Time course of the attenuation effect of repeated antipsychotic treatment on prepulse inhibition disruption induced by repeated phencyclidine treatment

Abstract

Antagonism of prepulse inhibition (PPI) deficits produced by psychotomimetic drugs has been widely used as an effective tool for the study of the mechanisms of antipsychotic action and identifying potential antipsychotic drugs. Many studies have relied on the acute effect of a single administration of antipsychotics, whereas patients with schizophrenia are treated chronically with antipsychotic drugs. The clinical relevance of acute antipsychotic effect in this model is still an open question. In this study, we investigated the time course of repeated antipsychotic treatment on persistent PPI deficit induced by repeated phencyclidine (PCP) treatment. After a baseline test with saline, male Sprague-Dawley rats were repeatedly injected with either vehicle, haloperidol (0.05mg/kg), clozapine (5.0 or 10.0mg/kg), olanzapine (2.0mg/kg), risperidone (1.0mg/kg) or quetiapine (10mg/kg), followed by PCP (1.5mg/kg, sc) and tested for PPI once daily for 6 consecutive days. A single injection of PCP disrupted PPI and this effect was maintained with repeated PCP injections throughout the testing period. Acute clozapine, but not other antipsychotic drugs, attenuated acute PCP-induced PPI disruption at both tested doses. With repeated treatment, clozapine and quetiapine maintained their attenuation, while risperidone enhanced its effect with a significant reduction of PCP-induced disruption toward the end of treatment period. In contrast, repeated haloperidol and olanzapine treatments were ineffective. The PPI effects of these drugs were more conspicuous at a higher prepulse level (e.g. 82dB) and were dissociable from their effects on startle response and general activity. Overall, the repeated PCP-PPI model appears to be a useful model for the study of the time-dependent antipsychotic effect, and may help identify potential treatments that have a quicker onset of action than current antipsychotics.

Fig. 1

Effects of repeated haloperidol (0.05 mg/kg, sc) or clozapine (10.0 mg/kg, sc) treatment on the repeated PCP (1.5 mg/kg, sc)-induced disruption of PPI at the 73 dB (A), 76 dB (B) and 82 dB (C) prepulse levels. *P<0.05 in comparison to the VEH+VEH group; #P<0.05 in comparison to the VEH+PCP group.

Fig. 1

Effects of repeated haloperidol (0.05 mg/kg, sc) or clozapine (10.0 mg/kg, sc) treatment on the repeated PCP (1.5 mg/kg, sc)-induced disruption of PPI at the 73 dB (A), 76 dB (B) and 82 dB (C) prepulse levels. *P<0.05 in comparison to the VEH+VEH group; #P<0.05 in comparison to the VEH+PCP group.

Fig. 2

Effects of repeated haloperidol (0.05 mg/kg, sc) or clozapine (10.0 mg/kg, sc) treatment on the repeated PCP (1.5 mg/kg, sc)-induced increase in the acoustic startle response (ASR) (A) and general activity (B). *P<0.05 in comparison to the VEH+VEH group; #P<0.05 in comparison to the VEH+PCP group.

Fig. 2

Effects of repeated haloperidol (0.05 mg/kg, sc) or clozapine (10.0 mg/kg, sc) treatment on the repeated PCP (1.5 mg/kg, sc)-induced increase in the acoustic startle response (ASR) (A) and general activity (B). *P<0.05 in comparison to the VEH+VEH group; #P<0.05 in comparison to the VEH+PCP group.

Fig. 3

Effects of repeated olanzapine (2.0 mg/kg, sc), risperidone (1.0 mg/kg, sc), or quetiapine (10.0 mg/kg, sc) treatment on the repeated PCP (1.5 mg/kg, sc)-induced disruption of PPI at the 73 dB (A), 76 dB (B) and 82 dB (C) prepulse levels. *P<0.05 in comparison to the VEH+VEH group; #P<0.05 in comparison to the VEH+PCP group.

Fig. 3

Effects of repeated olanzapine (2.0 mg/kg, sc), risperidone (1.0 mg/kg, sc), or quetiapine (10.0 mg/kg, sc) treatment on the repeated PCP (1.5 mg/kg, sc)-induced disruption of PPI at the 73 dB (A), 76 dB (B) and 82 dB (C) prepulse levels. *P<0.05 in comparison to the VEH+VEH group; #P<0.05 in comparison to the VEH+PCP group.

Fig. 4

Effects of repeated olanzapine (2.0 mg/kg, sc), risperidone (1.0 mg/kg, sc), or quetiapine (10.0 mg/kg, sc) treatment on the repeated PCP (1.5 mg/kg, sc)-induced increase in the acoustic startle response (ASR) (A) and general activity (B). *P<0.05 in comparison to the VEH+VEH group; #P<0.05 in comparison to the VEH+PCP group.

Fig. 5

Effects of repeated clozapine (5.0 and 10.0 mg/kg, sc) treatment on the repeated PCP (1.5 mg/kg, sc)-induced disruption of PPI at the 73 dB (A), 76 dB (B) and 82 dB (C) prepulse levels. *P<0.05 in comparison to the VEH+VEH group; #P<0.05 in comparison to the VEH+PCP group.

Fig. 5

Effects of repeated clozapine (5.0 and 10.0 mg/kg, sc) treatment on the repeated PCP (1.5 mg/kg, sc)-induced disruption of PPI at the 73 dB (A), 76 dB (B) and 82 dB (C) prepulse levels. *P<0.05 in comparison to the VEH+VEH group; #P<0.05 in comparison to the VEH+PCP group.

Fig. 6

Effects of repeated clozapine (5.0 and 10.0 mg/kg, sc) treatment on the repeated PCP (1.5 mg/kg, sc)-induced increase in the acoustic startle response (ASR) (A) and general activity (B). *P<0.05 in comparison to the VEH+VEH group; #P<0.05 in comparison to the VEH+PCP group.