Abstract
Development of new antipsychotics and their novel applications may be facilitated through the use of physiological markers in clinically normal individuals. Both genetic and neurochemical evidence suggests that reduced prepulse inhibition of startle (PPI) may be a physiological marker for individuals at-risk for schizophrenia, and the ability of antipsychotics to normalize PPI may reflect properties linked to their clinical efficacy. We assessed the effects of the atypical antipsychotic quetiapine (12.5 mg po) on PPI in 20 normal men with a ‘low PPI’ trait, based on PPI levels in the lowest 25% of a normal PPI distribution. The effects of quetiapine (7.5 mg/kg s.c.) on PPI were then assessed in rats with phenotypes of high PPI (Sprague Dawley (SD)) and low PPI (Brown Norway (BN)); effects of clozapine (7.5 mg/kg i.p.) and haloperidol (0.1 mg/kg s.c.) on PPI were also tested in SD rats. At a time of maximal psychoactivity, quetiapine significantly enhanced PPI to short prepulse intervals (20–30 ms) in ‘low gating’ human subjects. Quetiapine increased PPI in low gating BN rats for prepulse intervals <120 ms; this effect of quetiapine was limited to 20 ms prepulse intervals in SD rats, who also exhibited this pattern in response to clozapine but not haloperidol. In both humans and rats, normal ‘low gating’ appears to be an atypical antipsychotic-sensitive phenotype. PPI at short intervals may be most sensitive to pro-gating effects of these drugs.
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Acknowledgements
Studies described in this manuscript were supported in part by MH 68366, MH 59803, and MH 01436, a pilot grant from the VISN 22 MIRECC, and funding from AstraZeneca Pharmaceuticals and Repligen Pharmaceutical, Inc. We are grateful to Dr Mark Geyer for informative discussions, and Ms Michelle Bongiovanni for technical support.
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Swerdlow, N., Talledo, J., Sutherland, A. et al. Antipsychotic Effects on Prepulse Inhibition in Normal ‘Low Gating’ Humans and Rats. Neuropsychopharmacol 31, 2011–2021 (2006). https://doi.org/10.1038/sj.npp.1301043
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DOI: https://doi.org/10.1038/sj.npp.1301043
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