Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2013 Oct;18(10):1125-35.
doi: 10.1038/mp.2012.90. Epub 2012 Jul 10.

Disruption of Fatty Acid Amide Hydrolase Activity Prevents the Effects of Chronic Stress on Anxiety and Amygdalar Microstructure

Affiliations
Free PMC article

Disruption of Fatty Acid Amide Hydrolase Activity Prevents the Effects of Chronic Stress on Anxiety and Amygdalar Microstructure

M N Hill et al. Mol Psychiatry. .
Free PMC article

Abstract

Hyperactivation of the amygdala following chronic stress is believed to be one of the primary mechanisms underlying the increased propensity for anxiety-like behaviors and pathological states; however, the mechanisms by which chronic stress modulates amygdalar function are not well characterized. The aim of the current study was to determine the extent to which the endocannabinoid (eCB) system, which is known to regulate emotional behavior and neuroplasticity, contributes to changes in amygdalar structure and function following chronic stress. To examine the hypothesis, we have exposed C57/Bl6 mice to chronic restraint stress, which results in an increase in fatty acid amide hydrolase (FAAH) activity and a reduction in the concentration of the eCB N-arachidonylethanolamine (AEA) within the amygdala. Chronic restraint stress also increased dendritic arborization, complexity and spine density of pyramidal neurons in the basolateral nucleus of the amygdala (BLA) and increased anxiety-like behavior in wild-type mice. All of the stress-induced changes in amygdalar structure and function were absent in mice deficient in FAAH. Further, the anti-anxiety effect of FAAH deletion was recapitulated in rats treated orally with a novel pharmacological inhibitor of FAAH, JNJ5003 (50 mg per kg per day), during exposure to chronic stress. These studies suggest that FAAH is required for chronic stress to induce hyperactivity and structural remodeling of the amygdala. Collectively, these studies indicate that FAAH-mediated decreases in AEA occur following chronic stress and that this loss of AEA signaling is functionally relevant to the effects of chronic stress. These data support the hypothesis that inhibition of FAAH has therapeutic potential in the treatment of anxiety disorders, possibly by maintaining normal amygdalar function in the face of chronic stress.

Conflict of interest statement

Conflict of Interest

This research was supported, in part, by an unrestricted operating grant to BSM from Johnson and Johnson Pharmaceuticals. JMK is an employee of Janssen Research and Development L.L.C, of Johnson and Johnson Pharmaceuticals. The funding body had no role in the design of this study, collection or analysis of the data or decision to publish, outside of the development of the pharmacological compound, JNJ-5003, which was developed and used in a portion of this study.

Figures

Figure 1
Figure 1. Characterization of the amygdalar endocannabinoid system following chronic stress
Exposure of C57/Bl6 mice to chronic stress (21 days of 6 h/day restraint stress) increased the maximal velocity (Vmax) of AEA hydrolysis by fatty acid amide hydrolase (FAAH) within the amygdala (Panel A), although there was no difference in the binding affinity of AEA for FAAH (Km; Panel B). Consistent with this increase in FAAH activity, chronic stress resulted in a reduction in the tissue levels of the endocannabinoid anandamide (AEA) within the amygdala (Panel C); there was, however, no effect of chronic stress on amygdalar 2-arachidonoylglycerol (2-AG; Panel D). There was no effect of chronic stress on either the maximal binding site density (Bmax; Panel E) or the binding affinity (Kd; Panel F) of the cannabinoid CB1 receptor within the amygdala. Data are presented as means +/− SEM. * denotes significant differences (p < .05) between control and chronically stressed mice.
Figure 2
Figure 2. Deficiency in fatty acid amide hydrolase prevents the ability of chronic stress to promote dendritic arborization and complexity in pyramidal neurons of the basolateral amygdala
(A) Representative tracings of the total dendritic tree of pyramidal neurons from fatty acid amide hydrolase deficient mice (FAAH KO), or their wild type counterparts (WT), under conditions of no stress (CONTROL) or following 21 days of 6 h/day restraint stress (CHRONIC STRESS). (B) Morphological analysis of pyramidal neurons in the basolateral amygdala in FAAH KO, or their WT counterparts, under conditions of no stress (CONTROL) or following 21 days of 6 h/day restraint stress (CHRONIC STRESS). Analysis encompassed dendritic length (upper panel) and branch points (bottom panel) of pyramidal neurons. Data are displayed as mean ± SEM. * denotes significant differences (p < 0.05) between chronically stressed WT mice and all other treatment conditions.
Figure 3
Figure 3. Deficiency in fatty acid amide hydrolase prevents the ability of chronic stress to promote dendritic spinogenesis in pyramidal neurons of the basolateral amygdala
(A) Low-power photomicrograph of a Golgi stain-impregnated medium spiny neuron in the BLA (Scale bar 50μm.) (Inset) Image of spines on a dendritic segment from the same neuron. (B) Representative photomicrograph of a dendritic spine densities on a secondary dendritic branch on a pyramidal neuron in the basolateral amygdala from fatty acid amide hydrolase deficient mice (FAAH KO), or their wild type counterparts (WT), under conditions of no stress (Con) or following 21 days of 6 h/day restraint stress (Stress). Scale bars (5 μm) are seen in white in the photomicrograph. (C) Analysis of total dendritic spines on a secondary branch of pyramidal neurons in the basolateral amygdala in FAAH KO, or their WT counterparts, under conditions of no stress (CONTROL) or following 21 days of 6 h/day restraint stress (CHRONIC STRESS). Data are displayed as mean ± SEM. * denotes significant differences (p < 0.05) between chronically stressed WT mice and all other treatment conditions. (D) Segmental analysis of dendritic spine density along a secondary dendritic branch of pyramidal neurons in the basolateral amygdala from FAAH KO mice, or their WT counterparts, under conditions of no stress (CONTROL) or following 21 days of 6 h/day restraint stress (CHRONIC STRESS). Total number of dendritic spines along the dendritic branch are expressed for 20 μm segments starting from the origin of the branch up to 100 μm from the origin. Data are displayed as mean ± SEM. * denotes significant differences (p < 0.05) between chronically stressed WT mice and all other treatment conditions.
Figure 4
Figure 4. Deficiency in fatty acid amide hydrolase prevents the ability of chronic stress to promote anxiety-like behavior
Behavioral analysis of fatty acid amide hydrolase deficient (FAAH KO), or their wildtype counterparts (WT), under conditions of no stress (CONTROL) or following 21 days of 6 h/day restraint stress (CHRONIC STRESS), in the elevated plus maze. Analysis encompassed both the (A) percentage of time spent in and (B) the percentage of entires that the mice made into the open arms. Data are displayed as mean ± SEM. * denotes significant differences (p < 0.05) between chronically stressed WT mice and all other treatment conditions.

Similar articles

See all similar articles

Cited by 60 articles

See all "Cited by" articles

Publication types

MeSH terms

Substances

Feedback