Pavón, Francisco JavierPolis, Ilham Y.Stouffer, David G.Cravatt, Benjamin F.Roberto, MarisaMartin-Fardon, RémiRodríguez de Fonseca, FernandoParsons, Loren H.Serrano, Antonia2022-07-262022-07-262021-06-09Pavón FJ, Polis IY, Stouffer DG, Cravatt BF, Roberto M, Martin-Fardon R, et al. Selective inhibition of monoacylglycerol lipase is associated with passive coping behavior and attenuation of stress-induced dopamine release in the medial prefrontal cortex. Neurobiol Stress. 2021 Jan 9;14:100293http://hdl.handle.net/10668/3827The endocannabinoid system is involved in the regulation of the stress response, but the relative contribution of N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG) and their mechanisms have to be elucidated. In this study, we compared the effects of the pharmacological inhibition of the two major endocannabinoid-degrading enzymes [fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) for AEA and 2-AG, respectively] on stress-coping [forced swim test (FST) and tail suspension test (TST)] and anxiety-like [elevated-plus maze (EPM) and light-dark test (LDT)] behaviors in wild-type and FAAH knockout mice. In vivo microdialysis estimated the effects of FAAH and MAGL inhibition on dopamine (DA) and serotonin (5-HT) levels in the medial prefrontal cortex (mPFC) during an FST. Mice were treated with PF-3845 (FAAH inhibitor), JZL184 (MAGL inhibitor), JZL195 (dual FAAH/MAGL inhibitor) or vehicle. Our data showed that PF-3845 increased latency to immobility and decreased total immobility time in FST, but no effects were observed in TST compared with vehicle-treated wild-type mice. By contrast, JZL184 decreased latency and increased immobility in TST and FST. JZL195 in wild-type mice and JZL184 in FAAH knockout mice reproduced the same passive coping behaviors as JZL184 in wild-type mice in TST and FST. In the microdialysis experiment, FST was associated with increased DA and 5-HT levels in the mPFC. However, JZL184-treated wild-type mice displayed a significant attenuation of forced swim stress-induced DA release compared with vehicle-treated wild-type mice and PF-3845-treated wild-type mice. Finally, FAAH and/or MAGL inhibitors induced robust and consistent anxiolytic-like effects in EPM and LDT. These results suggested differences between FAAH and MAGL inhibition in stress-coping behaviors. Notably, MAGL inhibition induced a consistent avoidant coping behavior and attenuated the stress-induced mPFC DA response in FST. However, more investigation is needed to elucidate the functional association between DA and 2-AG signaling pathways, and the molecular mechanism in the regulation of passive coping strategies during inescapable stress.enAttribution-NonCommercial-NoDerivatives 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc-nd/4.0/2-ArachidonoylglycerolStress-coping behaviorDopamineMouseMicrodialysisDopaminaRatonesMicrodiálisisMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::MiceMedical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Hydrolases::Esterases::Carboxylic Ester Hydrolases::Monoacylglycerol LipasesMedical Subject Headings::Chemicals and Drugs::Lipids::Fatty Acids::EndocannabinoidsMedical Subject Headings::Chemicals and Drugs::Biological Factors::Inflammation Mediators::Autacoids::SerotoninMedical Subject Headings::Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Central Nervous System Agents::Central Nervous System Depressants::Tranquilizing Agents::Anti-Anxiety AgentsMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Immobilization::Restraint, Physical::Hindlimb SuspensionMedical Subject Headings::Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::Signal TransductionMedical Subject Headings::Psychiatry and Psychology::Behavior and Behavior Mechanisms::Adaptation, PsychologicalMedical Subject Headings::Anatomy::Nervous System::Central Nervous System::Brain::Prosencephalon::Telencephalon::Cerebrum::Cerebral Cortex::Frontal Lobe::Prefrontal CortexMedical Subject Headings::Psychiatry and Psychology::Behavior and Behavior Mechanisms::Emotions::Anxietyresearch article33490317open access10.1016/j.ynstr.2021.1002932352-2895PMC7809503