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 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.
Bongers
Gerald
G
Gladstone Institute of Neurological Disease, University of California, San Francisco, CA, USA.
Leurs
Rob
R
Robertson
Jennifer
J
Raber
Jacob
J
D000818:Animals; D001007:Anxiety / Q000235:genetics / Q000378:metabolism*; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D003071:Cognition / Q000187:drug effects / Q000502:physiology*; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D006633:Histamine Antagonists / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018100:Receptors, Histamine H3 / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D001057:Apolipoproteins E; D006633:Histamine Antagonists; D018100:Receptors, Histamine H3