Chronic low dose risperidone and clozapine alleviate positive but not negative symptoms in the rat neonatal ventral hippocampal lesion model of schizophrenia

Rationale: The rat neonatal ventral hippocampal (VH) ibotenic lesion model has been proposed as a developmental model of schizophrenia, based on evidence that it encompasses aspects of the disorder including psychomotor agitation (hyperactivity), deficits in prepulse inhibition (PPI), and deficits in social interaction (SI), measures presumed to reflect positive symptoms, sensory gating deficits and negative symptoms, respectively. However, validation of the model as a predictive pharmacological screening tool has been minimal. Objective: Determine the effects of a chronic 3-week low dose treatment of clozapine or risperidone on locomotor hyperactivity, PPI and SI in lesioned and control rats. Results: Both clozapine, 2.5 mg/kg per day IP and risperidone, 0.1 mg/kg per day IP, reversed lesion-induced locomotor hyperactivity; however, the compounds also decreased locomotor activity in the non-lesioned controls. Clozapine 2.5 mg/kg per day and risperidone 0.1 mg/kg per day significantly attenuated lesion-induced PPI deficits. Neither compound induced a significant attenuation of lesion-induced SI deficits. In order to see if SI deficits required a higher dose of an antipsychotic, the dose of clozapine was increased to 4 mg/kg per day; however this dose induced such marked decreases in the activity and startle responses in the control rats, i.e. up to 74% decrease, that the effects on the lesioned rats could not be adequately interpreted. Conclusions: These data add further support to the neonatal VH lesion model as a predictive pharmacological screening assay for identifying compounds effective in the treatment of positive symptoms of schizophrenia. However, the usefulness of the model in detecting compounds effective in treating negative symptoms of schizophrenia is still in question.