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Activation of a nitric-oxide-sensitive cAMP pathway with phencyclidine: elevated hippocampal cAMP levels are temporally associated with deficits in prepulse inhibition

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Abstract

Rationale

Schizophrenic patients show deficits in pre-attentive information processing as evidenced, for example, by disrupted prepulse inhibition, a measure of sensorimotor gating. A similar disruption can be observed in animals treated with the psychotomimetic agent, phencyclidine (PCP). However, the mechanism by which PCP alters brain function has not been fully elucidated. Recent studies have demonstrated that certain behavioural and neurochemical effects of PCP in rats and mice are blocked by nitric oxide (NO) synthase inhibition, suggesting an important role for NO in the effects of PCP.

Objective

The aim of the present study was to investigate the effects of PCP on cAMP production in the ventral hippocampus and the role of NO in these effects using in vivo microdialysis in rats. Furthermore, the effects of PCP on acoustic startle reactivity and prepulse inhibition of acoustic startle were compared with changes in cAMP levels in the ventral hippocampus.

Results

Significant increases in cAMP levels were observed in the ventral hippocampus following both local infusion (10−4 mol/l and 10−3 mol/l) and systemic administration (2 mg/kg) of PCP. The PCP-induced changes in prepulse inhibition and startle reactivity were associated in magnitude and duration with the increase in cAMP levels in the hippocampus. Furthermore, systemic administration of the NO synthase inhibitor, l-NAME (10 mg/kg), blocked both the changes in cAMP levels and the behavioural responses induced by PCP.

Conclusions

These findings indicate that the effects of PCP on prepulse inhibition and startle reactivity are associated with an increase in cAMP levels in the ventral hippocampus, and that this change in cAMP response may be linked to the production of NO.

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Acknowledgements

The helpful technical assistance of Gun Andersson is gratefully acknowledged. 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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Authors and Affiliations

  1. Department of Pharmacology, The Sahlgrenska Academy, Göteborg University, POB 431, SE 405 30, Goteborg, Sweden

    Daniel Klamer, Erik Pålsson, Kim Fejgin, Jörgen A. Engel & Lennart Svensson

  2. Department of Psychiatry, University of Toronto, Toronto, ON, Canada

    Jianhua Zhang

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  1. Daniel Klamer
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  2. Erik Pålsson
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  3. Kim Fejgin
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  4. Jianhua Zhang
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  5. Jörgen A. Engel
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  6. Lennart Svensson
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Correspondence to Lennart Svensson.

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Klamer, D., Pålsson, E., Fejgin, K. et al. Activation of a nitric-oxide-sensitive cAMP pathway with phencyclidine: elevated hippocampal cAMP levels are temporally associated with deficits in prepulse inhibition. Psychopharmacology 179, 479–488 (2005). https://doi.org/10.1007/s00213-004-2051-z

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