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Background TAK-831 is a potent inhibitor of the DAAO enzyme being developed for the cognitive deficits and negative symptoms of schizophrenia. Inhibition of DAAO results in an increase in D-serine, a co-agonist of the NMDA receptor and a full agonist of the δ2 glutamate receptor. Augmentation of NMDA and δ2 glutamate receptor function may be beneficial in schizophrenia. To determine this, rats given TAK-831 were tested in the Novel Object Recognition (NOR) test, a basic cognition test, the Attentional Set Shifting Task (ASST), an animal assay to assess executive function in rodents, and Social Interaction (SI), an animal model of negative symptoms. To determine the impact that a target localized in the cerebellum has on learning, the compound was also profiled in eyeblink conditioning (EBC), a model of cerebellar-based associative learning. Methods Rats were given an acute and chronic dose of TAK-831 and cerebrospinal fluid (CSF); cerebellar tissue and plasma were harvested after 6 hours. For NOR, mice were dosed acutely and chronically (14d) with TAK-831 and assessed in their ability to differentiate between novel and previously seen objects after a 4-hour inter-trial interval (ITI). Rats treated with a subchronic phencyclidine (PCP) regimen (2 mg/kg, 7 days bid) showed a deficit in the extra-dimensional shift (EDS) in the ASST. Acute and chronic (14d) doses of TAK-831 were assessed for reversal of the PCP-induced deficit. TAK-831 was dosed acutely and chronically (0.3, 1, 3 mg/kg, po) and assessed for its ability to reverse a naturally occurring SI deficit seen in Balb/c mice. The same dose range was used when the SI deficit was induced by maternal treatment with Poly(I:C). In EBC, a periorbital electrical stimulus was paired with a corneal air puff resulting in classical conditioning. TAK-831 (0.1 and 1 mg/kg, po, 10d chronic dosing) was assessed for its ability to improve acquisition of the conditioned response in the presence and absence of scopolamine. Results TAK-831 produced a dose-dependent increase in D-serine levels across CSF, cerebellum, and in plasma. After a 4-hour ITI, vehicle-treated mice were unable to differentiate between a novel and familiar object in NOR. Animals were able to identify the novel object when treated with TAK-831 at 0.3, 1, 3 and 10 mg/kg acute doses and at 0.003, 0.01, 0.03, 0.1, 1.0 and 3 mg/kg chronic doses. TAK-831 was able to reverse the PCP-induced deficit in rats in the EDS in the ASST at 3, 10, and 30 mg/kg acute doses and at 0.1, 1.0 and 10 mg/kg chronic doses. TAK-831 was efficacious in the Balb/c SI model at 1 and 3 mg/kg acute doses and at 0.01, 0.03, 0.1, 1.0 and 10 mg/kg chronic doses; it was efficacious at 3 mg/kg acute dosing in the Poly(I:C) SI model. TAK-831 caused an improvement in both the acquisition of the conditioned response and in reversing the scopolamine-induced deficit at 0.1 and 1 mg/kg in the EBC paradigm. Discussion TAK-831 shows utility at a range of doses in animal models associated with negative symptoms and cognitive impairment in schizophrenia. Its efficacy in EBC shows the impact on cerebellar-based learning; this region of the brain is now considered to also be involved in schizophrenia. TAK-831 shows a different range of efficacies pre-clinically, depending on whether the compound is dosed acutely or chronically, indicating a potential plasticity of effect in the brain of preclinical species. [ABSTRACT FROM AUTHOR]