Antidepressant-like effects of pharmacological inhibition of FAAH activity in socially isolated female rats
Introduction
Prolonged or repeated exposure to stressors of psychosocial nature can act as a precipitating factor for the onset of depression (Cohen et al., 2007; Dinan, 2005). One of the most susceptible brain regions to the effects of psychosocial stress is the hippocampus, a component of the limbic system that regulates emotional and cognitive processes related to psychiatric disorders (Belleau et al., 2019; Sheline et al., 2019). The hippocampus is also a major regulator of the hypothalamic-pituitary-adrenal (HPA) axis (Jacobson and Sapolsky, 1991), the neuroendocrine system responsible for the release of glucocorticoid stress hormones (i.e., cortisol in humans, corticosterone in rodents). In patients with depression, hippocampal volume is decreased (Sapolsky, 2000; Sheline, 1996) and the HPA axis is dysregulated (Stetler and Miller, 2011). Depletion of hippocampal neurogenesis has been implicated as one of the substrates that may explain the hippocampal volume loss seen in depression (Duman and Monteggia, 2006; Levone et al., 2015). Specifically, the neurotrophic hypothesis of depression proposes that stress-induced reductions in the expression of brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family regulating synaptic plasticity (Leal et al., 2017; Lu et al., 2014), occur in key limbic structures, including the hippocampus, to contribute to the pathogenesis of depression (Castren et al., 2007; Duman and Monteggia, 2006). Moreover, several lines of clinical and preclinical evidence indicate that conventional antidepressants (e.g., tricyclics, selective serotonin reuptake inhibitors and norepinephrine reuptake inhibitors) may in part exert their effects through BDNF upregulation (Hayley and Anisman, 2013; Pittenger and Duman, 2008; Tardito et al., 2006).
The past two decades have witnessed a driven focus on the identification of novel therapeutic targets for depression, in an attempt to overcome the notable limitations of conventional antidepressant treatments, poor efficacy being perhaps the most critical (Connolly and Thase, 2012). For example, substantial evidence has accumulated implicating a deficit in endocannabinoid (eCB) neurotransmission in the etiology of depression (for a comprehensive review see Gorzalka and Hill, 2011). At the preclinical level, a deficiency in the signaling mediated by the eCB N-arachidonoylethanolamine (or anandamide, AEA) has been noted in the hippocampus, hypothalamus, ventral striatum, and prefrontal cortex of rats exposed to several stressors (i.e., chronic unpredictable stress and social defeat stress) and presenting a "depressive-like" phenotype (reviewed in Carnevali et al., 2017b). These findings have triggered significant interest in the development of eCB-interacting drugs, including direct-acting receptor ligands and catabolism inhibitors for the pharmacotherapy of depression (Micale et al., 2013). Specifically, within preclinical models, facilitation of AEA signaling through pharmacological inhibition of its degrading enzyme (i.e., fatty acid amide hydrolase (FAAH)) can enhance monoaminergic transmission, increase cellular plasticity and neurotrophin expression within the hippocampus, dampen HPA axis activity, and evoke antidepressant-like behavioral effects (reviewed in Carnevali et al., 2017b). However, while the literature has been unequivocal in showing that women experience depression at twice the rate of men (e.g., Grigoriadis and Robinson, 2007), very few preclinical studies have been conducted on female experimental animals (Beery, 2018; Kokras and Dalla, 2014). Moreover, despite the existence of sex differences in response to antidepressant treatment (Sloan and Kornstein, 2003), preclinical research on the antidepressant action of FAAH inhibitors has been predominantly conducted in male rodents (Carnevali et al., 2017b; Fowler, 2015). Therefore, there is a clear need to use female animals in preclinical models of stress to either confirm and generalize to females the previously obtained male animal-based findings or underscore potential sex differences in the etiology of depression and/or in the efficacy of new treatments.
Based on this background, the purpose of the current study was two-fold. First, we aimed at documenting the development of behavioral (passive stress coping, anhedonia) and biological (reduced hippocampal BDNF levels, HPA axis hyperactivity, body weight loss) alterations in adult female rats exposed to prolonged social isolation, a mild chronic social stressor that has been widely used to model symptoms that are often associated with an increased risk of developing a depressive-like state in rodents (Carnevali et al., 2017a). Second, we tested the hypothesis that pharmacological inhibition of FAAH activity would correct the alterations associated with prolonged social isolation. To this aim, we employed the FAAH inhibitor URB694 (6‑hydroxy‑[1,1′-biphenyl]−3-yl-cyclohexylcarbamate) which was shown to exhibit higher selectivity and more prolonged and profound access to the brain than the standard inhibitor URB597 (Clapper et al., 2009).
Section snippets
Animals and housing conditions
Four-month-old female wild-type Groningen rats were used in this study. This rat population, originally derived from the University of Groningen (the Netherlands) and currently bred in our laboratory under standard conditions, shows considerable individual differences in trait-like patterns of behavioral and physiological responses to environmental challenges (Carnevali et al., 2014; de Boer et al., 2017). After weaning, female animals were housed in same-sex sibling pairs and kept in rooms
Body weight
There were no significant differences in body weight among groups at the start of the experiment (i.e., when animals were assigned to the different housing conditions) (PH + VEH = 230 ± 2 g; IS + VEH = 237 ± 5 g; PH + URB694 = 231 ± 4 g; IS + URB694 = 226 ± 8 g). However, a significant time x condition interaction emerged on body weight gain calculated as the difference between weight at the end (i.e., immediately before animals were euthanized) and at the start of the experiment (F = 7.1, p
Discussion
The major findings of the current investigation are the following. Compared to pair-housed females, socially isolated female rats developed behavioral (mild anhedonic state, passive stress coping) and physiological (reduced body weight gain, elevated plasma corticosterone levels) changes, and showed a reduction in BDNF and AEA levels within the hippocampus. Together, these changes are indicative of an increased risk of developing a depressive-like state. Notably, pharmacological inhibition of
Role of funding source
The funding sources had no role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.
Contributors
Authors LC and RS performed the experiments and analysed the data. Authors FV and FF analyzed the data. Authors LC, RS and AS designed the study. Author GS synthesized URB694. Author LC wrote the first draft of the manuscript. Authors RS, FV, SR, MM and AS revised the article critically for important intellectual content. All authors interpreted the results and contributed to and have approved the final manuscript.
Conflict of Interest
All authors declare that they have no conflicts of interest.
Acknowledgements
This research was financially supported by the Italian Ministry for University and Research (MIUR, PRIN 2017, 20175SA5JJ project) and the by the Programme “FIL-Quota Incentivante” of University of Parma and co-sponsored by Fondazione Cariparma.
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