Schizophrenia is a polygenic, multi-factorial disease whose etiology remains unknown. The wide range of symptoms and differences in the course and prognosis suggest that schizophrenia arises from the dysfunction of several neurotransmitter systems, generating a wide range of neurophysiological alterations that are not identifiable in all patients. Since its inception, schizophrenia has been managed with dopamine antagonists, which effectively reverses positive symptoms, but does not improve residual symptoms produced for the long term, such as cognitive impairment, social withdrawal, affective dysregulation, and disability [1]. In addition, 10-30% of patients do not improve with dopamine antagonists and become refractory to treatment [1].

Recently, the glutaminergic system has been suggested to be linked with schizophrenia, after it was shown that N-methyl-D-aspartate (NMDA) receptor antagonists such as ketamine, phencyclidine, and MK 801 were beneficial for both positive and negative symptoms of the disease [2]. Yet, the only available treatment for schizophrenia is the drugs that act on the dopaminergic system, and no alternative drugs that act on other neurotransmitter systems are available. Repeated treatment of ketamine in rats generates social withdrawal and aggression, alterations which are reminiscent of the symptoms of schizophrenia in humans [3]. In the present study, we attempted to reproduce a model of psychosis by treatment with ketamine in rats. After establishment of psychosis model, we assessed reversibility of the condition with memantine, a modulator of the NMDA receptor, and compared the effect with that of haloperidol, a potent dopamine antagonist. The degrees of social withdrawal were analyzed in the social interaction test (SIT) and quantified.

The ketamine-induced psychosis model in rats reproduces behavioral symptoms that mimic schizophrenic psychosis in humans [3], as well as the primary pathophysiological changes generated by this disease [4]. When the membrane NMDA receptor is blocked by ketamine in GABAergic interneurons, there is a failure to correctly interpret the degree of excitation of pyramidal neurons; resulting in an excessive glutamate action; thus, inducing an overstimulation of the ventral tegmental area and finally, the classic hyper-dopaminergic state characteristic of schizophrenia [5]. Ketamine has hepatic clearance of 19.1 ml·min^-1·kg^-1, which ensures the excretion of its eight active metabolites about 24 h after administration [6]. Ketamine, which blocks NMDA, is known to generate long lasting molecular changes in the brain at least 14 days after complete withdrawal [4]. In our study, memantine was administered at 10 mg·kg^-1 after ketamine treatment and memantine treatment resulted in a greater reversal of social isolation than that of the placebo or haloperidol (0.25 mg·kg^-1). This antipsychotic action did not show a dose-effect. Memantine induced a reduction in the total traveled distance, and a dose dependent effect at 10 and 15 mg·kg^-1. Thus, the sedative effect of memantine must be considered to explain this observation. Although previous studies described the use of higher doses of memantine [7], all of our rats died in a preliminary study at doses >30 mg·kg^-1.

No correlation was observed between the distance traveled per second (speed) and DBR (social isolation), suggesting that the effect of memantine on this ketamine-induced psychotic symptom probably was not due to an action of memantine on rat motility. In addition, regarding that a social withdrawal model induced by ketamine in rats is an approach to behavioral changes of schizophrenia in human, these data suggest that memantine has a therapeutic potential for this disease.

The therapeutic effect of memantine in ketamine-induced psychosis model of schizophrenia suggests the importance of glutamatergic dysfunction in schizophrenia. In fact, glutamatergic dysfunction in schizophrenia has been suggested to be one of the neurotransmitter systems involved. Current evidence suggests that the wide variety of clinical conditions among patients with schizophrenia could be caused by different endophenotypes [8], which in turn, induce differences in the response to antipsychotic treatments. For example, 10-30% of patients with schizophrenia become resistant to conventional antipsychotic treatment [1], but respond to clozapine, which is an atypical antipsychotic drug with a high impact on NMDA receptor modulation [9], suggesting that these patients may have a different endophenotype that requires an alternative pharmacological intervention.

Table 1. Distance between rats in the groups immediate after ketamine treatment and 5 days after washout

Table 2. Distance between rats and speed measured in groups and/or experimental phases

Table 3. Post hoc analysis of the distance between rats and average speed of rats during the social interaction test