TY - JOUR
T1 - SAR110894, a potent histamine H3-receptor antagonist, displays procognitive effects in rodents
AU - Griebel, Guy
AU - Pichat, Philippe
AU - Pruniaux, Marie Pierre
AU - Beeské, Sandra
AU - Lopez-Grancha, Mati
AU - Genet, Elisabeth
AU - Terranova, Jean Paul
AU - Castro, Antonio
AU - Sánchez, Juan Antonio
AU - Black, Mark
AU - Varty, Geoffrey B.
AU - Weiner, Ina
AU - Arad, Michal
AU - Barak, Segev
AU - De Levie, Amaya
AU - Guillot, Etienne
PY - 2012/8
Y1 - 2012/8
N2 - SAR110894 is a novel histamine H3-R ligand, displaying high and selective affinity for human, rat or mouse H3-Rs. SAR110894 is a potent H3-R antagonist at native receptors, reversing R-α-methylhistamine-induced inhibition of electrical field stimulation contraction in the guinea-pig ileum. Additionally, SAR110894 inhibited constitutive GTPγS binding at human H3-Rs demonstrating inverse agonist properties. In behavioral models addressing certain aspects of cognitive impairment associated with schizophrenia (CIAS) and attention deficit/hyperactivity disorder (ADHD), SAR110894 improved memory performances in several variants of the object recognition task in mice (0.3-3 mg/kg, p.o.) or rats (0.3-1 mg/kg, p.o.). Moreover, SAR110894 (1 mg/kg, p.o.) reversed a deficit in working memory in the Y-maze test, following an acute low dose of phencyclidine (PCP) (0.5 mg/kg, i.p.) in mice sensitized by repeated treatment with a high dose of PCP (10 mg/kg, i.p.). In the latent inhibition (LI) model, SAR110894 potentiated LI in saline-treated rats (1 and 3 mg/kg, i.p.) and reversed abnormally persistent LI induced by neonatal nitric oxide synthase (NOS) inhibition in rodents (0.3-3 mg/kg, i.p.). In a social novelty discrimination task in rats, SAR110894 attenuated selective attention deficit induced by neonatal PCP treatment (3 and 10 mg/kg, p.o.) or a parametric modification of the procedure (3 and 10 mg/kg, p.o.). SAR110894 showed efficacy in several animal models related to the cognitive deficits in Alzheimer's disease (AD). It prevented the occurrence of episodic memory deficit induced by scopolamine in rats (0.01-10 mg/kg, p.o.) or by the central infusion of the toxic amyloid fragment β25-35 in the object recognition test in mice (1 and 3 mg/kg, p.o.). Altogether, these findings suggest that SAR110894 may be of therapeutic interest for the treatment of the cognitive symptoms of AD, schizophrenia and certain aspects of ADHD.
AB - SAR110894 is a novel histamine H3-R ligand, displaying high and selective affinity for human, rat or mouse H3-Rs. SAR110894 is a potent H3-R antagonist at native receptors, reversing R-α-methylhistamine-induced inhibition of electrical field stimulation contraction in the guinea-pig ileum. Additionally, SAR110894 inhibited constitutive GTPγS binding at human H3-Rs demonstrating inverse agonist properties. In behavioral models addressing certain aspects of cognitive impairment associated with schizophrenia (CIAS) and attention deficit/hyperactivity disorder (ADHD), SAR110894 improved memory performances in several variants of the object recognition task in mice (0.3-3 mg/kg, p.o.) or rats (0.3-1 mg/kg, p.o.). Moreover, SAR110894 (1 mg/kg, p.o.) reversed a deficit in working memory in the Y-maze test, following an acute low dose of phencyclidine (PCP) (0.5 mg/kg, i.p.) in mice sensitized by repeated treatment with a high dose of PCP (10 mg/kg, i.p.). In the latent inhibition (LI) model, SAR110894 potentiated LI in saline-treated rats (1 and 3 mg/kg, i.p.) and reversed abnormally persistent LI induced by neonatal nitric oxide synthase (NOS) inhibition in rodents (0.3-3 mg/kg, i.p.). In a social novelty discrimination task in rats, SAR110894 attenuated selective attention deficit induced by neonatal PCP treatment (3 and 10 mg/kg, p.o.) or a parametric modification of the procedure (3 and 10 mg/kg, p.o.). SAR110894 showed efficacy in several animal models related to the cognitive deficits in Alzheimer's disease (AD). It prevented the occurrence of episodic memory deficit induced by scopolamine in rats (0.01-10 mg/kg, p.o.) or by the central infusion of the toxic amyloid fragment β25-35 in the object recognition test in mice (1 and 3 mg/kg, p.o.). Altogether, these findings suggest that SAR110894 may be of therapeutic interest for the treatment of the cognitive symptoms of AD, schizophrenia and certain aspects of ADHD.
KW - Alzheimer's disease
KW - Attention deficit/hyperactivity disorder
KW - Cognitive impairment associated with schizophrenia
KW - Histamine H receptor
KW - Rodents
UR - http://www.scopus.com/inward/record.url?scp=84861029254&partnerID=8YFLogxK
U2 - 10.1016/j.pbb.2012.04.004
DO - 10.1016/j.pbb.2012.04.004
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C2 - 22542742
AN - SCOPUS:84861029254
SN - 0091-3057
VL - 102
SP - 203
EP - 214
JO - Pharmacology Biochemistry and Behavior
JF - Pharmacology Biochemistry and Behavior
IS - 2
ER -