¹Division of Neurobiology 2, Centre de Recherche Pierre Fabre, Castres, France

Correspondence: Dr AL Auclair, Division of Neurobiology 2, Centre de Recherche Pierre Fabre, 17, Avenue Jean Moulin, 81106 Castres, France. Tel: +33 56371 4268; Fax: +33 56371 4363; E-mail: agnes.auclair@pierre-fabre.com

²Current address: Department of Psychology, University of Pennsylvania, 3720 Walnut Street, Philadelphia, PA 19104-6196, USA. E-mail: klevenms@psych.upenn.edu

Received 13 June 2005; Revised 6 October 2005; Accepted 17 November 2005; Published online 18 January 2006.

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 D₂ receptors, prevent this apomorphine-induced deficit. A novel class of antipsychotics possesses, in addition to D₂ 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 D₂ 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 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-HT_1A receptors exhibit diverse profiles against apomorphine-induced PPI deficits, depending on the balance between D₂ and 5-HT_1A activities, suggesting that they may display distinct activity on some aspects of gating deficits in schizophrenic patients.