Effects of acute versus chronic treatment with typical or atypical antipsychotics on d-amphetamine-induced sensorimotor gating deficits in rats

Abstract.

Rationale: Dopamine (DA) receptor agonists disrupt the prepulse inhibition (PPI) in rats which is considered to model PPI deficits observed in schizophrenic patients. Many laboratories have demonstrated that both "typical" and "atypical" antipsychotics reverse the disruptive effect of DA agonists on PPI in rats. These results are based on acute treatment with antipsychotics, which is different from clinical observations since humans receive treatment for months and the effects of antipsychotics only emerge after weeks of treatment. Objectives: We aimed to investigate the effect of chronic treatment with "typical" and "atypical" antipsychotics on the PPI model in rats. Methods: We investigated the effect of acute versus sub-chronic (3 days) and chronic (21 days) treatment with haloperidol or two "atypical" antipsychotics (olanzapine; sertindole) on d-amphetamine-disrupted PPI in rats. Results: We observed that all three antipsychotics dose-dependently reversed the disruptive effect of d-amphetamine after acute or sub-chronic treatment, but that this reversal effect disappeared after chronic treatment. We confirmed this effect in the same model using oral administration instead of mini-pumps, and in an additional model predictive of antipsychotic action, i.e. d-amphetamine-induced hyperactivity in rats. Conclusions: The d-amphetamine-disrupted PPI model highlighted a modification in the effects of antipsychotics after chronic treatment when compared to their acute effects, but only the acute treatment can be considered predictive of antipsychotic action in clinic.