The Histamine H3 Receptor Antagonist/Inverse Agoniste159attenuates Autistic-Like Behaviors Inbtbr T+Tf/J Mice
Autistic spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairment insocial communication and restricted/repetitive behavior patterns or interests. The involvement of Histamine H3 receptors (H3Rs) in memory, and the potential role of H3R antagonists in pharmacological control of therapeutic management of neuropsychiatric diseases, e.g. dementia is well established. Therefore, the effects of subchronic systemic treatment with the novel histamine H3 receptor (H3R) antagonist E159 (2.5, 5, and 10 mg/kg, i.p,) with high H3R antagonist affinity (hH3R pKi = 6.12) on sociability, social novelty, anxiety, and aggressive/repetitive behavior in male BTBR T+tf/J mice model of ASD were investigated.E159 dose-dependently mitigated sociability and social novelty deficits of BTBR mice, with 2.5 mg/kg being the most promising dose (all P<0.05). Also, E159 (2.5 and 5 mg/kg) significantly alleviated the increased percentage of marbles buried and nestlet shredded (all P<0.05). Subchronic systemic pretreatment with E159attenuated disturbed anxiety levels (all P<0.05). However, E159 failed to restore hyperactivity parameters, whereas donepezil (1 mg/kg) significantly obliterated the increased hyperactivity measures of mice (P<0.05). In addition, E159 (2.5 mg)-provided significant (P<0.05) effects on sociability and social novelty, which were completely reversed when mice were co-administered with the H3R agonist (R)-α-methylhistamine and the CNS-penetrant H2R antagonist zolantidine, but not with the centrally acting H1R antagonist mepyramine.These intial findings indicate that E159 facilitates brain histaminergic neurotransmissions important for modulation of sociability and social novelty processes, albeit further preclinical testsin other animal species are still warranted. Therefore, E159 holds promise for its potential use to mitigate autistic-like behaviors in a genotype mouse model of ASD.
Keywords - Autism-Like behaviors;BTBR mice; histamine H3R; antagonist; E159; sociability, social novelty, repetitive behaviors, anxiety, locomotor activity..