Role of H₃-receptor-mediated signaling in anxiety and cognition in wild-type and Apoe^-/- mice

Increasing evidence supports a role for histamine as a neurotransmitter and neuromodulator in emotion and cognition. The H₃ 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 H₃-receptor- mediated signaling in anxiety and cognition in mice Apoe^-/- and wild-type mice. H₃ antagonists increased measures of anxiety in wild-type, but not Apoe^-/-, mice. In contrast, H₃ antagonists similarly impaired object recognition in wild-type and Apoe ^-/- mice. In Apoe^-/- mice, reduced negative feedback via H₃ receptors could contribute to increased signaling of H ₁ receptors. Apoe^-/- mice showed higher sensitivity to the anxiety-reducing effects of the H₁ 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 H₃ receptor signaling. H₃ antagonists were proposed as a treatment for cognitive disorders such as Alzheimer's disease, which is associated with increased anxiety and cognitive impairments. As H₃ 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.