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Habituation of acoustic startle is disrupted by psychotomimetic drugs: differential dependence on dopaminergic and nitric oxide modulatory mechanisms

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Abstract

Rationale

A deficit in attention and information processing has been considered a central feature in schizophrenia, which might lead to stimulus overload and cognitive fragmentation. It has been shown that patients with schizophrenia display a relative inability to gate incoming stimuli. Thus, patients repeatedly subjected to acoustic startle-eliciting stimuli habituate less to these stimuli than controls. Furthermore, schizophrenia-like symptoms can be induced by pharmacological manipulations in humans by psychotomimetic drugs, e.g. phencyclidine (PCP) and d-amphetamine (d-AMP). Recent studies show that the behavioural and biochemical effects of PCP in rodents are blocked by nitric oxide synthase (NOS) inhibitors, suggesting that NO plays an important role in at least the pharmacological effects of PCP.

Objectives

The first aim of the present study was to investigate if PCP, MK-801 and d-AMP impair habituation of acoustic startle in mice. Secondly, we examine the effect of the NOS inhibitor, l-NAME, and the dopamine receptor antagonist, haloperidol, on drug-induced deficit in habituation.

Results

PCP (4 mg/kg), MK-801 (0.4 mg/kg) and d-AMP (5.0 mg/kg), impaired habituation of the acoustic startle response in mice. This effect was reversed by the NOS inhibitor, l-NAME. The typical antipsychotic, haloperidol, reversed the effects of PCP and d-AMP, but not that of MK-801.

Conclusions

The finding that PCP, MK-801 and d-AMP impair habituation in mice is consistent with the idea that these treatments model certain filter deficits seen in schizophrenic patients. Furthermore, the present results suggest that NO is critically involved in these effects on habituation, whereas that of dopamine is less clear.

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Acknowledgements

This study was supported by grants from the Swedish Medical Research Council (4247), the Theodore and Vada Stanley Foundation, Rådman och Fru Ernst Collianders Stiftelse, Magnus Bergvalls Stiftelse, Stiftelsen Clas Groschinskys Minnesfond, Göteborgs Läkaresällskap, Wilhelm och Martina Lundgrens Vetenskapsfond, Stiftelsen Bengt Dahréns fond, the Swedish Society of Medicine, Åke Wibergs Stiftelse, Adlerbertska forskningsstiftelsen, Fredrik och Ingrid Thurings stiftelse, Åhlén-Stiftelsen and Svenska Lundbeckstiftelsen.

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  1. Department of Pharmacology, The Sahlgrenska Academy, Göteborg University, PO Box 431, 405-30, Goteborg, Sweden

    Daniel Klamer, Erik Pålsson, Aron Revesz, Jörgen A. Engel & Lennart Svensson

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  1. Daniel Klamer
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  2. Erik Pålsson
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  3. Aron Revesz
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  4. Jörgen A. Engel
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  5. Lennart Svensson
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Correspondence to Lennart Svensson.

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Klamer, D., Pålsson, E., Revesz, A. et al. Habituation of acoustic startle is disrupted by psychotomimetic drugs: differential dependence on dopaminergic and nitric oxide modulatory mechanisms. Psychopharmacology 176, 440–450 (2004). https://doi.org/10.1007/s00213-004-1901-z

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  • DOI: https://doi.org/10.1007/s00213-004-1901-z

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