Estrogen recruits the endocannabinoid system to modulate emotionality

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Summary

Estrogen administration elicits anxiolytic and antidepressant-like effects in female rats; however, the mechanism of this effect is unknown. Fatty acid amide hydrolase (FAAH), the enzyme which degrades the endocannabinoid anandamide, has been shown to be regulated by estrogen. Thus, we examined if the anxiolytic and antidepressant effects of estrogen implicated the endocannabinoid system. In the first experiment, ovariectomized female rats were administered a single injection of 17β-estradiol (10 μg) or oil, and 48 h later were given an injection of the cannabinoid CB1 receptor antagonist AM251 (1 mg/kg) or vehicle. One hour after AM251 or vehicle administration, subjects were tested in either the open field test (OFT), elevated plus maze (EPM) or the forced swim test (FST). Estradiol treatment resulted in a significant increase in open arm entries in the EPM and time spent in the center quadrant of the OFT, which were reversed by co-treatment with AM251, suggesting that endocannabinoids are integral to the anxiolytic effects of estrogen. No significant effects of estradiol or AM251 were seen in the FST. In the second experiment, administration of the FAAH inhibitor URB597 (0.1 and 0.3 mg/kg) increased open arm entries in the EPM and time spent in the center quadrant in the OFT as well as significantly reduced immobility in the FST. Collectively, these data demonstrate that estrogen may elicit changes in emotional behavior through an endocannabinoid mechanism, and suggest that inhibition of FAAH represents a therapeutic target for anxiety and depression in women.

Introduction

The effects of estrogen on mood and emotion have been well documented. For example, menopausal declines in circulating estrogen levels have been associated with an increase in mood disturbances, including symptoms of anxiety and depression in women (Weissman and Klerman, 1977; Wittchen and Hoyer, 2001). Ovariectomy in female rats mirrors the depletion of estrogen in menopause, and concurrently elicits a reliable increase in anxiety and depression-like behaviors in tests of emotionality, such as the elevated plus maze (EPM) and forced swim test, which are reversible by treatment with physiological doses of estradiol (Estrada-Camarena et al., 2003, Estrada-Camarena et al., 2006; Walf et al., 2004; Andrade et al., 2005a; Walf and Frye, 2005a; Picazo et al., 2006). These behavioral changes are likely mediated, at least in part, by classical nuclear actions of estrogen on gene transcription given the temporal lag required for consistent behavioral effects to be seen. There is evidence that the serotonergic 5-HT1A receptor is involved in these behavioral changes (Andrade et al., 2005; Estrada-Camarena et al., 2006); however, this role appears to be more related to rapid effects of estrogen rather than longer term effects. However, other neurotransmitter systems and neuromodulators warrant further investigation.

The endocannabinoid system is a neuromodulatory system and potential target to mediate the behavioral effects of estrogen. Activation of the cannabinoid CB1 receptor by both exogenous ligands, such as tetrahydrocannabinol, the psychoactive constituent of cannabis, and endogenous ligands, such as the arachidonate derived lipids arachidonylethanolamine (anandamide; AEA) and 2-arachidonylglycerol (2-AG), elicits profound effects on emotional behavior (Onaivi et al., 1990; Kathuria et al., 2003; Hill and Gorzalka, 2004, Hill and Gorzalka, 2005a; Viveros et al., 2005; Bortolato et al., 2006; Patel and Hillard, 2006). More specifically, inhibition of the primary enzyme involved in AEA metabolism, fatty acid amide hydrolase (FAAH), reduces anxiety on several rodent indices such as ultrasonic vocalizations and open arm avoidance in the EPM (Kathuria et al., 2003; Patel and Hillard, 2006). Similar effects on anxiety have been documented with the combined AEA transport/FAAH inhibitor AM404 (Bortolato et al., 2006). Inhibition of FAAH and/or AEA transport has also been found to induce an antidepressant-like effect in the forced swim test (Gobbi et al., 2005; Hill and Gorzalka, 2005a). However, it should be noted that opposing effects have also been demonstrated such that administration of antagonists to the CB1 receptor have been found to elicit similar anxiolytic and antidepressant-like effects (Griebel et al., 2005; Shearman et al., 2003; Tzavara et al., 2003), indicating that this system exhibits a complex regulation of emotional behavior. Regardless of this complexity, these behavioral effects elicited by enhancement of AEA/CB1 receptor signaling are quite similar to those seen following estrogen administration (Estrada-Camarena et al., 2003, Estrada-Camarena et al., 2006; Walf et al., 2004; Andrade et al., 2005; Walf and Frye, 2005a).

At the molecular level, the FAAH enzyme is a potential locus for an interaction between estrogen and endocannabinoid signaling. The FAAH enzyme possesses an estrogen response element in its genetic sequence, and translocation of the estrogen receptor to the nucleus results in inhibition of FAAH transcription (Waleh et al., 2002). In the periphery, estrogen has been found to downregulate FAAH expression and activity in uterine tissue (Maccarrone et al., 2000). Estrogen-induced downregulation of FAAH would result in a consequent increase in AEA signaling, which, if it occurred in the central nervous system could influence emotional processes. We performed a series of experiments to explore this hypothesis. First, we examined if the ability of estrogen to reduce anxiety in the EPM and open field test, and elicit an antidepressant response in the forced swim test, were sensitive to CB1 receptor antagonism. Second, we examined the effect of pharmacological inhibition of FAAH in these behavioral tests in ovariectomized female rats. Our data demonstrate that estrogen engages the endocannabinoid system, potentially through a FAAH-related mechanism, to modulate emotional behavior in the female rat.

Section snippets

Subjects

Female Long-Evans rats that were 10 weeks of age, at the time of testing, and weighed between 225 and 275 g were used in this study. All subjects were housed in groups of three in triple mesh wire cages in a colony room that had a maintained temperature of 21+/−1 °C and a 12 h:12 h light dark cycle (lights on at 0900 h). All females were ovariectomized under either Halothane anesthesia (2–4% flow rate as required to maintain stable respiration) or a combination of 75 mg/kg ketamine hydrochloride

Elevated plus maze

In the EPM, there was a significant interaction between estradiol and AM251 administration on the ratio of open arm entries relative to closed arm entries [F(1,22)=6.51, p<0.02; Fig. 1(a)]. Post hoc analysis revealed that estradiol administration increased the ratio of open arm entries relative to oil/vehicle treated animals (p<0.05); additionally, animals that had been co-treated with estradiol and AM251 were not different from those receiving oil/vehicle treatment (p>0.05) but were

Discussion

The results of Experiment 1 confirmed previous research by demonstrating that administration of physiological doses of estradiol to ovariectomized female rats produced an anxiolytic effect in the open field test and EPM. Our results also provided the first evidence to date that estradiol-induced alterations in emotionality are sensitive to antagonism of the cannabinoid CB1 receptor. Surprisingly, estradiol treatment did not elicit a significant antidepressant-like effect in the forced swim

Role of the funding source

There was no role of the funding source in the collection, analysis or interpretation of this data nor the writing or submission of this paper.

Conflict of interest statement

No authors on this paper have any conflict of interest to report with the data presented in this manuscript.

Matthew N. Hill

Eda S. Karacabeyli

Boris B. Gorzalka

Acknowledgments

This research was supported by operating grants provided to BBG by the Canadian Institutes of Health Research and the Natural Sciences and Engineering Research Council of Canada (NSERC) and graduate fellowships to MNH provided by NSERC and the Michael Smith Foundation for Health Research. The authors would like to thank Stephanie Lieblich, Larissa Froese, Anna Morrish, Cedric Gabilondo and Sarah Thompson for their technical assistance.

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