Interactions Between Anandamide and Corticotropin-Releasing Factor Signaling Modulate Human Amygdala Function and Risk for Anxiety Disorders: An Imaging Genetics Strategy for Modeling Molecular Interactions

Background One of the major mechanisms for terminating the actions of the endocannabinoid anandamide is hydrolysis by fatty acid amide hydrolase (FAAH) and inhibitors of the enzyme were suggested as potential treatment for human cannabis dependence. However, the status of brain FAAH in cannabis use disorder is unknown. Methods Brain FAAH binding was measured with positron emission tomography and [11C]CURB in 22 healthy control subjects and ten chronic, frequent cannabis users during early abstinence. The FAAH genetic polymorphism (rs324420) and blood, urine and hair levels of cannabinoids and metabolites were determined. Results In cannabis users FAAH binding was significantly lower by 14–20% across the brain regions examined as compared to matched control subjects (overall Cohen’s d=0.96). Lower binding was negatively correlated with cannabinoid concentrations in blood and urine and was associated with higher trait impulsiveness. Conclusions Lower FAAH binding levels in the brain may be a consequence of chronic and recent cannabis exposure and could contribute to cannabis withdrawal. This effect should be considered in the development of novel treatment strategies for cannabis use disorder that target FAAH and endocannabinoids. Further studies are needed to examine possible changes in FAAH binding during prolonged cannabis abstinence and whether lower FAAH binding predates drug use.

Section: Discussionmentioning

confidence: 86%

Fatty Acid Amide Hydrolase Binding in Brain of Cannabis Users: Imaging With the Novel Radiotracer [11C]CURB

Boileau

Mansouri

Williams

et al. 2016

“…We propose that the stress-sensitive features in msP rats relate to dysfunctional AEA signaling elements that regulate CeA glutamatergic transmission, and contribute to the etiopathology of anxiety. The evidence linking CRF 1 -FAAH dysfunction in amygdaloid circuitry with negative affective symptoms has translational value for recent work establishing a parallel between clinical symptoms of aberrant stress reactivity, anxiety disorders, and genomic variations in CRF 1 and FAAH (26, 30, 71, 72). Moreover, our previous work relating the point mutations in the Crhr1 gene in msPs to aberrant stress responses in fear conditioning studies (36, 38) suggest a possible link between innately dysregulated eCB systems and pathological symptoms of post-traumatic stress disorder.…”

Section: Discussionmentioning

confidence: 99%

Constitutive Increases in Amygdalar Corticotropin-Releasing Factor and Fatty Acid Amide Hydrolase Drive an Anxious Phenotype

Natividad

Buczynski

Herman

et al. 2017

Background Corticotropin-releasing factor (CRF) mediates anxiogenic responses by activating CRF1 receptors in limbic brain regions. Anxiety is further modulated by the endogenous cannabinoid (eCB) system that attenuates the synaptic effects of stress. In the amygdala, acute stress activates the enzymatic clearance of the eCB N-arachidonoylethanolamine (anandamide; AEA) via fatty acid amide hydrolase (FAAH), although it is unclear whether chronic stress induces maladaptive changes in amygdalar eCB signaling to promote anxiety. Here, we used genetically-selected Marchigian Sardinian P (msP) rats carrying an innate overexpression of CRF1 receptors to study the role of constitutive upregulation in CRF systems on amygdalar eCB function and persistent anxiety-like effects. Methods We applied behavioral, pharmacological, and biochemical methods to broadly characterize anxiety-like behaviors and amygdalar eCB clearance enzymes in msP versus non-selected Wistar rats. Subsequent studies examined the influence of dysregulated CRF and FAAH systems in altering excitatory transmission in the central amygdala (CeA). Results MsPs display an anxious phenotype accompanied by elevations in amygdalar FAAH activity and reduced dialysate AEA levels in the CeA. Elevations in CRF-CRF1 signaling dysregulate FAAH activity, and this genotypic difference is normalized with pharmacological blockade of CRF1 receptors. MsPs also exhibit elevated baseline glutamatergic transmission in the CeA, and dysregulated CRF-FAAH facilitates stress-induced increases in glutamatergic activity. Treatment with a FAAH inhibitor relieves sensitized glutamatergic responses in msPs and attenuates the anxiety-like phenotype. Conclusions Pathological anxiety and stress hyper-sensitivity are driven by constitutive increases in CRF1 signaling that dysregulate AEA signaling mechanisms and disable neuronal constraint of CeA glutamatergic synapses.

“…It assumes additivity alone (which is supported(111)) and neglects potential epistatic effects, which while observed in imaging genetics studies (112,113) have yet to be widely replicated (114). Also, by aggregating across the genome, when used in isolation, PRS provide no insight into potential underlying molecular mechanisms.…”

Section: Polygenic Approachesmentioning

confidence: 99%

Imaging Genetics and Genomics in Psychiatry: A Critical Review of Progress and Potential

Bogdan¹,

Salmeron

Carey³

et al. 2017

Self Cite

147

Imaging genetics and genomics research has begun to provide insight into the molecular and genetic architecture of neural phenotypes and the neural mechanisms through which genetic risk for psychopathology may emerge. As it approaches its third decade, imaging genetics is confronted by many challenges including the proliferation of studies using small sample sizes and diverse designs, limited replication, problems with harmonization of neural phenotypes for meta-analysis, unclear mechanisms, and evidence that effect sizes may be more modest than originally posited, with increasing evidence of polygenicity. These concerns have encouraged the field to grow in many new directions including the development of consortia and large scale data collection projects as well as the use of novel methods (e.g., polygenic approaches, machine learning), which enhance the quality of imaging genetic studies, but also introduce new challenges. Here, we critically review progress in imaging genetics and offer suggestions and highlight potential pitfalls of novel approaches. Ultimately, the strength of imaging genetics and genomics lies in its translational and integrative potential with other research approaches (e.g., non-human animal models, psychiatric genetics, pharmacologic challenge) to elucidate brain-based pathways that give rise to the vast individual differences in behavior as well as risk for psychopathology.