Brain Localization and c‐Fos Activation of Histamine H3 Receptor Antagonists

Abstract

We have previously shown that several H3 receptor (H3R) antagonists such as ABT-239 [4-(2-{2-[(2R)-2-methylpyrrolidinyl]-ethyl}-benzofuran-5-yl)-benzonitrile] enhance cognitive behavior whereas H3R antagonists like A-331440 [4′-[3-(3(R)-(dimethylamino)-pyrrolidin-1-yl)-propoxy]-biphenyl-4-carbonitrile] have antiobesity properties. Several hypotheses were explored in an attempt to reliably differentiate these activities including examining the differential localization of the H3R antagonists to discrete rat brain regions and evaluating the degree of c-FOS activation in various brain regions. Neither ABT-239 nor A-331440 demonstrated brain region specific localization. ABT-239 (1.0 mg/kg, i.v.) and A-331440 (5 mg/kg, i.v.) accessed rat frontal cortex, hippocampus, striatum, and hypothalamus within 1 hr at levels of 3.0, 2.8, 2.8, and 1.9 mg/gm and 23, 13.5, 14, and 11.5 mg/gm brain tissue homogenate, respectively, as quantified with mass spectrometry using deuterated analogs of each compound as internal standards. Both ABT-239 (3 and 30 mg/kg, i.p.) and A-331440 (1 and 30 mg/kg, i.p.) induced c-fos expression in the rat hypothalamic paraventricular nucleus (PVN), cingulate cortex, and hippocampal CA1, CA2/3, dentate regions 2 hr after administration. However, ABT-239 induced the greatest increases in c-fos expression in the hippocampal regions whereas A-331440 caused greatest induction in the hypothalamic PVN. Activation of c-fos in PVN, but not other regions, may differentiate antiobesity compounds such as A-331440 from procognitive leads such as ABT-239, which appears to primarily increase c-fos activity in areas associated with learning, in addition to activation in PVN. Research supported by Abbott Laboratories.