Abstract
RationaleAttentional processing deficits are a core feature of schizophrenia, likely contributing to the persistent functional and occupational disability observed in patients with schizophrenia. The pathophysiology of schizophrenia is hypothesized to involve dysregulation of NMDA receptor-mediated glutamate transmission, contributing to disruptions in normal dopamine transmission. Preclinical investigations often use NMDA receptor antagonists, such as phencyclidine (PCP), to induce cognitive disruptions relevant to schizophrenia. We sought to test the ability of partial dopamine D2/D3 agonists, cariprazine and aripiprazole, to attenuate PCP-induced deficits in attentional performance.ObjectivesThe objective of this study is to determine whether systemic administration of cariprazine or aripiprazole attenuated 5-choice serial reaction time task (5-CSRTT) deficits induced by repeated exposure to PCP.MethodsWe utilized a repeated PCP-treatment regimen (2 mg/kg, subcutaneous [s.c.], once daily for 5 days) in rats to induce deficits in the 5-CSRTT. Rats were pre-treated with cariprazine (0.03, 0.1, or 0.3 mg/kg, oral [p.o.]) or aripiprazole (1, 3, or 10 mg/kg, p.o.) to determine whether they prevented PCP-induced deficits in the 5-CSRTT performance.ResultsPCP treatment increased inappropriate responding in the 5-CSRTT, elevating incorrect, premature, and timeout responses. Cariprazine treatment reduced PCP-induced increases in inappropriate responding. However, at higher doses, cariprazine produced non-specific response suppression, confounding interpretation of the attenuated PCP-induced deficits. Aripiprazole treatment also attenuated PCP-induced deficits; however, unlike cariprazine treatment, aripiprazole reduced correct responding and increased omissions.ConclusionsCariprazine and aripiprazole both demonstrated potential in attenuating PCP-induced deficits in the 5-CSRTT performance. While both compounds produced non-specific response suppression, these effects were absent when 0.03 mg/kg cariprazine was administered.
Highlights
Schizophrenia is a chronic disorder associated with psychotic disturbances, negative symptoms, and cognitive dysfunction
The aim of the present study was to identify whether systemic administration of cariprazine or aripiprazole attenuated 5choice serial reaction time task (5-CSRTT) deficits induced by repeated exposure to PCP and to explore eventual differences between these compounds in this model
Significant interactions were evident for percent incorrect responses in the aripiprazole treatment experiments [F(3, 32) = 3.32, p < 0.05]
Summary
Schizophrenia is a chronic disorder associated with psychotic disturbances, negative symptoms, and cognitive dysfunction. Cognitive deficits are a prominent feature of schizophrenia. As cognitive impairments are largely unresponsive to currently available medications and are thought to significantly contribute to the functional disability associated with the disorder, the identification of novel and efficacious therapeutic strategies is essential. Attentional processing is suggested to form an underlying basis of several higher-order cognitive processes (Riedel et al 2006), many of which were implicated by the MATRICS initiative as being disrupted in schizophrenia (Kern et al 2004). Attentional deficits in schizophrenia may contribute to the spectrum of cognitive dysfunction observed in patients and the associated functional disabilities. Identifying the mechanism(s) that contribute to attentional deficits, and subsequent therapeutic strategies to improve attentional functioning, may be a key to improving the patients’ quality of life
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