Antidepressant-like effects of pharmacological inhibition of FAAH activity in socially isolated female rats

Carnevali, Luca; Statello, Rosario; Vacondio, Federica; Ferlenghi, Francesca; Spadoni, Gilberto; Rivara, Silvia; Mor, Marco; Sgoifo, Andrea

doi:10.1016/j.euroneuro.2019.12.119

Cited by 24 publications

(12 citation statements)

References 72 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…One gene of interest that was significantly upregulated in the PFS cell line was brain-derived neurotrophic factor ( BDNF ), with the microarray assay result validated by RT-qPCR ( Figure 6C ). Interestingly, previous work in rats has shown that pharmacological inhibition of the FAAH enzyme elevated BDNF levels (Carnevali et al , 2020; Shang et al , 2022; Vinod et al , 2012). We replicated this data in wild-type mice by showing that systemic injection of FAAH inhibitor URB597 showed a ∼25% increase in hippocampal BDNF levels, as determined by ELISA ( Supplementary Figure S7A ).…”

Section: Resultsmentioning

confidence: 97%

Molecular basis ofFAAH-OUT-associated human pain insensitivity

Mikaeili

Habib

Yeung

et al. 2022

Preprint

View full text Add to dashboard Cite

Chronic pain affects millions of people worldwide. Studying pain insensitive individuals helps to identify novel analgesic strategies. Here we report how the recently discovered FAAH-OUT lncRNA-encoding gene, which was found from studying a pain insensitive patient with reduced anxiety and fast wound healing, regulates the adjacent key endocannabinoid system gene FAAH, which encodes the anandamide-degrading fatty acid amide hydrolase enzyme. We demonstrate that the disruption in FAAH-OUT lncRNA transcription leads to DNMT1-dependent DNA methylation within the FAAH promoter. In addition, FAAH-OUT contains a conserved regulatory element, FAAH-AMP, that acts as an enhancer for FAAH expression. Furthermore, using transcriptomic analyses we have uncovered a network of genes that are dysregulated from disruption of the FAAH-FAAH-OUT axis, thus providing a coherent mechanistic basis to understand the human phenotype observed and a platform for development of future gene and small molecule therapies.

show abstract

Section: Resultsmentioning

confidence: 97%

Molecular basis ofFAAH-OUT-associated human pain insensitivity

Mikaeili

Habib

Yeung

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Lastly, a number of studies assessed sex differences with respect to FAAH. While two studies found significant sex differences in FAAH, three studies found no differences in FAAH between the sexes [49,50,62,65,67,68]. Evidently, the data on sex differences in FAAH are mixed, which could be due to differences in the animal model or species strain.…”

Section: Discussionmentioning

confidence: 95%

“…), which increased central and peripheral AEA levels and normalized changes in body weight, sucrose preference and immobility time on the FST. The same group then replicated this experiment in female rats [68]. Rats were exposed to social isolation, which caused less weight gain, reduction in sucrose preference and increased immobility time in the FST.…”

Section: Antidepressant-like Effects Of Urb597 Urb694 and Other Faahmentioning

confidence: 99%

“…The brain regions that are most influenced by FAAH inhibitors are the PFC, hippocampus, and striatum; dysregulated FAAH activity in these regions could explain MDD symptoms such as loss of motivation, cognitive dysfunction, and anhedonia [53]. Moreover, preclinical studies of FAAH inhibition also reveal some sex differences in depressive phenotypes; still, FAAH inhibitors seem to effectively reduce depressive-like behaviors in both male and female animals [62,65,68]. A number of studies provided evidence of dose-response effects that must be further studied and will be relevant for new clinical trials [56,57,60,69,75].…”

Section: Antidepressant-like Effects Of Urb597 Urb694 and Other Faahmentioning

confidence: 99%

See 1 more Smart Citation

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

Rafiei

Kolla

2021

IJMS

View full text Add to dashboard Cite

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.

show abstract

“…A relationship between anandamide, one of the main endocannabinoid metabolites, and the emotional state of animals was suggested. Previous studies found that decreasing anandamide levels by depletion of its producing enzyme may be a risk for the development of depression [ 37 ], and increasing its levels by blocking its hydrolase exerted antidepressant effects [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

Metabolomic changes in animal models of depression: a systematic analysis

Liu

Gui

et al. 2021

Mol Psychiatry

View full text Add to dashboard Cite

Extensive research has been carried out on the metabolomic changes in animal models of depression; however, there is no general agreement about which metabolites exhibit constant changes. Therefore, the aim of this study was to identify consistently altered metabolites in large-scale metabolomics studies of depression models. We performed vote counting analyses to identify consistently upregulated or downregulated metabolites in the brain, blood, and urine of animal models of depression based on 3743 differential metabolites from 241 animal metabolomics studies. We found that serotonin, dopamine, gamma-aminobutyric acid, norepinephrine, N-acetyl-L-aspartic acid, anandamide, and tryptophan were downregulated in the brain, while kynurenine, myo-inositol, hydroxykynurenine, and the kynurenine to tryptophan ratio were upregulated. Regarding blood metabolites, tryptophan, leucine, tyrosine, valine, trimethylamine N-oxide, proline, oleamide, pyruvic acid, and serotonin were downregulated, while N-acetyl glycoprotein, corticosterone, and glutamine were upregulated. Moreover, citric acid, oxoglutaric acid, proline, tryptophan, creatine, betaine, L-dopa, palmitic acid, and pimelic acid were downregulated, and hippuric acid was upregulated in urine. We also identified consistently altered metabolites in the hippocampus, prefrontal cortex, serum, and plasma. These findings suggested that metabolomic changes in depression models are characterized by decreased neurotransmitter and increased kynurenine metabolite levels in the brain, decreased amino acid and increased corticosterone levels in blood, and imbalanced energy metabolism and microbial metabolites in urine. This study contributes to existing knowledge of metabolomic changes in depression and revealed that the reproducibility of candidate metabolites was inadequate in previous studies.

show abstract

Antidepressant-like effects of pharmacological inhibition of FAAH activity in socially isolated female rats

Cited by 24 publications

References 72 publications

Molecular basis ofFAAH-OUT-associated human pain insensitivity

Molecular basis ofFAAH-OUT-associated human pain insensitivity

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

Metabolomic changes in animal models of depression: a systematic analysis

Contact Info

Product

Resources

About