Blockade of drug-induced deficits in prepulse inhibition of acoustic startle by ziprasidone

Ziprasidone, an antipsychotic with efficacy against core symptoms of schizo phrenia and schizoaffective disorder, has a low incidence of extrapyramidal syndrome (EPS). Because of its high 5-HT2A/D-2 binding-affinity ratio and low EPS liability, ziprasidone is considered to belong to the newer class o f "novel" antipsychotics typified by clozapine. Its unique pharmacological profile, however, distinguishes it from other novel agents. We evaluated zi prasidone in the prepulse inhibition (PPI) model, which is sensitive to cli nically active antipsychotics. Male Wistar rats were tested in acoustic sta rtle sessions in which some startle-eliciting stimuli were presented alone, and others were preceded by a weak prepulse. Administration of the dopamin e agonist apomorphine (1 mg/kg) or the N-methyl-D-aspartate (NMDA) antagoni st ketamine (10 mg/kg) significantly disrupted PPI. When coadministered wit h either of these compounds, clozapine (1-5.6 mg/kg sc) and ziprasidone (5. 6-17.8 mg/kg po) significantly attenuated the declines in PPI. Haloperidol (0.03-0.56 mg/kg) also attenuated drug-induced deficits in PPI but to a les ser extent (and at higher doses) with ketamine than with apomorphine. Toget her, these data confirm that ziprasidone shares common effects in PPI model s with other novel antipsychotics. Ziprasidone's affinity for non-D-2 recep tors in the central nervous system may partly account for its attenuation o f ketamine's effect. (C) 2001 Elsevier Science Inc. All rights reserved.