Functional mechanism of ASP5736, a selective serotonin 5-HT5A receptor antagonist with potential utility for the treatment of cognitive dysfunction in schizophrenia

Abstract

The 5-HT receptor is arguably the least understood 5-HT receptor. Despite widespread expression in human and rodent brains it lacks specific ligands. Our previous results suggest that 5-HT receptor antagonists may be effective against cognitive impairment in schizophrenia. In this study, using behavioral, immunohistochemical, electrophysiological and microdialysis techniques, we examined the mechanism by which ASP5736, a novel and selective 5-HT receptor antagonist, exerts a positive effect in animal models of cognitive impairment. We first confirmed the effect of ASP5736 on cognitive deficits in rats treated subchronically with phencyclidine hydrochloride (PCP) using an attentional set shifting task. Subsequently, we identified 5-HT receptors in dopaminergic (DAergic) neurons and parvalbumin (PV)-positive interneurons in the ventral tegmental area (VTA) and in PV-positive interneurons in the medial prefrontal cortex (mPFC). Burst firing of the DAergic cells in the parabrachial pigmental nucleus (PBP) in the VTA, which predominantly project to the mPFC, was significantly enhanced by treatment with ASP5736. In contrast, ASP5736 exerted no significant effect on either the firing rate or burst firing in the DA cells in the paranigral nucleus (PN), that project to the nucleus accumbens (N. Acc.). ASP5736 increased the release of DA and gamma-aminobutyric acid (GABA) in the mPFC of subchronically PCP-treated rats. These results support our hypothesis that ASP5736 might block the inhibitory 5-HT receptors on DAergic neurons in the VTA that project to the mPFC, and interneurons in the mPFC, and thereby improve cognitive impairment by preferentially enhancing DAergic and GABAergic neurons in the mPFC.

Serotonin type 5A receptor antagonists inhibit D-lysergic acid diethylamide discriminatory cue in rats

“…Last but not least, data from this laboratory indicate that SB 699551 reversed ketamine-induced cognitive deficits in the attentional set-shifting test and novel object recognition task, as well as ketamine-induced social withdrawal in social interaction and in the social choice tests, suggesting that the 5-HT 5A receptor antagonist may ameliorate cognitive impairments and 'negative-like' symptoms (Nikiforuk et al, 2016). The procognitive effects of another 5-HT 5A receptor antagonist, ASP 5736, in the PCP-induced model of schizophrenia symptoms were recently reported by Yamazaki et al (2018). Altogether, these data suggest that 5-HT 5A receptor antagonists display some antipsychotic-like effects.…”

5-HT5A Receptor Antagonist ASP5736 Ameliorates Several Abnormal Behaviors in an Fmr1-Targeted Transgenic Male Rat Model of Fragile X Syndrome

“…In our previous study, we showed that 0.001–0.03 mg/kg of ASP5736 was effective for improving cognitive performance in the water maze task in aged rats, with a maximum effect observed at 0.01 mg/kg ( Yamazaki et al, 2015 ). In a separate study ( Yamazaki et al, 2018 ), we showed that ASP5736 (0.001–0.01 mg/kg, po) significantly improved cognitive deficits exhibited by a subchronical phencyclidine-induced rat model in the attentional set-shifting task, with a maximum effect also observed at 0.01 mg/kg. A study by Ventura et al (2004) demonstrated that amphetamines improve the ability of Fmr1 -KO mice to discriminate between novel and familiar objects without significantly affecting locomotor activity.…”

“…We previously demonstrated that ASP5736, a 5-HT 5A receptor antagonist, ameliorated scopolamine-induced working memory deficits in mice, reference memory impairment in aged rats ( Yamazaki et al, 2015 ), and methamphetamine-induced positive symptoms ( Yamazaki et al, 2014 ) and phencyclidine-induced cognitive impairment in animal models of schizophrenia ( Yamazaki et al, 2018 ). Here, we characterized several behaviors of male Fmr1 -KO rats as an alternative preclinical model of FXS and evaluated the effects of ASP5736 in the male Fmr1 -KO rat model.…”

Sustained NMDA receptor hypofunction impairs brain-derived neurotropic factor signalling in the PFC, but not in the hippocampus, and disturbs PFC-dependent cognition in mice

“…While our study identified BDNF dysfunction as a key mechanism that contributes to the impact of subchronic PCP administration on PFC function, other mechanisms are also involved. This includes, for example, dysfunction of the dopaminergic (Balla et al, 2003; Jentsch, 1997; McLean et al, 2017), GABAergic (Amitai et al, 2012; Dawson et al, 2014; Gong et al, 2009) and serotonergic (Hori et al, 2000; Santini et al, 2013; Yamazaki et al, 2018) systems. Interestingly, there is also some evidence that these neurotransmitter systems regulate BDNF function (Fumagalli et al, 2006; Porcher et al, 2018), therefore future characterisation of the inter-related nature of these mechanisms in the PCP mouse model would be of interest.…”