Examination of drug-induced and isolation-induced disruptions of prepulse inhibition as models to screen antipsychotic drugs.
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.
Varty
G B
GB
Glaxo Unit of Behavioural Psychopharmacology, University of Hertfordshire, Herts, UK.
Higgins
G A
GA
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
D014150:Antipsychotic Agents; D011954:Receptors, Dopamine; D016194:Receptors, N-Methyl-D-Aspartate; D011985:Receptors, Serotonin