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Involvement of nNOS/NO/sGC/cGMP signaling pathway in cocaine sensitization and in the associated hippocampal alterations: does phosphodiesterase 5 inhibition help to drug vulnerability?

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Abstract

Rationale

Repeated cocaine administration induces behavioral sensitization in about 50 % of treated animals. Nitric oxide could be involved in the acquisition and maintenance of behavioral cocaine effects, probably by activation of neuronal nitric oxide synthase (nNOS)/NO/soluble guanylyl cyclase (sGC)/cyclic guanosine monophosphate (cGMP) signaling pathway, since inhibition of the nNOS enzyme attenuates development of sensitization in rats. On the other hand, increased cGMP availability by phosphodiesterase 5 inhibitors has been correlated to the misuse and recreational use of these agents and also to the concomitant use with illicit drugs in humans. Hippocampus is an important brain region for conditioning to general context previously associated to drug availability, influencing drug-seeking behavior and sensitization. Moreover, cocaine and other drugs of abuse can affect the strength of glutamate synapses in this structure, lastly modifying neuronal activity in main regions of the reward circuitry.

Objective

The objective of this study is to determine whether the pharmacological manipulation of nNOS/NO/sGC/cGMP signaling pathway altered changes induced by repeated cocaine exposure.

Results

The present investigation showed a relationship between behavioral cocaine sensitization, reduced threshold to generate long-term potentiation (LTP) in hippocampal dentate gyrus, and increased nNOS activity in this structure. However, when nNOS or sGC were inhibited, the number of sensitized animals was reduced, and the threshold to generate LTP was increased. The opposite occurred when cGMP availability was increased.

Conclusion

We demonstrate a key role of the nNOS activity and NO/sGC/cGMP signaling pathway in the development of cocaine sensitization and in the associated enhancement of hippocampal synaptic transmission.

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Acknowledgment

We thank Kerstin Ford who assisted us with the manuscript edition.

Funding source

Funding for this study was provided by SECyT (PICT number 2476), CONICET (PIP number 6381), and MINCyT (PID 100). The authors declare no conflict of interest.

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Authors and Affiliations

  1. IFEC-CONICET, Departamento de Farmacología, Facultad de Ciencias Químicas, UNC, Haya de la Torre y Medina Allende, 5000, Córdoba, Argentina

    Laura A. Gabach, María C. Monti, Laura E. Maglio, Susana Rubiales De Barioglio & Mariela F. Perez

  2. Cátedra de Fisiología Humana, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Santa Rosa 1085, X5000ESU, Córdoba, Argentina

    Valeria P. Carlini

  3. Departamento de Farmacología, Facultad de Ciencias Químicas, UNC, IFEC CONICET, Haya de la Torre y Medina Allende s/n, 5000, Córdoba, Argentina

    Mariela F. Perez

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  1. Laura A. Gabach
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  2. Valeria P. Carlini
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  3. María C. Monti
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  4. Laura E. Maglio
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  5. Susana Rubiales De Barioglio
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  6. Mariela F. Perez
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Correspondence to Mariela F. Perez.

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Gabach, L.A., Carlini, V.P., Monti, M.C. et al. Involvement of nNOS/NO/sGC/cGMP signaling pathway in cocaine sensitization and in the associated hippocampal alterations: does phosphodiesterase 5 inhibition help to drug vulnerability?. Psychopharmacology 229, 41–50 (2013). https://doi.org/10.1007/s00213-013-3084-y

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  • DOI: https://doi.org/10.1007/s00213-013-3084-y

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