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Received for publication September 27, 2004.
Revised December 7, 2004.
Accepted for publication December 13, 2004.
Acute pharmacological blockade of central histamine H3 receptors (H3Rs) enhances arousal/attention in rodents. However, there is little information available for other behavioral domains or for repeated administration using selective compounds. ABT-239 (4-(2-{2-[(2R)-2-methylpyrrolidinyl] ethyl}-benzofuran-5-yl)benzonitrile) exemplifies such a selective, non-imidazole H3R antagonist with high affinity for rat (pKi = 8.9) and human (pKi = 9.5) H3Rs. Acute functional blockade of central H3Rs was demonstrated by blocking the dipsogenia response to the selective H3R agonist (R)-a-methylhistamine ((R)-a-MeHA) in mice. In cognition studies, acquisition of a 5-trial, inhibitory avoidance test in rat pups was improved with ABT-239 (0.1-1.0 mg/kg), a 10-150-fold gain in potency, with similar efficacy, over previous antagonists such as thioperamide, ciproxifan, A-304121, A-317920 and A-349821. Efficacy in this model was maintained for 3-6 h, and following repeated dosing with ABT-239. Social memory was also improved in adult (0.01-0.3 mg/kg) and aged (0.3-1.0 mg/kg) rats. In schizophrenia models, ABT-239 improved gating deficits in DBA/2 mice using prepulse inhibition of startle (1.0-3.0 mg/kg) and N40 (1.0-10.0 mg/kg). Further, ABT-239 (1.0 mg/kg) attenuated methamphetamine-induced hyperactivity in mice. In freely-moving rat microdialysis studies, ABT-239 enhanced acetylcholine release (0.1-3.0 mg/kg) in adult rat frontal cortex and hippocampus and enhanced dopamine release in frontal cortex (3.0 mg/kg), but not striatum. In summary, broad efficacy was observed with ABT-239 across animal models such that potential clinical efficacy may extend beyond disorders such as ADHD to include Alzheimer's disease and schizophrenia.
Key words:
ABT-239, H3 receptor, behavior, cognition, histamine, schizophrenia
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