Investigation of cannabinoid mechanisms involved in extinction deficits in iNOS KO animals, a genetic model of PTSD

• Grant number: 22/09921-0
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: August 01, 2022
• End date: November 30, 2023
• Field of knowledge: Biological Sciences - Pharmacology - Neuropsychopharmacology
• Principal Investigator: Sabrina Francesca de Souza Lisboa
• Grantee: Anna Paula Amorim Marques
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 17/19731-6 - Identification of epigenetic mechanisms induced by stress which modulate endocannabinoid signaling and neuroimmunological mechanisms as new therapeutic targets to treat the posttraumatic stress disorder (PTSD), AP.JP
• Associated scholarship(s): 23/02029-8 - The use of genetic tools to understand the interaction between the endocannabinoid-nitrergic systems in PTSD-like behaviors, BE.EP.IC

Abstract

We have previously demonstrated that iNOS knockout animals show deficits in the extinction of contextually conditioned fear (Lisboa et al., 2015 doi: 10.1093/ijnp/pyv005). We also saw that this behavior could result from a compensatory increase in NO production in the medial prefrontal cortex (mPFC) of these animals, but not in the hippocampus, via nNOS, since the inhibition of this isoform normalized the behavior of these animals. Furthermore, we saw that conditioned KO animals show several alterations in the endocannabinoid system, such as increased expression of FAAH and MAGL enzymes and reduced expression of CB1 and CB2 also in mCPF, which could in part explain the extinction deficits, since these changes are related to extinction deficits. In this sense, we saw that a high dose of the FAAH enzyme inhibitor, URB597, was able to attenuate the behavior of these animals. We did not see, however, whether these responses could be related to altered levels of endocannabinoids and activation of TRPV1. So far, we have seen that the administration of the TRPV1 antagonist alone was not able to attenuate the PTSD-like behavior of these animals. However, considering that these receptors and cannabinoid receptors could act in the opposite way and that these conditioned animals have lower expression of CB1 and CB2, it is possible that the blockade of TRPV1 associated with increased endocannabinoid signaling with archidonoyl serotonin (AA-5HT) attenuates these levels. Thus, the aim of this project is to evaluate whether the extinction deficits observed in iNOS KO animals, a genetic model of PTSD that we established in the laboratory, are attenuated by treatment with Arachidonoyl serotonin (AA-5HT, TRPV1 antagonist, and FAAH inhibitor). Furthermore, if these animals show changes in the levels of endocannabinoids in the brain and changes in the expression of TRPV1 receptors, changes are related to extinction deficits.(AU)