The Effects of Cariprazine and Aripiprazole on PCP-Induced Deficits on Attention Assessed in the 5-Choice Serial Reaction Time Task

Abstract

Rationale: Attentional 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.

Objectives: The 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.

Methods: We 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.

Results: PCP 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.

Conclusions: Cariprazine 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.

Keywords: 5-CSRTT; Aripiprazole; Cariprazine; Cognition; PCP; Schizophrenia.

Fig. 1

Experimental study design. 5-CSRTT 5-choice serial reaction time test, PCP phencyclidine, PO oral gavage, SC subcutaneous

Fig. 2

Effects of cariprazine and aripiprazole on PCP-induced alterations in attentional processing: incorrect responses (a, b) and response accuracy (c, d). Measures are shown as means ± SEM; p values are based on ANOVA planned comparisons (cariprazine; incorrect responses) or post hoc Fisher least significant difference tests (cariprazine; response accuracy, and aripiprazole). **p < 0.01 compared to baseline. ARI aripiprazole, CAR cariprazine, PCP phencyclidine, Veh vehicle

Fig. 3

Effects of cariprazine (a) and aripiprazole (b) on PCP-induced impulsivity: premature responses. Measures are shown as mean ± SEM. p values are based on post hoc Fisher least significant difference test (cariprazine) or ANOVA planned comparison tests (aripiprazole). *p < 0.05; **p < 0.01 compared to baseline. ARI aripiprazole, CAR cariprazine, PCP phencyclidine, Veh vehicle. ^aTwo outliers were removed from the PCP + 1 mg/kg aripiprazole group

Fig. 4

Effects of cariprazine (a) and aripiprazole (b) on PCP-induced cognitive flexibility: timeout responses. Measures are shown as means ± SEM. p values are based on post hoc Fisher least significant difference test. *p < 0.05; **p < 0.01 compared to baseline. ARI aripiprazole, CAR cariprazine, PCP phencyclidine, Veh vehicle