Selective aryl hydrocarbon receptor modulators can act as antidepressants in obese female mice.

BACKGROUND: Obese females are more likely to suffer from depression and are also more likely to be resistant to current medications. This study examined the potential antidepressant-like effects of 1,4-dihydroxy-2-napthoic acid (DHNA), a selective aryl hydrocarbon receptor modulator (SAhRM), in obese female mice. METHODS: Obesity was established by feeding C57BL/6N female mice a high fat diet (HFD) for 9-10 weeks. Subsequently, mice were subjected to unpredictable chronic mild stress (UCMS) or remained unstressed. Daily administration of vehicle or 20 mg/kg DHNA began three weeks prior or on the third week of UCMS. Mice were examined for depression-like behaviors (sucrose preference, forced swim test (FST), splash and tape groom tests), anxiety (open-field test, light/dark test, novelty-induced hypophagia), and cognition (object location recognition, novel object recognition, Morris water maze). RESULTS: UCMS did not alter, and DHNA slightly increased, weight gain in HFD-fed females. HFD decreased sucrose preference, increased FST immobility time, but did not alter splash and tape tests' grooming time. UCMS did not have additional effects on sucrose preference. UCMS further increased FST immobility time and decreased splash and tape tests' grooming time; these effects were prevented and reversed by DHNA treatment. HFD did not affect behaviors in the cognitive tests. UCMS impaired spatial learning; this effect was not prevented nor reversed by DHNA. CONCLUSIONS: DHNA protected against UCMS-induced depression-like behaviors in HFD-fed female mice. DHNA neither improved nor worsened UCMS-induced impairment of spatial learning. Our findings indicate that DHNA has high potential to act as an antidepressant in obese females.

Intestinal epithelium aryl hydrocarbon receptor is involved in stress sensitivity and maintaining depressive symptoms.

The aryl hydrocarbon receptor (AhR) is a key regulator in the microbiome-gut-brain axis, and AhR-active microbial metabolites modulate multiple neuronal responses. We recently demonstrated that 3,3'-diindolylmethane (DIM) and 1,4-dihydroxy-2-naphthoic acid (DHNA), two selective AhR modulators (SAhRMs), act as antidepressants in female mice. Thus, to examine the role of intestinal AhR in depression, anxiety, and spatial learning, this study employed transgenic mice in which the AhR was knockout only in the intestinal epithelium (AhRΔIEC). Additionally, this study examined whether the antidepressant effects of dietary DIM and DHNA is mediated by intestinal AhR. AhRΔIEC and WT female mice were fed daily with vehicle, 20 mg/kg DIM or DHNA for three weeks prior to four weeks of unpredictable chronic mild stress (UCMS). Mice were examined for weight gain, anhedonia-like behavior (sucrose preference test), anxiety levels (open field, light/dark, elevated plus maze, novelty-induced hypophagia, and marble burying tests), and spatial learning (Morris water maze). UCMS reduced weight gain in AhRΔIECs, but not WTs. Moreover, UCMS initially reduced sucrose preference in both AhRΔIECs and WTs, but over 4 weeks of UCMS, AhRΔIECs develop resilience to UCMS-induced anhedonia. Additionally, AhRΔIECs exhibit slightly reduced anxiety in certain tests and faster spatial learning. DIM and DHNA acted as antidepressants in both AhRΔIECs and WTs. Thus, this study suggests that intestinal AhR plays differential roles, mitigating stress effects on weight gain, and increasing stress effects on mood. However, the site of antidepressant action of SAhRMs, such as DIM and DHNA, is not dependent on the expression of intestinal AhR.

Sex-dependent differences in the stress mitigating and antidepressant effects of selective aryl hydrocarbon receptor modulators.

BACKGROUND: Our recent study demonstrated that selective aryl hydrocarbon receptor modulators (SAhRMs), such as 1,4-dihydroxy-2-napthoic acid (DHNA) act as antidepressants in female mice. Given that some effects of certain SAhRMs are known to also be mediated via estrogen receptor signaling, this study examined whether the effects of SAhRMs on mood, emotional state, and cognition are sex-dependent. METHODS: C57BL/6N mice were fed with vehicle or 20 mg/kg DHNA for three weeks prior to four weeks of unpredictable chronic mild stress (UCMS). Mice were examined for depression-like behaviors (sucrose preference, forced swim test (FST), splash test, tape groom test), emotional state (open-field test, light/dark test, marble burying, novelty-induced hypophagia, elevated-plus maze), and cognition (object location recognition, novel object recognition, Morris water maze). RESULTS: In females, UCMS decreased sucrose preference and increased FST immobility time; both effects were prevented by DHNA. In males, UCMS increased FST immobility time, and increased the latency to groom in the splash test. These effects were not mitigated by DHNA. However, in males, UCMS induced an increase in novelty-induced locomotion, an increase in the time spent in the light compartment in the L/D test, and an increase in the time spent with an object in a novel location. These effects were prevented by DHNA. CONCLUSIONS: Our findings indicate that DHNA has high potential to act as antidepressants in females. However, given classical interpretation, DHNA did not appear to act as an antidepressant in males. Nonetheless, our findings indicate that DHNA can mitigate stress effects and reactivity in males.

3,3'-Diindolylmethane and 1,4-dihydroxy-2-naphthoic acid prevent chronic mild stress induced depressive-like behaviors in female mice.

BACKGROUND: Current pharmaceutical treatments for depression are sometimes ineffective and may have unwanted side effects that interfere with patient compliance. This study examined the potential antidepressant-like effects of dietary- and microbial-derived aryl hydrocarbon receptor (AhR) ligands, 3,3'-diindolylmethane (DIM) and 1,4-dihydroxy-2-naphthoic acid (1,4-DHNA). METHODS: Female C57BL/6 mice were subjected to unpredictable chronic mild stress (UCMS) or were unstressed. For three weeks prior to UCMS mice were fed daily with vehicle or 20 mg/kg DIM, 1,4-DHNA or AhR-inactive isomer 3,7-DHNA; another group was subjected to two weeks UCMS before ligand administration began. Mice were examined for anhedonia-like behavior as measured by the sucrose preference test. Additionally, anxiety levels of the mice were examined before UCMS and ligand administration began and at the end in the open field, light/dark, elevated plus maze, novelty-induced hypophagia, and marble burying tests. At the end of the experiment they were also examined in the Morris water maze (MWM) task. RESULTS: Both DIM and 1,4-DHNA, but not 3,7-DHNA, successfully prevented and reversed UCMS-induced anhedonia-like behavior. Furthermore, both DIM and DHNA had little to no effect on anxiety levels and did not induce spatial learning deficits. LIMITATIONS: Additional studies are required to determine to what degree the antidepressant-like effects of DIM and 1,4-DHNA can be attributed to their activities as AhR ligands. CONCLUSIONS: Our findings indicate that dietary and microbial-derived AhR ligands may have clinical applications as potential antidepressants. Future studies are necessary to elucidate the role of AhR in depression-like states and the underlying mechanisms of action.