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.

Background: Inducible (iNOS) or neuronal (nNOS) nitric oxide synthase gene deletion increases or decreases anxiety-like behavior in mice, respectively. Since NO and endocannabinoids (ECBs) interact to modulate defensive behavior, the former effect could involve a compensatory increase in basal brain NOS activity and/or changes in the ECB system. Thus, we investigated the expression and extinction of contextual fear conditioning (CFC) of iNOS knockout (KO) mice and possible involvement of ECBs in these responses. Methods: We evaluated the effects of a preferential nNOS inhibitor, 7-nitroindazol (7-NI), NOS activity and mRNA changes of nitrergic and ECB systems components in the medial prefrontal cortex (MPFC) and hippocampus (HIP) of wild-type (WT) and KO mice. The effects of URB597, an inhibitor of the FAAH enzyme, which metabolize the ECB anandamide, WIN55,212-2, a non-selective cannabinoid agonist, and AM281, a selective CB1 antagonist, on CFC were also evaluated. Results: CFC expression was similar in WT and KO mice, but KO presented extinction deficits and increased basal NOS activity in the MPFC. 7-NI decreased fear expression and facilitated extinction in WT and KO mice. URB597 decreased fear expression in WT mice and facilitated extinction in KO mice whereas WIN and AM281 increased it in WT mice. Non-conditioned KO mice showed changes in the mRNA expression of nitrergic and ECB system components in the MPFC and HIP that were modified by fear conditioning. Conclusion: These data reinforce the involvement of the NO and ECBs (anandamide) in stress-related disorders and point out to a deregulation of the ECB system in situations where NO signaling is increased.
© The Author 2014. Published by Oxford University Press on behalf of CINP.