scholarly journals FAAH polymorphism (rs324420) modulates extinction recall in healthy humans: an fMRI study

2021 ◽  
Author(s):  
Jennifer Spohrs ◽  
Martin Ulrich ◽  
Georg Grön ◽  
Paul L. Plener ◽  
Birgit Abler
Keyword(s):  
Fatty Acid Amide Hydrolase ◽  
Acid Amide ◽  
Endocannabinoid System ◽  
Insular Cortex ◽  
Anterior Cingulate ◽  
Neural Activation ◽  
Extinction Learning ◽  
Healthy Humans ◽  
Fmri Study ◽  
Amide Hydrolase

AbstractGold standard treatments for anxiety- and trauma-related disorders focus on exposure therapy promoting extinction learning and extinction retention. However, its efficacy is limited. Preclinical and particularly animal research has been able to demonstrate that homozygosity for the fatty acid amide hydrolase (FAAH) C385A allele, similar to FAAH inhibition, is associated with elevated concentrations of anandamide (AEA) and facilitates extinction learning and extinction recall. However, in humans, the underlying neurobiological processes are less well understood, and further knowledge might enhance the development of more effective therapies. In this functional magnetic resonance imaging (fMRI) study, a fear conditioning, fear extinction and extinction recall paradigm was conducted with 55 healthy male adults. They were genotyped for the FAAH single-nucleotide polymorphism (SNP) rs324420 to investigate differences related to extinction recall in neural activation and State–Trait Anxiety Inventory (STAI) ratings between AC heterozygotes and CC homozygotes (FAAH C385A SNP). Differential brain activation upon an unextinguished relative to an extinguished stimulus, was greater in AC heterozygotes as compared to CC homozygotes in core neural structures previously related to extinction recall, such as the medial superior frontal gyrus, the dorsal anterior cingulate and the anterior and middle insular cortex. Furthermore, AC heterozygotes displayed higher AEA levels and lower STAI-state ratings. Our data can be interpreted in line with previous suggestions of more successful extinction recall in A-allele carriers with elevated AEA levels. Data corroborate the hypothesis that the endocannabinoid system, particularly AEA, plays a modulatory role in the extinction of aversive memory.

scholarly journals Fear extinction learning and anandamide: an fMRI study in healthy humans

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jennifer Spohrs ◽  
Martin Ulrich ◽  
Georg Grön ◽  
Michael Prost ◽  
Paul Lukas Plener ◽  
...  
Keyword(s):  
Treatment Options ◽  
Endocannabinoid System ◽  
Anxiolytic Effect ◽  
Fear Extinction ◽  
Anterior Cingulate ◽  
Fear Learning ◽  
Neural Activation ◽  
Extinction Learning ◽  
Healthy Humans ◽  
And Task

AbstractAnxiety- and trauma-related disorders are severe illnesses with high prevalence. Current treatment options leave room for improvement and the endocannabinoid system (ECS) has become a key target in psychopharmacological research. Rodent models suggest an anxiolytic effect of endocannabinoids and demonstrated that the ECS is involved in the modulation of fear learning and aversive memory consolidation. So far, one prominent target was inhibition of fatty acid amino hydrolase (FAAH), the degrading enzyme of the endocannabinoid anandamide (AEA). Research in humans remains scarce, but genetic studies have found that the single-nucleotide polymorphism (SNP) FAAH C385A (rs324420) is associated with lower catabolic performance of FAAH and increased levels of AEA. Translational research on the ECS in fear learning processes is rare, yet crucial to understand the mechanisms involved. To address this lack of research, we designed a fear conditioning, extinction learning paradigm with 51 healthy, male humans who underwent functional magnetic resonance imaging (fMRI) before analysing baseline and task-related changes of AEA, as well as the FAAH polymorphism (rs324420). The results indicate higher AEA levels in AC-heterozygotes than in CC-individuals (SNP rs324420), but no difference between the groups during extinction learning. However, neural activation of the anterior cingulate cortex and anterior insular cortex during extinction learning correlated positively with AEA baseline levels, and task-related changes in AEA were found particularly during fear extinction, with a modulatory effect on neural activation related to extinction learning. Results indicate a putative role for AEA in fear extinction learning. Pre-treatment with AEA-enhancing drugs could promote extinction learning during psychotherapeutic interventions.

scholarly journals Elevated Brain Fatty Acid Amide Hydrolase Induces Depressive-Like Phenotypes in Rodent Models: A Review

2021 ◽  
Vol 22 (3) ◽  
pp. 1047
Author(s):  
Dorsa Rafiei ◽  
Nathan J. Kolla
Keyword(s):  
Depressive Symptoms ◽  
Fatty Acid ◽  
Animal Models ◽  
Fatty Acid Amide Hydrolase ◽  
Acid Amide ◽  
Endocannabinoid System ◽  
Animal Models Of Depression ◽  
Amide Hydrolase ◽  
Fatty Acid Amide

Altered activity of fatty acid amide hydrolase (FAAH), an enzyme of the endocannabinoid system, has been implicated in several neuropsychiatric disorders, including major depressive disorder (MDD). It is speculated that increased brain FAAH expression is correlated with increased depressive symptoms. The aim of this scoping review was to establish the role of FAAH expression in animal models of depression to determine the translational potential of targeting FAAH in clinical studies. A literature search employing multiple databases was performed; all original articles that assessed FAAH expression in animal models of depression were considered. Of the 216 articles that were screened for eligibility, 24 articles met inclusion criteria and were included in this review. Three key findings emerged: (1) FAAH expression is significantly increased in depressive-like phenotypes; (2) genetic knockout or pharmacological inhibition of FAAH effectively reduces depressive-like behavior, with a dose-dependent effect; and (3) differences in FAAH expression in depressive-like phenotypes were largely localized to animal prefrontal cortex, hippocampus and striatum. We conclude, based on the animal literature, that a positive relationship can be established between brain FAAH level and expression of depressive symptoms. In summary, we suggest that FAAH is a tractable target for developing novel pharmacotherapies for MDD.

Fatty Acid Amide Hydrolase Inhibitors from Virtual Screening of the Endocannabinoid System

2006 ◽  
Vol 49 (15) ◽  
pp. 4650-4656 ◽  
Author(s):  
Susanna M. Saario ◽  
Antti Poso ◽  
Risto O. Juvonen ◽  
Tomi Järvinen ◽  
Outi M. H. Salo-Ahen
Keyword(s):  
Fatty Acid ◽  
Virtual Screening ◽  
Fatty Acid Amide Hydrolase ◽  
Acid Amide ◽  
Endocannabinoid System ◽  
Amide Hydrolase ◽  
Fatty Acid Amide

scholarly journals Equipotent Inhibition of Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase – Dual Targets of the Endocannabinoid System to Protect against Seizure Pathology

2012 ◽  
Vol 9 (4) ◽  
pp. 801-813 ◽  
Author(s):  
Vinogran Naidoo ◽  
David A. Karanian ◽  
Subramanian K. Vadivel ◽  
Johnathan R. Locklear ◽  
JodiAnne T. Wood ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Amide Hydrolase ◽  
Acid Amide ◽  
Endocannabinoid System ◽  
Monoacylglycerol Lipase ◽  
Amide Hydrolase ◽  
Fatty Acid Amide

scholarly journals UPLC-MS/MS Method for Analysis of Endocannabinoid and Related Lipid Metabolism in Mouse Mucosal Tissue

2021 ◽  
Vol 12 ◽  
Author(s):  
Mark B. Wiley ◽  
Pedro A. Perez ◽  
Donovan A. Argueta ◽  
Bryant Avalos ◽  
Courtney P. Wood ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Amide Hydrolase ◽  
Acid Amide ◽  
Endocannabinoid System ◽  
The Body ◽  
Mucosal Tissues ◽  
Degradative Enzymes ◽  
Health And Disease ◽  
Amide Hydrolase

The endocannabinoid system is expressed in cells throughout the body and controls a variety of physiological and pathophysiological functions. We describe robust and reproducible UPLC-MS/MS-based methods for analyzing metabolism of the endocannabinoids, 2-arachidonoyl-sn-glycerol and arachidonoyl ethanolamide, and related monoacylglycerols (MAGs) and fatty acid ethanolamides (FAEs), respectively, in mouse mucosal tissues (i.e., intestine and lung). These methods are optimized for analysis of activity of the MAG biosynthetic enzyme, diacylglycerol lipase (DGL), and MAG degradative enzymes, monoacylglycerol lipase (MGL) and alpha/beta hydrolase domain containing-6 (ABHD6). Moreover, we describe a novel UPLC-MS/MS-based method for analyzing activity of the FAE degradative enzyme, fatty acid amide hydrolase (FAAH), that does not require use of radioactive substrates. In addition, we describe in vivo pharmacological methods to inhibit MAG biosynthesis selectively in the mouse small-intestinal epithelium. These methods will be useful for profiling endocannabinoid metabolism in rodent mucosal tissues in health and disease.

Endocannabinoid System: Overview and Therapeutic Relevance

2021 ◽  
Author(s):  
Alex Mabou Tagne
Keyword(s):  
Fatty Acid ◽  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Fatty Acid Amide Hydrolase ◽  
Acid Amide ◽  
Endocannabinoid System ◽  
Receptor Subtypes ◽  
Monoacylglycerol Lipase ◽  
Amide Hydrolase ◽  
Fatty Acid Amide

The endocannabinoid system (ECS) modulates a variety of physiological processes, attracting considerable attention as a potential target for therapeutic intervention. This complex system is activated by the lipid-derived mediators anandamide and 2-arachidonoyl-sn-glycerol (2-AG), which mainly engage the cannabinoid receptor subtypes 1 (CB1) and 2 (CB2). The biological actions of anandamide and 2-AG are terminated by internalization and intracellular enzymatic hydrolysis catalyzed primarily by the serine hydrolases fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL), respectively. Here, we provide an overview of ECS and discuss the implications for advancing pharmacological tools that interfere with such a system as next-generation therapeutics. This review contains 4 figures, 3 tables and 41 references Keywords: Endocannabinoid; anandamide; 2-Arachidonoyl-sn-glycerol; fatty acid amide hydrolase; monoacylglycerol lipase; cannabinoid receptors; N-acylethanolamine acid amidase; Δ9-tetrahydrocannabinol.

Interplay Between Endocannabinoid System and Neurodegeneration: Focus on Polypharmacology

2021 ◽  
Vol 28 ◽  
Author(s):  
Francesca Seghetti ◽  
Silvia Gobbi ◽  
Federica Belluti ◽  
Angela Rampa ◽  
Alessandra Bisi
Keyword(s):  
Neurodegenerative Diseases ◽  
Cannabinoid Receptor ◽  
Fatty Acid Amide Hydrolase ◽  
Acid Amide ◽  
Endocannabinoid System ◽  
Receptor Subtype ◽  
Disease Development ◽  
Therapeutic Approaches ◽  
Promising Therapeutic Target ◽  
Amide Hydrolase

: Pharmacological treatment of complex pathologies such as neurodegenerative diseases still represents a major challenge, due to the networked pathways involved in their onset and progression that may require equally complex therapeutic approaches. Polypharmacology, based on the simultaneous modulation of multiple targets involved in the disease, may offer the potential to increase effectiveness and reduce the drawbacks related to the use of drug combinations. Clearly, this approach requires both the knowledge of the systems responsible for disease development and the discovery of new attractive targets to be exploited to design a multitarget drug. Over the last years, an ever increasing interest has focused on the endocannabinoid system, implicated in the modulation of several physiological functions, among which neuroinflammation, a crucial process for most neurodegenerative diseases. In this respect, the cannabinoid receptor subtype 2 represents a promising therapeutic target, being overexpressed in microglia cells and thus involved in neuroinflammation. The indirect modulation of this system through the inhibition of the main enzymes responsible for endocannabinoids metabolism, namely fatty acid amide hydrolase and monoacylglycerol lipase, may also significantly affect neurodegenerative processes. The aim of this review is to give an overview of the opportunities posed by the endocannabinoid system for neurodegenerative diseases management, mainly focusing on the potential for a multitarget strategy.

Enol Carbamates as Inhibitors of Fatty Acid Amide Hydrolase (FAAH) Endowed with High Selectivity for FAAH over the Other Targets of the Endocannabinoid System

ChemMedChem ◽  
2010 ◽  
Vol 5 (3) ◽  
pp. 357-360 ◽  
Author(s):  
Sonia Gattinoni ◽  
Chiara De Simone ◽  
Sabrina Dallavalle ◽  
Filomena Fezza ◽  
Raffaella Nannei ◽  
...  
Keyword(s):  
Fatty Acid ◽  
High Selectivity ◽  
Fatty Acid Amide Hydrolase ◽  
Acid Amide ◽  
Endocannabinoid System ◽  
The Other ◽  
Amide Hydrolase ◽  
Fatty Acid Amide

scholarly journals Anandamide Activity and Degradation Are Regulated by Early Postnatal Aging and Follicle-Stimulating Hormone in Mouse Sertoli Cells

Endocrinology ◽  
2003 ◽  
Vol 144 (1) ◽  
pp. 20-28 ◽  
Author(s):  
Mauro Maccarrone ◽  
Sandra Cecconi ◽  
Gianna Rossi ◽  
Natalia Battista ◽  
Riccardo Pauselli ◽  
...  
Keyword(s):  
Sertoli Cells ◽  
Hormonal Regulation ◽  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Fatty Acid Amide Hydrolase ◽  
Acid Amide ◽  
Endocannabinoid System ◽  
Membrane Transporter ◽  
Immature Mouse ◽  
Amide Hydrolase

Abstract Anandamide (AEA), a prominent member of the endogenous ligands of cannabinoid receptors (endocannabinoids), is known to adversely affect female fertility. However, a potential role of AEA in male reproductive functions is unknown. Here we report evidence that immature mouse Sertoli cells have the biochemical tools to bind and inactivate AEA, i.e. a functional type-2 cannabinoid receptor (CB2R), a selective AEA membrane transporter, and an AEA-degrading enzyme fatty acid amide hydrolase. We show that, unlike CB2R, the activity of AEA membrane transporter and the activity and expression of FAAH decrease, whereas the apoptosis-inducing activity of AEA increases with age during the neonatal period. We also show that FSH reduces the apoptotic potential of AEA, but not that of its nonhydrolyzable analog methanandamide. Concomitantly, FSH enhances FAAH activity in a manner dependent on mRNA transcription and protein synthesis and apparently involving cAMP. These data demonstrate that Sertoli cells partake in the peripheral endocannabinoid system, and that FSH reduces the apoptotic potential of AEA by activating FAAH. Taken together, it can be suggested that the endocannabinoid network plays a role in the hormonal regulation of male fertility.

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