title: Iloperidone reduces sensorimotor gating deficits in pharmacological models, but not a developmental model, of disrupted prepulse inhibition in rats.
abstract: Iloperidone is a novel atypical antipsychotic which acts as a broad spectrum dopamine/serotonin/norepinephrine receptor antagonist. To compare iloperidone behaviorally to other known antipsychotics, we evaluated the drug in three pharmacological models and one developmental model of disrupted prepulse inhibition (PPI) in rats. Firstly, 0.5 mg/kg apomorphine induced PPI deficits that were prevented by pretreatment with iloperidone (1 and 3 mg/kg). Secondly, treatment with the N-methyl-D-aspartate (NMDA)-receptor antagonist phencyclidine (PCP) produced robust deficits in PPI. Both doses of iloperidone (1 and 3 mg/kg) prevented the PPI-disruptive effects of treatment with 1 mg/kg PCP. Thirdly, treatment with the alpha1-adrenoceptor agonist cirazoline (0.6 mg/kg) disrupted PPI, and produced a concurrent large increase in startle magnitude. A relatively low dose of iloperidone (0.3 mg/kg) prevented cirazoline-induced PPI deficits, independent of its effects on startle magnitude. Finally, iloperidone (1 mg/kg) did not reverse PPI deficits in the isolation-rearing model of schizophrenia. These results indicate that iloperidone exerts behavioral effects in pharmacological models of disrupted sensorimotor gating consistent with "atypical" antipsychotics, mediated by antagonism of dopaminergic and noradrenergic receptors. The absence of effect in isolation-reared rats may be due to the relatively small effect size of isolation rearing on PPI or dose of iloperidone.
authors.affiliation: Molecular and Integrative Neurosciences Department, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Alasdair M
authors.initials: AM
authors.lastname: Barr
authors.forename: Susan B
authors.initials: SB
authors.lastname: Powell
authors.forename: Athina
authors.initials: A
authors.lastname: Markou
authors.forename: Mark A
authors.initials: MA
authors.lastname: Geyer
mesh_terms: D000161:Acoustic Stimulation / Q000379:methods; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D001058:Apomorphine / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D004195:Disease Models, Animal; D018491:Dopamine Agonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004347:Drug Interactions; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D020233:Gait Disorders, Neurologic / Q000139:chemically induced / Q000188:drug therapy*; D007093:Imidazoles / Q000494:pharmacology; D007555:Isoxazoles / Q000627:therapeutic use*; D008297:Male; D009433:Neural Inhibition / Q000187:drug effects*; D010622:Phencyclidine / Q000494:pharmacology; D010880:Piperidines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013216:Reflex, Startle / Q000187:drug effects*
chemical_list: D000316:Adrenergic alpha-Agonists; D014150:Antipsychotic Agents; D018491:Dopamine Agonists; D018691:Excitatory Amino Acid Antagonists; D007093:Imidazoles; D007555:Isoxazoles; D010880:Piperidines; D010622:Phencyclidine; D001058:Apomorphine; C014282:cirazoline; C081732:iloperidone