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Intracerebroventricular administration of nitric oxide-sensitive guanylyl cyclase inhibitors induces catalepsy in mice

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Abstract

Rationale

Catalepsy is a preclinical test that predicts extrapyramidal symptoms in humans. It models symptoms of acute extrapyramidal side effects induced at the beginning of antipsychotic treatment. Nitric oxide (NO) plays a role in a series of neurobiological functions underlying behavior. For example, inhibition of NO synthesis disrupts rodent exploratory behavior and induces catalepsy. Although several effects mediated by NO involve the activation of soluble guanylyl cyclase (sGC), the transduction mechanism of the catalepsy-inducing effect of NO has not yet been investigated.

Objectives

The study was designed to test if intracerebroventricular (i.c.v.) microinjection of NO-sensitive inhibitors of sGC (NO-sGC) induces catalepsy in mice similar to that induced by NO synthase (NOS) inhibitors. Exploratory behavior was tested in the open field. In addition, the effects of a NOS inhibitor on oxidative metabolites of NO were measured in the striatum.

Materials and methods

Drug effects were examined in the hanging-bar test after the following i.c.v. treatments: oxadiazolo-quinoxalin (ODQ, 30–300 nmol) or methylene blue (MB, 3–100 nmol), selective and nonselective sGC inhibitors, respectively, or 7-nitroindazole (7-NI, 3–90 nmol) and G-nitro-l-arginine methyl ester (l-NAME, 3–90 nmol), selective and nonselective neuronal NOS inhibitors. To test if the effects were related to interference with the NO system, additional groups received 7-NI (30 nmol), ODQ (100 nmol), or L-NAME (90 nmol) preceded by l-arginine (l-arg, 30–100 nmol, i.c.v. 30 min before). A possible interference of ODQ and 7-NI on exploratory behavior was tested in an open field. The concentration of nitrites and nitrates (NO x ) in striatum homogenates was measured by the Griess reaction.

Results

Both NO-sGC and NOS inhibitors induced catalepsy in mice that lasted for at least 2 h. The range of effective doses of these drugs, however, was limited, and the dose–effect curves had an inverted U shape. The cataleptic effect induced by l-NAME was inversely correlated with NO x products in the striatum. The cataleptic effect of 7-NI and ODQ was prevented by pretreatment with l-arginine. No drug changed exploratory behavior in the open field.

Conclusion

This study showed that pharmacological disruption of the endogenous NO-sGC signaling in the central nervous system induces long-lasting catalepsy in mice. Moreover, the cataleptic effect of NOS inhibition correlates with the decrease in NO x products formation in the striatum. The results give further support to the hypothesis that NO plays a role in motor behavior control mediated, at least in part, by cyclic guanosine monophosphate production in the striatum.

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Abbreviations

7-NI:

7-nitroindazole

ANOVA:

one-way analysis of variance

cAMP:

3′-5′-cyclic adenosine monophosphate

cGMP:

cyclic guanosine monophosphate

DA:

dopamine

DMSO:

dimethyl sulfoxide

i.c.v.:

intracerebroventricular

l-arg:

l-arginine

l-NAME:

NG-nitro-l-arginine methyl ester hydrochloride

MANOVA:

multivariate analysis of variance

MB:

methyl blue

NMDA:

N-methyl d-aspartate

nNOS:

neuronal nitric oxide synthase isoform

NO:

nitric oxide

NO3 :

nitrate

NO2 :

nitrite

NO-sGC:

nitric oxide-sensitive soluble guanylyl cyclases

NOS:

nitric oxide synthase

NO x :

nitrogen oxides

ODQ:

oxadiazolo-quinoxalin

sGC:

soluble guanylyl cyclase

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Acknowledgments

The authors acknowledge the helpful technical support provided by S. Saltareli, P. Marchi, G. Bertozi-Francisco and R. Ferreira-da-Silva. We thank our coworker L.P. Nucci-da-Silva who participated in some of the experiments described in this manuscript. We are in debt to Prof. F.S. Guimarães for manuscript discussion and suggestions. The study was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP).

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Authors and Affiliations

  1. Department MEF—Physiology, FORP, University of Sao Paulo, Av. Café S/No., 14040-904, Ribeirão Preto, SP, Brazil

    M. B. Echeverry, M. L. Salgado, C. A. da-Silva & E. A. Del Bel

  2. Department of Pharmacology, FMRP, University of Sao Paulo, Ribeirão Preto, SP, 14049-900, Brazil

    F. R. Ferreira

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  1. M. B. Echeverry
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  2. M. L. Salgado
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  3. F. R. Ferreira
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  4. C. A. da-Silva
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  5. E. A. Del Bel
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Correspondence to E. A. Del Bel.

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Echeverry, M.B., Salgado, M.L., Ferreira, F.R. et al. Intracerebroventricular administration of nitric oxide-sensitive guanylyl cyclase inhibitors induces catalepsy in mice. Psychopharmacology 194, 271–278 (2007). https://doi.org/10.1007/s00213-007-0834-8

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  • DOI: https://doi.org/10.1007/s00213-007-0834-8

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