Actions of Novel Antipsychotic Agents on Apomorphine-Induced PPI Disruption: Influence of Combined Serotonin 5-HT1A Receptor Activation and Dopamine D2 Receptor Blockade

Abstract

The dopamine D1/D2 agonist apomorphine (0.63 mg/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-HT 1A 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-HT 1A agonist properties, reversed PPI deficits at some doses only, whereas the anti-dyskinetic agent sarizotan (0.16-10 mg/kg), an efficacious 5-HT 1A agonist, did not. New generation antipsychotics with marked 5-HT 1A 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-HT 1A agonist properties in the lack of effects of SLV313 and SSR181507, we pretreated rats with the 5-HT 1A antagonist WAY100635 (0.63 mg/kg). Under these conditions, significant reversal of PPI deficit was observed, indicating that D 2 antagonist properties of SLV313 and SSR181507 are now sufficient to overcome the disruptive effects of apomorphine. To summarize, antipsychotics possessing agonist efficacy at 5-HT 1A receptors exhibit diverse profiles against apomorphine-induced PPI deficits, depending on the balance between D 2 and 5-HT 1A activities, suggesting that they may display distinct activity on some aspects of gating deficits in schizophrenic patients.

Effect of Aripiprazole on 5-HT2 Receptor–mediated Wet-Dog Shake Responses and Disruption of Prepulse Inhibition in Rats

“…Moreover, aripiprazole (10 and 30 mg / kg) improved the disruption of the PPI induced by apomorphine and DOI dose-dependently. The effect of aripiprazole on the PPI disruption induced by apomorphine was previously reported by other researchers (13). In their investigation, not only high dose of aripiprazole (10 mg / kg), but also Fig.…”

Differential Effects of Antipsychotic Drugs on Serotonin-1A Receptor-Mediated Disruption of Prepulse Inhibition

“…Of the antipsychotics we also included, pretreatment with haloperidol, risperidone, and olanzapine blocked the effect of apomorphine, whereas clozapine and aripiprazole were less effective (Auclair et al, 2006). Interestingly, when pretreatment with mixed D 2 /5-HT 1A ligands was combined with a 5-HT 1A receptor antagonist, the ability to block the action of apomorphine was enhanced.…”

“…In a recent study, several antipsychotics were tested against the disruption of PPI induced by treatment with the dopamine receptor agonist, apomorphine (Auclair et al, 2006). Of the antipsychotics we also included, pretreatment with haloperidol, risperidone, and olanzapine blocked the effect of apomorphine, whereas clozapine and aripiprazole were less effective (Auclair et al, 2006).…”

Behavioral Indices in Antipsychotic Drug Discovery

“…Apomorphine-induced PPI deficits can be reversed by haloperidol (Auclair et al, 2006). Some reports describe reversal of apomorphine-induced PPI deficits by clozapine, although its effects are often limited to a narrow dose range (Martin et al, 2003).…”