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

Author(s)

Lisboa, Sabrina F. ^{[1, 2]} ; Gomes, Felipe V. ^{[1, 2]} ; Silva, Andreia L. ^[1] ; Uliana, Daniela L. ; Camargo, Laura H. A. ; Guimaraes, Francisco S. ^[2] ; Cunha, Fernando Q. ^[1] ; Joca, Samia R. L. ^{[2, 3]} ; Resstel, Leonardo B. M. ^{[1, 2]}

Affiliation

^[1] Univ Sao Paulo, Med Sch Ribeirao Preto, Dept Pharmacol, BR-14049900 Sao Paulo - Brazil

^[2] Univ Sao Paulo, Ctr Interdisciplinary Res Appl Neurosci, BR-14049900 Sao Paulo - Brazil

^[3] Univ Sao Paulo, Dept Pharmacol, Sch Pharmaceut Sci Ribeirao Preto, BR-14049900 Sao Paulo - Brazil

• Document type: Journal article
• Source: INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY; v. 18, n. 8 JUN 2015.
• Web of Science Citations: 16

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. (AU)

• FAPESP's process: 11/22523-0 - Possible neuroinflammatory mechanisms involved in the extinction deficits of conditioning fear following exposing rats to a predator: the role of endocannabinoid system
• Grantee: Sabrina Francesca de Souza Lisboa
• Support Opportunities: Scholarships in Brazil - Post-Doctoral