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Critical role of nitric oxide in the modulation of prepulse inhibition in Swiss mice

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Abstract

Rationale

Nitric oxide (NO) modulates the dopamine uptake and release processes and appears to be implicated in dopamine-related pathologies, such as schizophrenia. However, it is unclear whether there is excess or deficient NO synthesis in schizophrenia pathophysiology. Analyses of the intracellular pathways downstream of NO system activation have identified the cyclic nucleotide cyclic guanosine monophosphate (cGMP) as a possible target for drug development. Defects in the sensorimotor gating of the neural mechanism underlying the integration and processing of sensory information have been detected across species through prepulse inhibition (PPI).

Objectives

The aim of this study was to investigate the effects of NO/cGMP increase on sensorimotor gating modulation during dopamine hyperfunction.

Methods

Mice were treated with NO donors and subjected to the PPI test. Treatment with the NO donor sodium nitroprusside was preceded by pretreatment with a soluble guanylate cyclase (sGC) inhibitor. Additionally, the mice were treated with NO donors and phosphodiesterases inhibitors prior to amphetamine treatment.

Results

Pretreatment with the NO donors enhanced the PPI response and attenuated the amphetamine-disruptive effects on the PPI. The sGC inhibitor did not modify the sodium nitroprusside effects. Additionally, the cGMP increase induced by a specific phosphodiesterase inhibitor did not modify the amphetamine-disruptive effect.

Conclusions

This study provides the first demonstration that an increase in NO can improve the PPI response and block the amphetamine-disruptive effects on the PPI response. Our data are consistent with recent clinical results. However, these effects do not appear to be related to an increase in cGMP levels, and further investigation is thus required.

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Acknowledgments

We would like to thank Célia Aparecida da Silva for the technical support. The equipment and drugs used in this work were acquired from FAPESP, CNPq, CAPES, Brazil. The experiments presented in this manuscript comply with the current Brazilian laws. This work was supported by FAPESP.

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  1. Departamento de Morfologia, Estomatologia e Patologia Básica, Faculdade de Odontologia, Universidade de São Paulo, 14049-904, Ribeirão Preto, São Paulo, Brazil

    Ana C. Issy, João Francisco C. Pedrazzi, Bruno H. Yoneyama & Elaine A. Del-Bel

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  1. Ana C. Issy
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  2. João Francisco C. Pedrazzi
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  3. Bruno H. Yoneyama
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  4. Elaine A. Del-Bel
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Correspondence to Elaine A. Del-Bel.

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Issy, A.C., Pedrazzi, J.F.C., Yoneyama, B.H. et al. Critical role of nitric oxide in the modulation of prepulse inhibition in Swiss mice. Psychopharmacology 231, 663–672 (2014). https://doi.org/10.1007/s00213-013-3277-4

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