the therapeutic potential of H 3 R antagonists/inverse agonists for correcting cognitive deficits is raising great interest Esbenshade et al, 2008). Although Bongers et al (2004) reported that H 3 R antagonists/inverse agonists impaired object recognition in mice, numerous other studies have shown that their administration to experimental animals can elicit procognitive effects in several cognitive tasks (Esbenshade et al, 2008). The broad spectrum of efficacy observed across different cognitive domains increases confidence in using H 3 R antagonists for the treatment of cognitive deficits in a number of central nervous system disorders.…”