Atypical Antipsychotic Prevents and Reverses Negative Symptoms in Models of Schizophrenia

Abstract

Introduction: Negative symptoms associated with cognitive impairment as a core symptom of schizophrenia with significant poor quality of life and remain an unmet clinical need. Administration of N-methyl-D-aspartate (NMDA) receptor antagonists in rodents has been proposed as an animal model of negative symptoms in this disorder. Evidence from both animal models and human studies implicates a dysfunction of NMDA receptor function may attribute to pathophysiology of schizophrenia. Objectives: This study was undertaken to investigate the ability of sub-chronic co-administration of clozapine and haloperidol to both prevent and attenuate the social deficits induced by the NMDA receptor antagonist, phencyclidine (PCP) in the social interaction tasks. Methods: In the first test, female Sprague-Dawley rats were treated with saline, clozapine 5.0 mg/kg or haloperidol 0.05 mg/kg, 30 min later followed by either saline or PCP 2.0 mg/kg twice daily for 7 days, followed by 7 days drug free before tested in social interaction tasks. For the second test, female Sprague-Dawley rats received either vehicle or PCP 2.0 mg/kg for 7 days followed by 7 days drug free. Then rats received clozapine 5.0 mg/kg, haloperidol 0.05 mg/kg or vehicle twice daily for 7 days and were tested 120 min following the last dose of antipsychotic in social interaction tasks. Results: PCP treatment produced a significantly reduced social behaviours and that effect significantly prevented and improved by clozapine, but not haloperidol. Conclusions: These results suggest that antagonism of the consequences of reduced NMDA receptor function could contribute to the superior efficacy of atypical antipsychotic agents in improving negative symptoms in schizophrenia. These negative symptoms impairment likely reflect clinically relevant and can be used to evaluate the antipsychotic potential of new compounds on cognitive symptoms of schizophrenia.