5-HT5A Receptor Antagonist ASP5736 Ameliorates Several Abnormal Behaviors in an Fmr1-Targeted Transgenic Male Rat Model of Fragile X Syndrome.
Fragile X syndrome (FXS) is a genetic condition that causes a range of developmental problems, including intellectual disability, aggressive behavior, anxiety, abnormal sensory processing, and cognitive impairment. Despite intensive preclinical research in Fmr1-targeted transgenic mice, an effective treatment for FXS has yet to be developed. We previously demonstrated that ASP5736, a 5-Hydroxytryptamine (serotonin) receptor 5A receptor antagonist, ameliorated scopolamine-induced working memory deficits in mice, reference memory impairment in aged rats, and methamphetamine-induced positive symptoms and phencyclidine-induced cognitive impairment in animal models of schizophrenia. We hypothesized that ASP5736 may be effective for ameliorating similar behavior deficits in male Fmr1-targeted transgenic rats as a preclinical model of FXS. We evaluated the effect of acute oral administration of ASP5736 on the abnormal behavior of hyperactivity (0.01, 0.1 mgkg), prepulse inhibition (0.01, 0.03, 0.1 mgkg), and the novel object recognition task (0.1 mgkg) in Frmr1-knockout (KO) rats. Fmr1-KO rats showed body weight gain, hyperactivity, abnormal sensory motor gating, and cognitive impairment. ASP5736 (0.1 mgkg) reversed the hyperactivity and ameliorated the sensory motor gating deficits (0.03-0.1 mgkg). ASP5736 (0.01 mgkg) also improved cognitive impairment. ASP5736 is a potential drug candidate for FXS. Further studies are needed to confirm its clinical efficacy.