Examination of drug-induced and isolation-induced disruptions of prepulse inhibition as models to screen antipsychotic drugs |
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Authors: | G. B. Varty G. A. Higgins G. A. Higgins |
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Affiliation: | (1) Glaxo Unit of Behavioural Psychopharmacology, University of Hertfordshire, College Lane, AL10 9AB Hatfield, Herts, UK;(2) Glaxo Wellcome Medicine Research Centre, Gunnels Wood Road, SG1 2NY Stevenage, Herts, UK |
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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. |
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Keywords: | Prepulse inhibition Schizophrenia Dopamine Serotonin Glutamate Social isolation Clozapine Raclopride Haloperidol Rirsperidone Rat |
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