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Increased Contextual Fear Conditioning in iNOS Knockout Mice: Additional Evidence for the Involvement of Nitric Oxide in Stress-Related Disorders and Contribution of the Endocannabinoid System.
Int J Neuropsychopharmacol. 2015 Jan 24; 18(8)IJ

Abstract

BACKGROUND

Inducible or neuronal nitric oxide synthase gene deletion increases or decreases anxiety-like behavior in mice, respectively. Since nitric oxide and endocannabinoids interact to modulate defensive behavior, the former effect could involve a compensatory increase in basal brain nitric oxide synthase activity and/or changes in the endocannabinoid system. Thus, we investigated the expression and extinction of contextual fear conditioning of inducible nitric oxide knockout mice and possible involvement of endocannabinoids in these responses.

METHODS

We evaluated the effects of a preferential neuronal nitric oxide synthase inhibitor, 7-nitroindazol, nitric oxide synthase activity, and mRNA changes of nitrergic and endocannabinoid systems components in the medial prefrontal cortex and hippocampus of wild-type and knockout mice. The effects of URB597, an inhibitor of the fatty acid amide hydrolase enzyme, which metabolizes the endocannabinoid anandamide, WIN55,212-2, a nonselective cannabinoid agonist, and AM281, a selective CB1 antagonist, on contextual fear conditioning were also evaluated.

RESULTS

Contextual fear conditioning expression was similar in wild-type and knockout mice, but the latter presented extinction deficits and increased basal nitric oxide synthase activity in the medial prefrontal cortex. 7-Nitroindazol decreased fear expression and facilitated extinction in wild-type and knockout mice. URB597 decreased fear expression in wild-type and facilitated extinction in knockout mice, whereas WIN55,212-2 and AM281 increased it in wild-type mice. Nonconditioned knockout mice showed changes in the mRNA expression of nitrergic and endocannabinoid system components in the medial prefrontal cortex and hippocampus that were modified by fear conditioning.

CONCLUSION

These data reinforce the involvement of the nitric oxide and endocannabinoids (anandamide) in stress-related disorders and point to a deregulation of the endocannabinoid system in situations where nitric oxide signaling is increased.

Authors+Show Affiliations

Department of Pharmacology, Medical School of Ribeirão Preto (Drs Lisboa, Gomes, Silva, Cunha, and Resstel, Ms Uliana and Ms Camargo), Department of Pharmacology, School of Pharmaceutical Sciences of Ribeirão Preto (Dr Joca), and Center for Interdisciplinary Research on Applied Neurosciences, University of São Paulo, Brazil (Drs Lisboa, Gomes, Guimarães, Joca, and Resstel). sabrinalisboa@usp.br.Department of Pharmacology, Medical School of Ribeirão Preto (Drs Lisboa, Gomes, Silva, Cunha, and Resstel, Ms Uliana and Ms Camargo), Department of Pharmacology, School of Pharmaceutical Sciences of Ribeirão Preto (Dr Joca), and Center for Interdisciplinary Research on Applied Neurosciences, University of São Paulo, Brazil (Drs Lisboa, Gomes, Guimarães, Joca, and Resstel).Department of Pharmacology, Medical School of Ribeirão Preto (Drs Lisboa, Gomes, Silva, Cunha, and Resstel, Ms Uliana and Ms Camargo), Department of Pharmacology, School of Pharmaceutical Sciences of Ribeirão Preto (Dr Joca), and Center for Interdisciplinary Research on Applied Neurosciences, University of São Paulo, Brazil (Drs Lisboa, Gomes, Guimarães, Joca, and Resstel).Department of Pharmacology, Medical School of Ribeirão Preto (Drs Lisboa, Gomes, Silva, Cunha, and Resstel, Ms Uliana and Ms Camargo), Department of Pharmacology, School of Pharmaceutical Sciences of Ribeirão Preto (Dr Joca), and Center for Interdisciplinary Research on Applied Neurosciences, University of São Paulo, Brazil (Drs Lisboa, Gomes, Guimarães, Joca, and Resstel).Department of Pharmacology, Medical School of Ribeirão Preto (Drs Lisboa, Gomes, Silva, Cunha, and Resstel, Ms Uliana and Ms Camargo), Department of Pharmacology, School of Pharmaceutical Sciences of Ribeirão Preto (Dr Joca), and Center for Interdisciplinary Research on Applied Neurosciences, University of São Paulo, Brazil (Drs Lisboa, Gomes, Guimarães, Joca, and Resstel).Department of Pharmacology, Medical School of Ribeirão Preto (Drs Lisboa, Gomes, Silva, Cunha, and Resstel, Ms Uliana and Ms Camargo), Department of Pharmacology, School of Pharmaceutical Sciences of Ribeirão Preto (Dr Joca), and Center for Interdisciplinary Research on Applied Neurosciences, University of São Paulo, Brazil (Drs Lisboa, Gomes, Guimarães, Joca, and Resstel).Department of Pharmacology, Medical School of Ribeirão Preto (Drs Lisboa, Gomes, Silva, Cunha, and Resstel, Ms Uliana and Ms Camargo), Department of Pharmacology, School of Pharmaceutical Sciences of Ribeirão Preto (Dr Joca), and Center for Interdisciplinary Research on Applied Neurosciences, University of São Paulo, Brazil (Drs Lisboa, Gomes, Guimarães, Joca, and Resstel).Department of Pharmacology, Medical School of Ribeirão Preto (Drs Lisboa, Gomes, Silva, Cunha, and Resstel, Ms Uliana and Ms Camargo), Department of Pharmacology, School of Pharmaceutical Sciences of Ribeirão Preto (Dr Joca), and Center for Interdisciplinary Research on Applied Neurosciences, University of São Paulo, Brazil (Drs Lisboa, Gomes, Guimarães, Joca, and Resstel).Department of Pharmacology, Medical School of Ribeirão Preto (Drs Lisboa, Gomes, Silva, Cunha, and Resstel, Ms Uliana and Ms Camargo), Department of Pharmacology, School of Pharmaceutical Sciences of Ribeirão Preto (Dr Joca), and Center for Interdisciplinary Research on Applied Neurosciences, University of São Paulo, Brazil (Drs Lisboa, Gomes, Guimarães, Joca, and Resstel).

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25618404

Citation

Lisboa, Sabrina F., et al. "Increased Contextual Fear Conditioning in iNOS Knockout Mice: Additional Evidence for the Involvement of Nitric Oxide in Stress-Related Disorders and Contribution of the Endocannabinoid System." The International Journal of Neuropsychopharmacology, vol. 18, no. 8, 2015.
Lisboa SF, Gomes FV, Silva AL, et al. Increased Contextual Fear Conditioning in iNOS Knockout Mice: Additional Evidence for the Involvement of Nitric Oxide in Stress-Related Disorders and Contribution of the Endocannabinoid System. Int J Neuropsychopharmacol. 2015;18(8).
Lisboa, S. F., Gomes, F. V., Silva, A. L., Uliana, D. L., Camargo, L. H., Guimarães, F. S., Cunha, F. Q., Joca, S. R., & Resstel, L. B. (2015). Increased Contextual Fear Conditioning in iNOS Knockout Mice: Additional Evidence for the Involvement of Nitric Oxide in Stress-Related Disorders and Contribution of the Endocannabinoid System. The International Journal of Neuropsychopharmacology, 18(8). https://doi.org/10.1093/ijnp/pyv005
Lisboa SF, et al. Increased Contextual Fear Conditioning in iNOS Knockout Mice: Additional Evidence for the Involvement of Nitric Oxide in Stress-Related Disorders and Contribution of the Endocannabinoid System. Int J Neuropsychopharmacol. 2015 Jan 24;18(8) PubMed PMID: 25618404.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Increased Contextual Fear Conditioning in iNOS Knockout Mice: Additional Evidence for the Involvement of Nitric Oxide in Stress-Related Disorders and Contribution of the Endocannabinoid System. AU - Lisboa,Sabrina F, AU - Gomes,Felipe V, AU - Silva,Andréia L, AU - Uliana,Daniela L, AU - Camargo,Laura H A, AU - Guimarães,Francisco S, AU - Cunha,Fernando Q, AU - Joca,Sâmia R L, AU - Resstel,Leonardo B M, Y1 - 2015/01/24/ PY - 2014/06/03/received PY - 2015/01/12/accepted PY - 2015/1/26/entrez PY - 2015/1/27/pubmed PY - 2016/2/26/medline KW - 212-2 KW - 7-nitroindazole KW - AM281 KW - CB1 receptors KW - URB597 KW - WIN55 KW - anandamide KW - extinction KW - fear conditioning KW - nitric oxide JF - The international journal of neuropsychopharmacology JO - Int. J. Neuropsychopharmacol. VL - 18 IS - 8 N2 - BACKGROUND: Inducible or neuronal nitric oxide synthase gene deletion increases or decreases anxiety-like behavior in mice, respectively. Since nitric oxide and endocannabinoids interact to modulate defensive behavior, the former effect could involve a compensatory increase in basal brain nitric oxide synthase activity and/or changes in the endocannabinoid system. Thus, we investigated the expression and extinction of contextual fear conditioning of inducible nitric oxide knockout mice and possible involvement of endocannabinoids in these responses. METHODS: We evaluated the effects of a preferential neuronal nitric oxide synthase inhibitor, 7-nitroindazol, nitric oxide synthase activity, and mRNA changes of nitrergic and endocannabinoid systems components in the medial prefrontal cortex and hippocampus of wild-type and knockout mice. The effects of URB597, an inhibitor of the fatty acid amide hydrolase enzyme, which metabolizes the endocannabinoid anandamide, WIN55,212-2, a nonselective cannabinoid agonist, and AM281, a selective CB1 antagonist, on contextual fear conditioning were also evaluated. RESULTS: Contextual fear conditioning expression was similar in wild-type and knockout mice, but the latter presented extinction deficits and increased basal nitric oxide synthase activity in the medial prefrontal cortex. 7-Nitroindazol decreased fear expression and facilitated extinction in wild-type and knockout mice. URB597 decreased fear expression in wild-type and facilitated extinction in knockout mice, whereas WIN55,212-2 and AM281 increased it in wild-type mice. Nonconditioned knockout mice showed changes in the mRNA expression of nitrergic and endocannabinoid system components in the medial prefrontal cortex and hippocampus that were modified by fear conditioning. CONCLUSION: These data reinforce the involvement of the nitric oxide and endocannabinoids (anandamide) in stress-related disorders and point to a deregulation of the endocannabinoid system in situations where nitric oxide signaling is increased. SN - 1469-5111 UR - https://www.unboundmedicine.com/medline/citation/25618404/Increased_Contextual_Fear_Conditioning_in_iNOS_Knockout_Mice:_Additional_Evidence_for_the_Involvement_of_Nitric_Oxide_in_Stress_Related_Disorders_and_Contribution_of_the_Endocannabinoid_System_ L2 - https://academic.oup.com/ijnp/article-lookup/doi/10.1093/ijnp/pyv005 DB - PRIME DP - Unbound Medicine ER -