title: Examination of drug-induced and isolation-induced disruptions of prepulse inhibition as models to screen antipsychotic drugs.
abstract: Prepulse inhibition (PPI) of an acoustic startle response is impaired in schizophrenics. PPI can also be studied in the rat, and is impaired by dopamine (DA) D2/3 receptor agonists such as apomorphine. This disruption is reversed by DA antagonists, leading to proposals that this approach may be a useful means to identify novel antipsychotics. There is also evidence to suggest a role of serotonergic (5-HT) and glutamatergic systems in schizophrenia, and accordingly PPI can be disrupted by the 5-HT2 agonist DOI, and the non-competitive NMDA antagonist, dizocilpine. In the present study we have examined the effect of four antipsychotic drugs, haloperidol (0.1-0.3 mg/kg), raclopride (0.03-0.3 mg/kg), risperidone (0.3-3 mg/kg) and clozapine (0.0001-10 mg/kg), against the PPI disruptions induced by apomorphine (0.5 mg/kg), DOI (3 mg/kg) and dizocilpine (0.15 mg/kg). Furthermore, these drugs have been examined for their ability to restore a PPI deficit produced by housing rats under conditions of social isolation. All drugs except clozapine reversed an apomorphine-induced disruption. However, clozapine and risperidone, but not raclopride and haloperidol, reversed a DOI-induced disruption. Only risperidone was effective in restoring a PPI deficit produced by dizocilpine. In contrast to the drug-induced disruptions which were differentially sensitive to the various neuroleptics, isolation-induced disruptions were restored by each drug. These results support the idea that non-drug induced disruptions of PPI, such as social isolation, may be a more viable approach to identify novel antipsychotics.
authors.affiliation: Glaxo Unit of Behavioural Psychopharmacology, University of Hertfordshire, Herts, UK.
authors.forename: G B
authors.initials: GB
authors.lastname: Varty
authors.forename: G A
authors.initials: GA
authors.lastname: Higgins
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D011954:Receptors, Dopamine / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D011985:Receptors, Serotonin / Q000502:physiology; D013216:Reflex, Startle / Q000187:drug effects* / Q000502:physiology; D012934:Social Isolation
chemical_list: D014150:Antipsychotic Agents; D011954:Receptors, Dopamine; D016194:Receptors, N-Methyl-D-Aspartate; D011985:Receptors, Serotonin