[Abstract Title]. - Society for Neuroscience

Abstract: Enhanced vigilance and attention are observed with histamine H3 receptor antagonists
in preclinical models of cognition, which may result from increased release of neurotransmitters
that include acetylcholine, norepinephrine, and histamine. In the later case, studies in H1 receptor
knockout mice have shown a lack of arousal normally produced by H3 antagonists, suggesting
that the pro-vigilant effects of these agents may involve increasing extracellular histamine and
subsequent H1 receptor stimulation. We hypothesize here that this mechanism of H3 antagonist -
evoked histamine release would block the sedative and amnesic effects of the H1 antagonist
diphenhydramine by increasing the amount of histamine available to H1 receptors. To test this
hypothesis, the selective H3 receptor antagonist ABT-239 (0.3 mg/kg) was administered to rats
and was found to block the sedative-like increases of slow-wave EEG produced by
diphenhydramine (10.0 mg/kg). Furthermore, the amnesic effects of diphenhydramine (10.0
mg/kg) were also blocked by ABT-239 (0.1-1.0 mg/kg) in a mouse 24-hour inhibitory avoidance
(IA) assay. As previously reported, ABT-239 improves 5-trial IA learning in spontaneously
hypertensive rat (SHR) pups, an indication of potential therapeutic efficacy in Attention Deficit /
Hyperactivity Disorder (Fox et. al., 2005). In the current study, diphenhydramine (10.0 mg/kg)
blocked the ability of ABT-239 to improve IA learning in SHR pups, suggesting that the
histaminergic system contributes to efficacy observed in this model. The doses of ABT-239 that
either reverse the effects of diphenhydramine in rat EEG or mouse IA, or were blocked by
diphenhydramine in SHR pups, were within a range that increased extracellular histamine in the
rat pre-frontal cortex as measured by in vivo microdialysis. Together, these data support a
histaminergic mechanism for ABT-239 to enhance vigilance and attention.
Disclosures: R.J. Radek, Abbott Laboratories, A. Employment (full or part-time); K.E.
Browman, Abbott Laboratories, A. Employment (full or part-time); M.D. Cowart, Abbott
Laboratories, A. Employment (full or part-time); M. Cheng, Abbott Laboratories, A.
Employment (full or part-time); T.A. Esbenshade, Abbott Laboratories, A. Employment (full or
part-time); T.A. Fey, Abbott Laboratories, A. Employment (full or part-time); G.B. Fox, Abbott
Laboratories, A. Employment (full or part-time); V.A. Komater, Abbott Laboratories, A.
Employment (full or part-time); N.R. Rustay, Abbott Laboratories, A. Employment (full or parttime);
M.J. Voorbach, Abbott Laboratories, A. Employment (full or part-time); J.B. Wetter,
Abbott Laboratories, A. Employment (full or part-time); J.D. Brioni, Abbott Laboratories, A.
Employment (full or part-time); R.S. Bitner, Abbott Laboratories, A. Employment (full or parttime).
Poster
291. Animal Cognition and Behavior: Learning and Memory: Pharmacology II
Time: Sunday, November 16, 2008, 1:00 pm - 5:00 pm
Program#/Poster#: 291.7/RR82
Topic: F.02.j. Learning and memory: Pharmacology