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.