Effect of ‘chronic’ versus ‘acute’ ketamine administration and its ‘withdrawal’ effect on behavioural alterations in mice: Implications for experimental psychosis

Lack of appropriate animal models simulating core behavioural aspects of human psychosis is a major limitation in schizophrenia research. The use of drugs, that is believed to act through N-methyl d-aspartate receptor, has been demonstrated to mimic relatively broader range of behavioural symptoms in putative animal models. Our goal in this study has been to further evaluate one such drug, ketamine in mice and characterize some selective behavioural phenotypes associated with the drug dosage, treatment period and withdrawal effects to extend the understanding of this model. Our results indicate that acute treatment of ketamine (100 mg/kg, i.p.) induced hyperlocomotory response and reduced the ‘transfer-latency time’ in passive avoidance test but did not have any effect in the forced swim test (negative symptoms). In contrast, chronic administration of ketamine not only produced significant ‘hyperactivity’ response but also enhanced the immobility period in animals during the forced swim test and reduced the latency period in the passive avoidance test. Further, these behavioural alterations persisted at least for 10 days after the withdrawal of ketamine treatment. These observations were substantiated by using standard typical and atypical antipsychotic drugs, haloperidol (0.25 mg/kg, i.p.), clozapine (10 mg/kg, i.p.) and risperidone (0.025 mg/kg, i.p.). Therefore, the present study suggests that the chronic treatment with ketamine has the potential of exhibiting changes in broader range of behavioural domains than the acute treatment. Hence, animals chronically treated with ketamine might serve as a useful tool to study the underlying pathogenic mechanisms associated with some symptoms in schizophrenia and other psychiatric disorders.

Research highlights▶ Acute ketamine induces hyperactive and memory impairment symptoms in mice. ▶ Chronic ketamine treatment induces positive, negative and memory impairment symptoms common in schizophrenic patients. ▶ Chronic ketamine-induced symptoms persists even after drug withdrawal. ▶ Both typical and atypical antipsychotics attenuated ketamine induced positive symptoms but only atypical antipsychotics attenuates the negative and cognitive symptoms. ▶ Chronic ketamine model can be a useful tool for antipsychotic screening.