Effect of PDE10A inhibitors on MK-801-induced immobility in the forced swim test.

RATIONALE: Negative symptoms of schizophrenia are insufficiently treated by current antipsychotics. However, research is limited by the lack of validated models. Clinical data indicate that phencyclidine (PCP) abuse may induce symptoms resembling negative symptoms in humans. Based on that, Noda et al. proposed a model of PCP-induced increase of immobility in the forced swim test in mice as a model of depression-like negative symptoms of schizophrenia.

OBJECTIVES

The aim of the study was to evaluate the effect of phosphodiesterase 10A (PDE10A) inhibition in this model which was modified by using MK-801 instead of PCP.

METHODS

Increase of immobility in the forced swim test was induced by repeated MK-801 treatment followed by a 2-day washout in mice. The effect of haloperidol, clozapine, risperidone and PDE10A inhibitors was evaluated in this model, on open-field activity and acute MK-801-induced hyperactivity.

RESULTS

Repeated MK-801 treatment significantly increased immobility in the forced swim test without affecting open-field activity. It induced hypersensitivity to the dopamine D1 agonist A-68930, suggesting a hypofunction of the D1 pathway. The increase of immobility is reversed by clozapine and PDE10A inhibitors, but not by haloperidol. Clozapine and the PDE10A inhibitors did not enhance activity at effective doses.

CONCLUSION

The possibility to substitute PCP by MK-801 in this model indicates that the effect is mediated by their common mechanism of NMDA antagonism. PDE10A inhibitors similar to clozapine significantly antagonize the increase of immobility, suggesting a therapeutic potential for the treatment of negative symptoms. However, further validation of the model is necessary.