cariprazine and Cognition-Disorders

Negative symptoms and cognitive impairment associated with schizophrenia are strongly associated with poor functional outcome and reduced quality of life and remain an unmet clinical need. Cariprazine is a dopamine D3/D2 receptor partial agonist with preferential binding to D3 receptors, recently approved by the FDA for the treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder. The aim of this study is to evaluate effects of cariprazine in an animal model of cognitive deficit and negative symptoms of schizophrenia. Following sub-chronic PCP administration (2mg/kg, IP for 7 days followed by 7 days drug-free), female Lister Hooded rats were administered cariprazine (0.05, 0.1, or 0.25mg/kg, PO) or risperidone (0.16 or 0.1mg/kg, IP) before testing in novel object recognition (NOR), reversal learning (RL), and social interaction (SI) paradigms. As we have consistently demonstrated, sub-chronic PCP significantly impaired behavior in these tests. Deficits were significantly improved by cariprazine, in a dose dependent manner in the operant RL test with efficacy at lower doses in the NOR and SI tests. Locomotor activity was reduced at the highest doses of 0.1mg/kg and 0.25mg/kg in NOR and SI. Risperidone also reversed the PCP-induced deficit in all tests. In conclusion, cariprazine was effective to overcome PCP-induced deficits in cognition and social behavior in a thoroughly validated rat model in tests representing specific symptom domains in schizophrenia patients. These findings support very recent results showing efficacy of cariprazine in the treatment of negative symptoms in schizophrenia patients.

Topics: Animals; Antipsychotic Agents; Cognition; Cognition Disorders; Conditioning, Operant; Disease Models, Animal; Dopamine Agonists; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Exploratory Behavior; Female; Motor Activity; Nootropic Agents; Phencyclidine; Piperazines; Rats; Recognition, Psychology; Risperidone; Schizophrenia; Schizophrenic Psychology; Social Behavior

A major challenge in the pharmacological treatment of psychotic disorders is the effective management of the associated cognitive dysfunctions. Novel concepts emphasize a potential benefit of partial agonists acting upon dopamine D(2)-like receptors in ameliorating these cognitive deficits, and pre-clinical studies suggest that D(3)-receptor-preferring compounds can exert pro-cognitive effects.. The objective of the study was to use acute phencyclidine (PCP) treatment to model the cognitive deficits of schizophrenia in mice, and to test the efficacy of the novel, dopamine D(3)-receptor-preferring drug cariprazine in ameliorating the severity of PCP-triggered cognitive deficits.. One group of wild-type or D(3)-receptor knockout mice was acutely treated with either saline or phencyclidine (PCP, 1 mg/kg). A separate group of mice was treated with cariprazine prior to PCP administration. Both groups were then tested in three cognitive tasks: social interaction/recognition and recognition memory, spatial working memory, and attention-set-shifting.. PCP effectively disrupted social recognition and social recognition memory, spatial working memory, and extradimensional attention set-shifting. Cariprazine pretreatment significantly attenuated the emergence of these cognitive deficits in PCP-treated wild-type mice, but not in PCP-treated D(3)-receptor knockout mice.. In an animal model of PCP-induced cognitive impairment, cariprazine pretreatment significantly diminished PCP-triggered cognitive deficits, and studies on knockout mice show that dopamine D(3) receptors contribute to this effect.

Topics: Analysis of Variance; Animals; Attention; Cognition Disorders; Drug Partial Agonism; Male; Maze Learning; Memory, Episodic; Memory, Short-Term; Mice; Mice, Inbred C57BL; Mice, Knockout; Phencyclidine; Piperazines; Receptors, Dopamine D3; Recognition, Psychology; Set, Psychology