Actions of novel antipsychotic agents on apomorphine-induced PPI disruption:: Influence of combined serotonin 5-HT1A receptor activation and dopamine D2 receptor blockade

The dopamine D1/D2 agonist apomorphine (0.63mg/kg) disrupted prepulse inhibition (PPI) of acoustic startle in rats, a model of sensorimotor gating deficits observed in schizophrenia. All current antipsychotics, which antagonize D-2 receptors, prevent this apomorphine-induced deficit. A novel class of antipsychotics possesses, in addition to D-2 antagonist property, various levels of 5-HTIA agonist activity. Considering that the latter itself produces PPI deficits, it appeared necessary to assess the potential of this novel class of antipsychotics to reverse apomorphine-PPI deficits. Potent D-2 antagonists, like haloperidol (0.63-2.5 mg/kg), risperidone (0.63-10 mg/kg), and olanzapine (0.63-40 mg/kg) prevented apomorphine PPI disruption. The atypical antipsychotics, clozapine (40 mg/kg), nemonapride (0.01-2.5 mg/kg), ziprasidone (10 mg/kg), and aripiprazole (0.01 and 10 mg/kg), which all exhibit 5-HTIA agonist properties, reversed PPI deficits at some doses only, whereas the anti-dyskinetic agent sarizotan (0.16-10 mg/kg), an efficacious 5-HTIA agonist, did not. New generation antipsychotics with marked 5-HTIA agonist properties, such as SLV313 and SSR181507 (0.0025-10 mg/kg and 0.16-10 mg/kg, respectively) did not reverse these deficits whereas bifeprunox (0.04-2.5 mg/kg) did. To reveal the contribution of 5-HTIA agonist properties in the lack of effects of SLV313 and SSR181507, we pretreated rats with the 5-HTIA antagonist WAY100635 (0.63 mg/ kg). Under these conditions, significant reversal of PPI deficit was observed, indicating that D2 antagonist properties of SLV313 and SSR181507 are now sufficient to overcome the disruptive effects of apomorphine. To summarize, antipsychotics possessing agonist efficacy at 5-HTIA receptors exhibit diverse profiles against apomorphine-induced PPI deficits, depending on the balance between D2 and 5-HTIA activities, suggesting that they may display distinct activity on some aspects of gating deficits in schizophrenic patients.