Previous studies have shown that the administration of NMDA antagonist can induce negative symptoms of schizophrenia which can be tested through the enhanced immobility observed in the forced swim test (FST). In the present study, we have compared the effects of acute as well as chronic administration of a noncompetitive NMDA receptor antagonist, ketamine on FST, and another behaviour despair model, tail suspension test (TST). Our observations suggest that chronic ketamine administration induced a state of enhanced immobility in FST, but such findings were not replicated in the TST model. Further, in FST, treatment with clozapine reverses the ketamine-induced immobility in mice, whereas it enhances the immobility duration in the TST model. However, haloperidol showed no protective effects in both models. The data suggests that although both of these tests show common behavioural measure of feeling despair, however, the underlying pathophysiology seems to be different. Hence, forced swim test but not tail suspension test can be used as a model of negative symptom of psychosis in mice. 1. Introduction Schizophrenia is perhaps the most devastating and enduring psychotic disorder affecting as many as 1% of the population worldwide, with a similar prevalence between the sexes and throughout diverse cultures and geographic areas [1]. Patients may present with positive symptoms (such as conceptual disorganization, delusions, hallucinations, hyperactivity, or stereotypy behaviour) or negative symptoms (social withdrawal, loss of function, anhedonia, decreased emotional expression, impaired concentration, and diminished social engagement). The latter predominate in one-third of the schizophrenic population and are associated with a poor long-term outcome and a poor response to drug treatment [2]. The treatment of schizophrenic patients with a typical antipsychotic, haloperidol, has been successful against positive symptoms but has a poor effect on primary negative symptoms [3], and clozapine, an atypical antipsychotic, apparently shows a partial effect on negative symptoms [4, 5]. Very little progress has been made in developing new antipsychotics with a combined effect on positive and primary negative symptoms, and part of the reason for this failure is the limited number of appropriate animal models that can mimic these symptoms and can be used for drug screening [6, 7]. Consequently, it is of great importance to determine whether and how antipsychotics improve negative symptoms in patients with schizophrenia, and also the effect of the antipsychotics can be
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