Brain histamine and schizophrenia: potential therapeutic applications of H3-receptor inverse agonists studied with BF2.649

• Published in: Biochemical pharmacology 2007-04, Vol.73 (8), p.1215-1224
• Main Authors: Ligneau, Xavier, Landais, Laurent, Perrin, David, Piriou, Johanne, Uguen, Marilyne, Denis, Emmanuel, Robert, Philippe, Parmentier, Régis, Anaclet, Christelle, Lin, Jian-Sheng, Burban, Aude, Arrang, Jean-Michel, Schwartz, Jean-Charles
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Disease Models, Animal; Histamine Antagonists - therapeutic use; Human health and pathology; Life Sciences; Mice; Neurons and Cognition; Piperidines - therapeutic use; Receptors, Histamine H3 - metabolism; Receptors, Histamine H3 - physiology; Schizophrenia - drug therapy; Tissues and Organs
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2007.01.023

BF2.649, a high affinity and selective non-imidazole histamine H(3)-receptor antagonist/inverse agonist, was found to easily enter the brain after oral administration to mice: it displayed a ratio of brain/plasma levels of about 25 when considering either C(max) or AUC values. At low oral doses (2.5-20mg/kg), it elicited in mice a dose-dependent wakening effect accompanied with a shift towards high frequency waves of the EEG, a sign of cortical activation. DOPAC/dopamine ratios were enhanced in the prefrontal cortex but not in the striatum, indicating a selective activation of a sub-population of dopaminergic neurons. BF2.649 showed significant inhibitory activity in several mouse models of schizophrenia. It reduced locomotor hyperactivity elicited by methamphetamine or dizolcipine without significantly affecting spontaneous locomotor activity when administered alone. It also abolished the apomorphine-induced deficit in prepulse inhibition. These observations suggest that H(3)-receptor inverse agonists/antagonists deserve attention as a novel class of antipsychotic drugs endowed with pro-cognitive properties.