Endocannabinoid signaling and stress resilience

C H A P T E R

22 Endocannabinoid signaling and stress resilience Matthew N. Hill1, Sachin Patel2 1

Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; 2Departments of Psychiatry and Behavioral Sciences, Pharmacology, Molecular Physiology & Biophysics, and The Vanderbilt Brain Institute, Vanderbilt University Medical Center, Nashville, TN, United States

The endocannabinoid (eCB) system derives its name from the fact that eCBs and plantderived cannabinoids both exert their effects on physiology through common molecular receptor targets (Mechoulam and Parker, 2013). The eCB system is a neuromodulatory lipid system that consists of the cannabinoid receptor type 1 and type 2 (CB1 and CB2 receptor, respectively; Herkenham et al, 1991; Matsuda et al, 1990) and two well-studied endogenous ligands, N-arachidonoyl ethanolamine (anandamide, AEA; Devane et al, 1992) and 2-arachidonoyl glycerol (2-AG; Sugiura et al., 1995). Cannabinoid receptors were first characterized as the primary biological target of cannabis-derived tetrahydrocannabinol and couple to Gi/o proteins that function to inhibit adenylyl cyclase activity, activate potassium channels, and inhibit voltage-gated calcium channels (Howlett et al, 2002). Given that CB1 receptors are primarily localized to axon terminals, activation of these receptors results in a robust suppression of neurotransmitter release (Katona and Freund, 2012). CB1 receptors represent the most abundant class of G-proteinecoupled receptors in the central nervous system (Herkenham et al, 1991) but are also present in a variety of peripheral tissues, including the liver, adipose, vasculature, and immune cells (Howlett et al, 2002). Within the brain, CB1 receptors are primarily expressed on GABAergic and glutamatergic neurons, but they also have some expression on serotonergic, noradrenergic, and cholinergic terminals (Katona and Freund, 2012). A growing body of evidence also indicates that CB1 receptors are functionally expressed on astrocytes and can regulate the release of a host of gliotransmitters (Metna-Laurent and Marsicano, 2015; Navarette et al., 2014). CB2 receptors are mostly located in immune cells, and when activated, they can modulate immune cell migration and cytokine release both outside and within the brain (Pertwee, 2005). There is also evidence that they are possibly expressed by some neurons (Van Sickle et al, 2005), but the role of these putative neuronal

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CB2 receptors is yet to be established (Atwood and Mackie, 2010). In addition, some eCB ligands are active at other receptor targets including peroxisome proliferatoreactivated receptor and transient receptor potential vanilloid type 1 and can also directly affect activity of some ion channels (Mechoulam and Parker, 2013). AEA and 2-AG are synthesized predominantly “on demand” from phospholipid precursors in the postsynaptic membrane by Ca2þ-dependent and -independent enzymatic processes (Katona and Freund, 2012) and feedback in a retrograde manner onto presynaptic terminals, thus suppressing afferent neurotransmitter release via activation of CB1 receptors (Katona and Freund, 2012). The synthesis of 2-AG is tightly coupled to the generation of diacylglycerol from phospholipase C activity, which is rapidly converted to 2-AG by the enzyme diacylglycerol lipase (DAGL; Sugiura et al., 1995). The synthesis of AEA, on the other hand, is far less clear and appears to be performed by at least three redundant pathways, none of which have been verified as the primary source of AEA within the brain (Ahn et al., 2008). Following release into the synaptic cleft, AEA and 2-AG are subsequently taken back into the cell by a still poorly defined uptake process mediated by a transporter mechanism (Hillard et al., 1997) and primarily degraded by distinct hydrolytic enzymes, the fatty acid amide hydrolase (FAAH; Cravatt et al., 2001) and monoacylglycerol lipase (MAGL; Dinh et al., 2002), respectively. These two degrading enzymes display distinct subcellular localization, suggesting different signaling properties for AEA and 2-AG (Gulyas et al., 2004). All studies to date have indicated that FAAH is predominantly located on intracellular membranes in postsynaptic cells, while MAGL is positioned in close proximity of CB1 receptors, in presynaptic terminals, at least within the brain regions that have been examined to date such as the hippocampus, amygdala, and cerebellum (Gulyas et al., 2004). In addition to these two primary metabolic enzymes, both AEA and 2-AG are also oxygenated by cyclooxygenase 2 to form bioactive prostaglandin derivatives (Morgan et al., 2018; Hermanson et al., 2013). Additionally, a small proportion of 2-AG is also metabolized by the alpha-beta hydrolase domain (ABHD) class of enzymes, specifically ABHD6 and ABHD12 (Blankman et al., 2007; Marrs et al., 2010). The functional role of these alternate metabolic pathways is not well characterized. For instance, because of its postsynaptic localization (Blankman et al., 2007; Marrs et al., 2010), it is possible that ABHD6 might be involved in the regulation of 2-AG levels released into the synaptic cleft. However, to date, studies have clearly identified the physiological significance of FAAH and MAGL as regulators of eCB levels as pharmacological or genetic inactivation of these two enzymes results in profound accumulation of AEA and 2-AG, respectively (Cravatt et al., 2001; Long et al., 2009). In general, eCB signaling in the synapse leads to a short or a sustained suppression of neurotransmitter release from the presynaptic compartment. Despite the fact that both AEA and 2-AG similarly act to regulate presynaptic transmitter release, it is thought that these two molecules of the eCB system may differentially contribute to phasic and tonic modes of signaling, thereby differentially mediating homeostatic, short-term, and longterm synaptic plasticity processes throughout the brain (Ahn et al., 2008; Hill and Tasker, 2012; Katona and Freund, 2012). It is thought that AEA may represent more of a “tonic” signaling molecule of the eCB system, which acts to regulate basal synaptic transmission, whereas 2-AG may represent more of a “phasic” signaling molecule activated during sustained neuronal depolarization, which in turn mediates many forms of synaptic plasticity (Ahn et al., 2008; Katona and Freund, 2012).

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Anatomically, within the corticolimbic circuit that regulates the stress response, eCB synthetic and degradative enzymes and CB1 receptors are prominently expressed in the amygdala (primarily in the basolateral nucleus [BLA], but also in the central nucleus as well) (Ramikie et al., 2014; Ramikie and Patel, 2012), hippocampus, medial prefrontal cortex (mPFC), and nucleus accumbens (Herkenham et al., 1991; McPartland et al., 2007), where they modulate both excitatory and inhibitory signaling within specific neuronal circuits. This chapter will focus on how eCB signaling throughout these corticolimbic circuits modulates stress responses and describe what is known about how dynamic changes in eCB signaling in response to stress could influence the development of susceptibility or resilience to stress exposure.

Impact of stress on endocannabinoid signaling In general, most stressors have been found to have differential effects on AEA versus 2-AG signaling. The typical pattern of changes that have been documented from stress exposure find that both acute and chronic stress cause a reduction in tissue levels of AEA while also transiently elevating 2-AG levels. The magnitude of these changes seems to be somewhat amplified under conditions of repeated exposure to the same stressor (homotypic stress) and different across various regions of the brain. For a greater discussion of the nuance and details of how stress modulates eCB signaling, please refer to our previous review (Morena et al., 2016). With respect to AEA, the current model is that in response to acute stress, the stresssensitive neuropeptide cortictropin-releasing factor (CRF) is released and activates CRFR1 receptors, which then triggers the hydrolytic activity of FAAH (Gray et al., 2015; Natividad et al., 2017). This increase in FAAH activity results in a depletion of AEA levels and decline in AEA/CB1 receptor signaling. These effects are most prominently seen within the amygdala (Gray et al., 2015; Hill et al., 2009a; Patel et al., 2005; Rademacher et al., 2008), but they have also been documented to occur in the mPFC (McLaughlin et al., 2012) and the hippocampus (Wang et al., 2012; Dubreucq et al., 2012). Even 24 h following acute exposure to a footshock, brain wide levels of AEA have been found to still be reduced (Bluett et al., 2014). Similar to this, chronic exposure to stress also results in a loss of AEA levels across multiple brain regions (Hill et al., 2008a, 2010b; 2013b; Patel et al., 2005; Rademacher et al., 2008; Dubreucq et al., 2012). This effect of chronic stress again seems to be driven by a CRFR1 mechanism, but here, it appears that chronic elevations in glucocorticoid hormones drive CRF production in the amydgala and mPFC, which then results in sustained CRFR1 signaling and a consequent upregulation of AEA hydrolysis by FAAH (Bowles et al., 2012; Gray et al., 2016). Unlike AEA, stress-induced changes in 2-AG signaling go in the opposite direction, appear to be driven by different molecular mechanisms than AEA, and occur on a different time scale. Acute stress generally elevates 2-AG content in the brain (Hill et al., 2011b; Bedse et al., 2017; Wang et al., 2012; Evanson et al., 2010), although this effect does seem to require a temporal delay and is not uniformly seen after every type of stressor examined. This delay is likely driven by the fact that it does appear that elevations in glucocorticoid signaling, which occur at a later time point than CRF release does, mediate increased 2-AG signaling

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after stress (Hill et al., 2011b; Wang et al., 2012). The effects of stress on 2-AG, similar to AEA, appear to be augmented after exposure to repeated stress, especially homotypic stress (Hill et al., 2010b; Patel et al., 2005, 2009; Dubreucq et al., 2012; Rademacher et al., 2008; Sumislawski et al., 2011). In contrast to this transient increase in 2-AG from repeated stress, several studies have recently shown a delayed reduction in 2-AG levels within limbic regions after the termination of the stress response in a manner similar to that observed for AEA (Qin et al., 2015; Hill et al., 2005; Zhong et al., 2014; Lomazzo et al., 2015).

Endocannabinoid regulation of the stress response The predominance of data generated to date indicates that a normative function of the eCB system could be to dampen or buffer against the effects of stress. Consistent with this hypothesis, pharmacological or genetic disruption of eCB signaling reliably produces a neurobehavioral phenotype that directly parallels the classical manifestation of a stress response, including activation of the hypothalamicepituitaryeadrenal (HPA) axis, increased anxiety, suppressed feeding behavior, reduced responsiveness to rewarding stimuli, hypervigilance and arousal, enhanced grooming behavior, and impaired cognitive flexibility (see Morena et al., 2016). As such, these data indicate that there is a prominent stress-inhibitory role of the eCB system. Utilizing both genetic and pharmacological approaches, it has been widely established that dynamic changes in AEA and 2-AG signaling functionally contribute to an array of physiological and behavioral changes induced by stress exposure. As AEA signaling is believed to represent a mediator of “tonic” eCB signaling, it would appear that the depletion of AEA in response to acute stress results in a disruption of tonic eCB signaling, which in turn facilitates the manifestation and orchestration of the stress response (see Morena et al., 2016 for more discussion on this topic). Consistent with this model, inhibition of AEA hydrolysis by FAAH can dampen or prevent several biological changes induced by stress exposure. For example, pharmacological augmentation of AEA signaling has been found to reduce stress-induced activation of the HPA axis (Patel et al., 2004; Hill et al., 2009a; Bedse et al., 2014; Surkin et al., 2018). The ability of FAAH inhibition to dampen activation of the HPA axis appears to largely involve the BLA as local administration of an FAAH inhibitor into the BLA dampens stress-induced HPA axis activation (Hill et al., 2009a), and local administration of a CB1 receptor antagonist into the BLA can prevent the HPA axisereducing effects of systemic FAAH inhibition (Bedse et al., 2014). Similar to effects on HPA axis activation, a loss of AEA signaling in response to stress also seems to contribute to the generation of an anxiety state. Specifically, while inhibition of FAAH was found to reduce behavioral indices of anxiety (Kathuria et al., 2003), additional work has convincingly demonstrated that FAAH inhibition is more effective at reducing anxiety-related behaviors under challenging environmental conditions or after overt stressor exposure (Bluett et al., 2014; Dincheva et al., 2015; Haller et al., 2009; Naidu et al., 2007; Hill et al., 2013b; Rossi et al., 2010; Lomazzo et al., 2015; Carnevali et al., 2015; Griebel et al., 2018; Fidelman et al., 2018; Bedse et al., 2018; Danandeh et al., 2018). Consistent with this model, we have demonstrated that stress-induced release of CRF rapidly triggers FAAH activity in the BLA to reduce AEA signaling, which in turn promotes the generation of anxiety (Gray et al., 2015; Natividad

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et al., 2017). Importantly, central AEA levels are negatively correlated with anxiety-like behaviors, and elevating AEA signaling can effectively curb anxiety induced by acute stress (Bluett et al., 2014; Campos et al., 2010). As such, it has been proposed that AEA may function as a mediator of “emotional homeostasis” (Marco and Viveros, 2009), functioning to keep anxiety at bay in resting conditions, from which disruption of this signal by stress could contribute to the generation of an anxious state (Gunduz-Cinar et al., 2013). In line with the ability of AEA signaling to regulate the HPA axis, it seems that the ability of AEA to regulate anxiety does involve specific actions within the BLA proper (Gray et al., 2015); however, there is also evidence to indicate that AEA signaling in the mPFC (Rubino et al., 2008) and ventral hippocampus (Campos et al., 2010) similarly gate the development of anxiety in response to stress. While stress results in a reduction in tonic AEA signaling, as discussed above, it also amplifies 2-AG signaling acutely. This increase in “phasic” eCB signaling triggered by stress exposure is believed to contribute to limiting the magnitude, and promoting the termination, of stress-induced HPA axis activity (Morena et al., 2016; Hill and Tasker, 2012). Specifically, acute administration of a CB1 receptor antagonist enhances neuronal activation within the paraventricular nucleus (PVN) in response to stress and potentiates the magnitude and duration of stress-induced corticosterone secretion (Hill et al., 2011b; Newsom et al., 2012; Patel et al., 2004; Roberts et al., 2014). Coupled to the biochemical data, these data would suggest that stress-induced elevations in 2-AG content in the mPFC and hypothalamus (Evanson et al., 2010; Hill et al., 2011b), brain regions known to be important for glucocorticoid negative feedback on the HPA axis (Dallman, 2005), contribute to termination of the stress response. Specifically, local administration of a CB1 receptor antagonist into the PVN impairs glucocorticoid-mediated rapid feedback inhibition of the HPA axis (Evanson et al., 2010), while blockade of CB1 receptors within the mPFC impairs normative recovery of the HPA axis following cessation of stress (Hill et al., 2011b). These findings are consistent with the ability of glucocorticoids to elevate 2-AG content (Atsak et al., 2012; Di et al., 2005; Hill et al, 2010a, 2011b) and suggest that 2-AG signaling is a necessary component of glucocorticoid-mediated negative feedback in the brain. With respect to anxiety, elevating 2-AG signaling through the inhibition of MAGL has been shown to limit the induction of anxiety induced by stressful, aversive environmental stimuli (Aliczki et al, 2012, 2013; Busquets-Garcia et al., 2011; Sciolino et al., 2011; Bedse et al., 2017, 2018). As stress increases 2-AG signaling, these data would suggest that the mobilization of 2-AG also acts to buffer against stress-induced anxiety and that augmentation of this signal through the inhibition of MAGL potentiates this effect. Given that stress causes a loss of tonic AEA signaling, one potential model to explain these data is that the elevations in 2-AG signaling in response to stress act to compensate for the loss of AEA signaling and provide a means of maintaining CB1 receptor signaling and preventing the induction of anxiety (Bedse et al., 2017). Inhibition of MAGL promotes 2-AG signaling and thus amplifies the ability of endogenous 2-AG to compensate for the loss of AEA, while inhibition of DAGL to deplete 2-AG and prevent this compensation results in and further exacerbation of anxiety (Bedse et al., 2017; Bluett et al., 2017). Collectively, these data present a complex picture of how eCB signaling regulates the stress response. Exposure to stress results in a rapid induction of CRF signaling, which triggers FAAH activity and depletes tonic AEA signaling. This loss of AEA/CB1 receptor signaling

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contributes to the activation of the stress response, which then promotes the release of glucocorticoid hormones. Once glucocorticoids enter the brain, they enhance 2-AG signaling, which then compensates for the loss of AEA signaling at CB1 receptors and acts to dampen neuronal activation in stress-responsive circuits, such as the BLA, mPFC, and PVN, which then facilitates termination of the stress response. For a more in-depth discussion regarding how eCB signaling regulates acute stress-induced activation of the HPA axis and behavioral changes produced by stress, please refer to Hill and Tasker (2012) and Morena et al. (2016).

Endocannabinoid signaling in the context of susceptibility and resilience to repeated stress Acute stress has proven to be a useful model to understand the mechanisms and dynamics by which eCB signaling can modulate stress-related outcomes, but with respect to disease, outside of exposure to extreme, traumatic stress (such as the case is for posttraumatic stress disorder; PTSD), the relationship of stress to pathology typically occurs in the context of repeated or chronic stress (McEwen and Gianaros, 2011). Here, individual differences in the magnitude and nature of responses to repeated stress tend to associate with susceptibility to the development stress-related psychiatric illnesses, such as mood and anxiety disorders, or resilience to the onset of these disease states (McEwen and Gianaros, 2011; Karatsoreos and McEwen, 2011). Clearly, understanding the neural mechanisms subserving susceptibility or resilience to stress are paramount to targeting novel approaches to the treatment of stressrelated psychiatric illnesses. At a most basic level, one perspective on susceptibility and resilience is that a failure to engage in typical, adaptive responses to repeated/chronic stress enhances susceptibility of an organism to the adverse effects of stress. A clear example of this is an inability of the HPA axis to appropriately adapt to repeated stress and how excess activation of this axis, and persistent secretion of glucocorticoid hormones, can result in biological changes that relate to the development of mood and anxiety disorders (McEwen and Gianaros, 2011; Karatsoreos and McEwen, 2011). As the study of susceptibility and resilience has increased in recent years (Russo et al., 2012), another perspective has developed, which suggests that the development of resilience to stress relates to individual differences in the engagement of active neurobiological processes that favor resilience by constraining the adverse effects of stress (Russo et al., 2012). Although the current state of the literature exploring the role of eCB signaling in stress resilience is relatively sparse, several key findings do support a potentially important role of eCB signaling in this process. The importance of eCB signaling in mitigating the adverse effects of chronic stress exposure has been well described. As mentioned, adaptation of the HPA axis to repeated stress (a process referred to as “stress habituation”; Grissom and Bhatnagar, 2009) is considered a beneficial response as it limits the exposure of an organism to persistently elevated levels of this catabolic hormone, which is known to promote structural and metabolic alterations in the brain (Karatsoreos and McEwen, 2011). The role of eCB signaling in the process of stress adaptation has been well established. First off, mice lacking CB1 receptors have been found to exhibit impaired habituation of behavioral responses to repeated exposure to audiogenic stress (Fride et al., 2005). Similarly, the impacts of chronic stress on various end points

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of emotional behavior related to anxiety or reward sensitivity have all been shown to be exacerbated in mice lacking CB1 receptors (Hill et al., 2011a; Martin et al., 2002; Dubreucq et al., 2012). Given the potential confounds associated with global and germline deletion of the CB1 receptor, it is important to highlight pharmacological studies that have more convincingly demonstrated the importance of eCB signaling to stress adaptation and habituation. Acute pharmacological blockade of CB1 receptors in animals that have been repeatedly exposed to stressors has found what is best described as a “dishabituation” of the stress response. First demonstrated by Patel et al. (2005), animals repeatedly exposed to restraint stress exhibit habituation of both stress-induced behavioral struggling and the induction of the activity-dependent early immediate gene c-fos throughout stress regulatory brain regions. Administration of a CB1 receptor antagonist immediately before exposure to the final stressor resulted in a reversal of habituation characterized by elevations in struggling behavior and c-fos induction comparable with that seen under acute, novel conditions. These data would indicate that, in a stress-dependent manner, 2-AG levels progressively increase in the brain to reduce neuronal activation in stress-responsive circuits and promote habituation of the neurobehavioral responses to stress. Consistent with this, additional work from Hill et al. (2010b) focused on the amygdala specifically and found that repeated stress produced a robust and transient increase in 2-AG content within the amygdala and that local blockade of CB1 receptors just within the BLA itself was sufficient to reverse habituation of the HPA axis. These data have led to the hypothetical model that eCB signaling is essential for stress adaptation and that the active recruitment of 2-AG signaling during repeated stress dampens neural circuits activated by stress, thereby resulting in a system-level habituation to stress (Hill et al., 2010b; Patel and Hillard, 2008). Given the importance of 2-AG signaling during repeated stress to promote normative stress adaptation, it is logical to assume that eCB signaling in turn would relate to the development of resilience. The first evidence to functionally demonstrate this came from a study performed by Bluett et al. (2017). In this study, mice were repeatedly exposed to footshock stress and segregated based on their response to develop anxiety in response to shock (susceptible) or show no changes in anxiety-like behavior, following shock relative to their baseline behavior (resilient). This effect was stable and replicable and maintained after multiple exposures to stress. Pharmacological blockade of CB1 receptors elevated anxiety under basal conditions and amplified stress-induced anxiety in this model similar as to what has been found in previous reports. Importantly, when looking at the proportion of animals that would be categorized as “susceptible” or “resilient” after exposure to repeated stress, depletion of 2-AG through pharmacological disruption of DAGL activity roughly tripled the percentage of animals that were “susceptible,” resulting in a significant reduction in the proportion of animals that were “resilient”. In line with this, and with the previous work highlighting the BLA as an important nexus for the stress-inhibitory role of 2-AG signaling, genetic deletion of DAGL exclusively within the BLA similarly resulted in an approximate 50% reduction in the proportion of animals that were classified as “resilient” following repeated stress. Taken together, these data all support a model by which the progressive recruitment of 2-AG signaling in response to repeated stress is required for the development of stress resilience.

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In parallel to these studies, pharmacological augmentation of 2-AG signaling has similarly been found to promote the development of stress resilience. Further work from Bluett et al. (2017) found that while depleting 2-AG favored the development of susceptibility to stress, elevating 2-AG signaling through the blockade of MAGL elevated the proportion of animals that were “resilient” following exposure to repeated stress. In fact, following treatment with an MAGL inhibitor, it was found that less than 10% of animals were classified as “susceptible” following repeated stress exposure, as opposed to the 25%e35% that were typically found to be “susceptible.” Building off of these findings, further work found that these changes in resilience and susceptibility related to eCB-mediated regulation of synaptic transmission within the BLA. Specifically, animals that were found to be resilient after stress were also found to have relatively enhanced eCB-mediated retrograde inhibition BLA glutamatergic synaptic transmission than mice that were susceptible to stress. The administration of an MAGL inhibitor was found to reduce glutamatergic transmission in the BLA in both resilient and susceptible animals, indicating that pharmacological interventions that elevated 2-AG were sufficient to reduce excitatory synaptic transmission in the BLA, which is consistent with the ability of MAGL inhibition to promote stress resilience. Further circuit-based work using optogenetics demonstrated that the difference between resilient and susceptible animals could be linked to differences in the ability of 2-AG signaling to regulate excitatory input to the BLA from the ventral hippocampus. As such, this work indicates that in responses to repeated stress exposure, animals that recruit 2-AG signaling within the BLA in response to repeated stress, and thus exhibit a greater dynamic range in their ability to regulate afferent excitatory input to the BLA, are those which exhibit stress resilience, while those that do not mount this 2-AG responses favor the development of stress susceptibility. In line with these findings, similar work from Bosch-Bouju et al. (2016) also found that following exposure to repeated stress, animals could be categorized as resilient or susceptible based on their development of anxiety. Again, the development of resilience was related to changes in synaptic function, albeit in this study, the focus was on the nucleus accumbens where spike timingedependent plasticity was abolished in animals that developed susceptibility. Consistent with the findings described above, administration of an MAGL inhibitor favored the development of resilience over susceptibility in tandem with its ability to normalize eCB-mediated plasticity changes. Although these findings do implicate additional brain regions beyond the BLA, it is striking to note the parallels in the data set and the consistency between these studies in the ability of MAGL inhibition and the elevation of 2-AG signaling to promote resilience in the face of repeated stress. All of the discussion on resilience to this point has focused on 2-AG, as this is where most of the data are found. It is important to note, however, that inhibition of FAAH and elevations in AEA signaling have also been found to counter the effects of chronic stress on a multitude of end points including reward sensitivity, anxiety, and both synaptic and structural plasticity (Hill et al., 2013b; Rossi et al., 2010; Lomazzo et al., 2015; Griebel et al., 2018; Danandeh et al., 2018). While FAAH inhibition has never been examined in explicit studies looking at the development of stress susceptibility or resilience, based on what we know about eCB signaling, and the ability of elevated AEA signaling to counter the effects of impaired 2-AG signaling, it seems plausible to hypothesize that elevating AEA signaling may also favor stress resilience. Further work is required to determine the role of AEA signaling in the development of stress susceptibility versus resilience.

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Conclusions

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Endocannabinoid Activity

This chapter reviewed the data regarding what is known about interactions between stress and the eCB system and how eCB signaling could influence the development of stress resilience after exposure to repeated stress. The model that can be generated from the current state of the science would suggest that stress resilience is driven, at least in part, by a progressive recruitment of 2-AG signaling that regulates synaptic activity and plasticity in key stressresponsive circuits, such as the BLA and nucleus accumbens. A failure to elevate eCB signaling, or in the case of AEA, a progressive loss of eCB signaling, in response to repeated stress exposure may limit appropriate buffer mechanisms in the brain to constrain the effects of stress and result in the development of stress susceptibility (see Fig. 22.1 for model). In line with this, there is also evidence that chronic stress compromises CB1 receptor expression and function (Hill et al., 2005; Wang et al., 2010; Zhong et al., 2014; Wamsteeker et al., 2010; Wamsteeker Cusulin et al., 2014), suggesting that a failure of CB1 receptors to maintain signaling capacity in the face of stress could also be a mechanism relating to susceptibility. Additional work is required to understand the role of CB1 receptor regulation in relation to outcomes from stress relating to pathology or resilience. While still in early days, there is some support from the human literature for this model. Specifically, chronic isolation stress exposure associated with reduced 2-AG levels in the circulation was found to correlate with reduced positive mood and elevated catecholamine levels (Yi et al., 2016). More so, stress-related psychiatric illnesses, such as major depression and PTSD, have been found to be associated with reduced eCB levels (Hill et al., 2008c, 2009b; 2013a; Neumeister et al., 2013). Based on these data, we predict that pharmacological approaches that augment eCB signaling may represent a novel approach to sculpt stress resilience. With the development, and initial human validation, of both FAAH (D’Souza et al., 2019) and MAGL (Cisar et al., 2018) inhibitors, we are hopeful that the potential utility of these compounds will be explored in the near future and their putative application in the context of stress-related psychiatry illnesses will be examined.

FIGURE 22.1 Repeated exposure to stress results in a progressive recruitment of endocannabinoid signaling (particularly 2-arachidonoylglycerol signaling), which in turn promotes synaptic plasticity and modifies synaptic transmission in key brain regions, such as the amygdala and nucleus accumbens, to promote stress resilience. A failure to elevate endocannabinoid (eCB) signaling, or a progressive loss of eCB signaling (as has been seen with anandamide), in response to repeated stress exposure may limit appropriate buffer mechanisms in the brain to constrain the effects of stress and result in the development of susceptibility to stress-related psychiatric disorders.

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References Ahn, K., McKinney, M.K., Cravatt, B.F., 2008. Enzymatic pathways that regulate endocannabinoid signaling in the nervous system. Chemical Reviews 108 (5), 1687e1707. Aliczki, M., Balogh, Z., Tulogdi, A., Haller, J., 2012. The temporal dynamics of the effects of monoacylglycerol lipase blockade on locomotion, anxiety, and body temperature. Behavioural Pharmacology 23 (4), 348e357. Aliczki, M., Zelena, D., Mikics, E., Varga, Z.K., Pinter, O., Bakos, N.V., et al., 2013. Monoacylglycerol lipase inhibitioninduced changes in plasma corticosterone levels, anxiety and locomotor activity in male CD1 mice. Hormones and Behavior 63 (5), 752e758. Atsak, P., Hauer, D., Campolongo, P., Schelling, G., McGaugh, J.L., Roozendaal, B., 2012. Glucocorticoids interact with the hippocampal endocannabinoid system in impairing retrieval of contextual fear memory. Proceedings of the National Academy of Sciences of the United States of America 109 (9), 3504e3509. Atwood, B.K., Mackie, K., 2010. CB2: a cannabinoid receptor with an identity crisis. British Journal of Pharmacology 160 (3), 467e479. Bedse, G., Colangeli, R., Lavecchia, A.M., Romano, A., Altieri, F., Cifani, C., et al., 2014. Role of the basolateral amygdala in mediating the effects of the fatty acid amide hydrolase inhibitor URB597 on HPA axis response to stress. European Neuropsychopharmacology 24 (9), 1511e1523. Bedse, G., Hartley, N.D., Neale, E., Gaulden, A.D., Patrick, T.A., Kingsley, P.J., et al., 2017. Functional redundancy between canonical endocannabinoid signaling systems in the modulation of anxiety. Biological Psychiatry 82 (7), 488e499. Bedse, G., Bluett, R.J., Patrick, T.A., Romness, N.K., Gaulden, A.D., Kingsley, P.J., et al., 2018. Therapeutic endocannabinoid augmentation for mood and anxiety disorders: comparative profiling of FAAH, MAGL and dual inhibitors. Translational Psychiatry 8 (1), 92. Blankman, J.L., Simon, G.M., Cravatt, B.F., 2007. A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol. Chemical Biology 14 (12), 1347e1356. Bluett, R.J., Gamble-George, J.C., Hermanson, D.J., Hartley, N.D., Marnett, L.J., Patel, S., 2014. Central anandamide deficiency predicts stress-induced anxiety: behavioral reversal through endocannabinoid augmentation. Translational Psychiatry 4, e408. Bluett, R.J., Baldi, R., Haymer, A., Gaulden, A.D., Hartley, N.D., Parrish, W.P., et al., 2017. Endocannabinoid signaling modulates susceptibility to traumatic stress exposure. Nature Communications 8, 14782. Bosch-Bouju, C., Larrieu, T., Linders, L., Manzoni, O.J., Laye, S., 2016. Endocannabinoid mediated plasticity in nucleus accumbens controls vulnerability to anxiety after social defeat stress. Cell Reports 16 (5), 1237e1242. Bowles, N.P., Hill, M.N., Bhagat, S.M., Karatsoreos, I.N., Hillard, C.J., McEwen, B.S., 2012. Chronic, noninvasive glucocorticoid administration suppresses limbic endocannabinoid signaling in mice. Neuroscience 204, 83e89. Busquets-Garcia, A., Puighermanal, E., Pastor, A., de la Torre, R., Maldonado, R., Ozaita, A., 2011. Differential role of anandamide and 2-arachidonoylglycerol in memory and anxiety-like responses. Biological Psychiatry 70 (5), 479e486. Campos, A.C., Ferreira, F.R., Guimaraes, F.S., Lemos, J.I., 2010. Facilitation of endocannabinoid effects in the ventral hippocampus modulates anxiety-like behaviors depending on previous stress experience. Neuroscience 167 (2), 238e246. Carnevali, L., Vacondio, F., Rossi, S., Macchi, E., Spadoni, G., Bedini, A., et al., 2015. Cardioprotective effects of fatty acid amide hydrolase inhibitor URB694 in a rodent model of trait anxiety. Scientific Reports 5, 18218. Cisar, J.S., Weber, O.D., Clapper, J.R., Blankman, J.L., Henry, C.L., Simon, G.M., et al., 2018. Identification of ABX-1431, a selective inhibitor of monoacylglycerol lipase and clinical condition for treatment of neurological disorders. Journal of Medicinal Chemistry 61 (20), 9062e9084. Cravatt, B.F., Demarest, K., Patricelli, M.P., Bracey, M.H., Giang, D.K., Martin, B.R., et al., 2001. Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase. Proceedings of the National Academy of Sciences of the United States of America 98 (16), 9371e9376. D’Souza, D.C., Cortes-Briones, J., Creatura, G., Bluez, G., Thurnauer, H., Deaso, E., et al., 2019. Efficacy and safety of a fatty acid amide hydrolase inhibitor (PF-04457845) in the treatment of cannabis withdrawal and dependence in men: a double blind, placebo-controlled, parallel group, phase 2a single-site randomised controlled trial. Lancet Psychiatry 6 (1), 35e45. Dallman, M.F., 2005. Adrenocortical function, feedback, and alphabet soup. American Journal of Physiology. Endocrinology and Metabolism 289 (3), E361eE362.

References

359

Danandeh, A., Vozella, V., Lim, J., Oveisi, F., Ramirez, G.L., Mears, D., et al., 2018. Effects of fatty acid amide hydrolase inhibitor URB597 in a rat model of trauma-induced long-term anxiety. Psychopharmacology 235 (11), 3211e3221. Devane, W.A., Hanus, L., Breuer, A., Pertwee, R.G., Stevenson, L.A., Griffin, G., et al., 1992. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258 (5090), 1946e1949. Di, S., Malcher-Lopes, R., Marcheselli, V.L., Bazan, N.G., Tasker, J.G., 2005. Rapid glucocorticoid-mediated endocannabinoid release and opposing regulation of glutamate and gamma-aminobutyric acid inputs to hypothalamic magnocellular neurons. Endocrinology 146 (10), 4292e4301. Dincheva, I., Drysdale, A.T., Hartley, C.A., Johnson, D.C., Jing, D., King, E.C., et al., 2015. FAAH genetic variation enhances fronto-amygdala function in mouse and human. Nature Communications 6, 6395. Dinh, T.P., Carpenter, D., Leslie, F.M., Freund, T.F., Katona, I., Sensi, S.L., et al., 2002. Brain monoglyceride lipase participating in endocannabinoid inactivation. Proceedings of the National Academy of Sciences of the United States of America 99 (16), 10819e10824. Dubreucq, S., Matias, I., Cardinal, P., Haring, M., Lutz, B., Marsicano, G., et al., 2012. Genetic dissection of the role of cannabinoid type-1 receptors in the emotional consequences of repeated social stress in mice. Neuropsychopharmacology 37 (8), 1885e1900. Evanson, N.K., Tasker, J.G., Hill, M.N., Hillard, C.J., Herman, J.P., 2010. Fast feedback inhibition of the HPA axis by glucocorticoids is mediated by endocannabinoid signaling. Endocrinology 151 (10), 4811e4819. Fidelman, S., Mizrachi Zer-Aviv, T., Lange, R., Hillard, C.J., Akirav, I., 2018. Chronic treatment with URB597 ameliorates post-stress symptoms in a rat model of PTSD. European Neuropsychopharmacology 28 (5), 63e642. Fride, E., Suris, R., Weidenfeld, J., Mechoulam, R., 2005. Differential response to acute and repeated stress in cannabinoid CB1 receptor knockout newborn and adult mice. Behavioural Pharmacology 16 (5e6), 431e440. Gray, J.M., Vecchiarelli, H.A., Morena, M., Lee, T.T., Hermanson, D.J., Kim, A.B., et al., 2015. Corticotropin-releasing hormone drives anandamide hydrolysis in the amygdala to promote anxiety. Journal of Neuroscience 35 (9), 3879e3892. Gray, J.M., Wilson, C.D., Lee, T.T., Pittman, Q.J., Deussing, J.M., Hillard, C.J., et al., 2016. Sustained glucocorticoid exposure recruits cortico-limbic CRH signaling to modulate endocannabinoid function. Psychoneuroendocrinology 66, 151e158. Griebel, G., Stemmelin, J., Lopez-Grancha, M., Fauchey, V., Slowinski, F., Pichat, P., et al., 2018. The selective reversible FAAH inhibitor SSR411298, restores the development of maladaptive behaviors to acute and chronic stress in rodents. Scientific Reports 8 (1), 2416. Grissom, N., Bhatnagar, S., 2009. Habituation to repeated stress: get used to it. Neurobiology of Learning and Memory 92 (2), 215e224. Gulyas, A.I., Cravatt, B.F., Bracey, M.H., Dinh, T.P., Piomelli, D., Boscia, F., et al., 2004. Segregation of two endocannabinoid-hydrolyzing enzymes into pre- and postsynaptic compartments in the rat hippocampus, cerebellum and amygdala. European Journal of Neuroscience 20 (2), 441e458. Gunduz-Cinar, O., Hill, M.N., McEwen, B.S., Holmes, A., 2013. Amygdala FAAH and anandamide: mediating protection and recovery from stress. Trends in Pharmacological Sciences 34 (11), 637e644. Haller, J., Barna, I., Barsvari, B., Gyimesi Pelczer, K., Yasar, S., Panlilio, L.V., et al., 2009. Interactions between environmental aversiveness and the anxiolytic effects of enhanced cannabinoid signaling by FAAH inhibition in rats. Psychopharmacology (Berl) 204 (4), 607e616. Herkenham, M., Lynn, A.B., Johnson, M.R., Melvin, L.S., de Costa, B.R., Rice, K.C., 1991. Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study. Journal of Neuroscience 11 (2), 563e583. Hermanson, D.J., Hartley, N.D., Gamble-George, J., Brown, N., Shonesy, B.C., Kingsley, P.J., et al., 2013. Substrateselective COX-2 inhibition decreases anxiety via endocannabinoid activation. Nature Neuroscience 16 (9), 1291e1298. Hill, M.N., Bierer, L.M., Makotkine, I., Golier, J.A., Galea, S., McEwen, B.S., et al., 2013a. Reductions in circulating endocannabinoid levels in individuals with post-traumatic stress disorder following exposure to the world trade center attacks. Psychoneuroendocrinology 38 (12), 2952e2961. Hill, M.N., Carrier, E.J., Ho, W.S., Shi, L., Patel, S., Gorzalka, B.B., et al., 2008a. Prolonged glucocorticoid treatment decreases cannabinoid CB1 receptor density in the hippocampus. Hippocampus 18 (2), 221e226. Hill, M.N., Carrier, E.J., McLaughlin, R.J., Morrish, A.C., Meier, S.E., Hillard, C.J., et al., 2008b. Regional alterations in the endocannabinoid system in an animal model of depression: effects of concurrent antidepressant treatment. Journal of Neurochemistry 106 (6), 2322e2336.

360

22. Endocannabinoid signaling and stress resilience

Hill, M.N., Hillard, C.J., McEwen, B.S., 2011a. Alterations in corticolimbic dendritic morphology and emotional behavior in cannabinoid CB1 receptor-deficient mice parallel the effects of chronic stress. Cerebral Cortex 21 (9), 2056e2064. Hill, M.N., Karatsoreos, I.N., Hillard, C.J., McEwen, B.S., 2010a. Rapid elevations in limbic endocannabinoid content by glucocorticoid hormones in vivo. Psychoneuroendocrinology 35 (9), 1333e1338. Hill, M.N., Kumar, S.A., Filipski, S.B., Iverson, M., Stuhr, K.L., Keith, J.M., et al., 2013b. Disruption of fatty acid amide hydrolase activity prevents the effects of chronic stress on anxiety and amygdalar microstructure. Molecular Psychiatry 18 (10), 1125e1135. Hill, M.N., McLaughlin, R.J., Bingham, B., Shrestha, L., Lee, T.T., Gray, J.M., et al., 2010b. Endogenous cannabinoid signaling is essential for stress adaptation. Proceedings of the National Academy of Sciences of the United States of America 107 (20), 9406e9411. Hill, M.N., McLaughlin, R.J., Morrish, A.C., Viau, V., Floresco, S.B., Hillard, C.J., et al., 2009a. Suppression of amygdalar endocannabinoid signaling by stress contributes to activation of the hypothalamic-pituitary-adrenal axis. Neuropsychopharmacology 34 (13), 2733e2745. Hill, M.N., McLaughlin, R.J., Pan, B., Fitzgerald, M.L., Roberts, C.J., Lee, T.T., et al., 2011b. Recruitment of prefrontal cortical endocannabinoid signaling by glucocorticoids contributes to termination of the stress response. Journal of Neuroscience 31 (29), 10506e10515. Hill, M.N., Miller, G.E., Carrier, E.J., Gorzalka, B.B., Hillard, C.J., 2009b. Circulating endocannabinoids and N-acyl ethanolamines are differentially regulated in major depression and following exposure to social stress. Psychoneuroendocrinology 34 (8), 1257e1262. Hill, M.N., Miller, G.E., Ho, W.S., Gorzalka, B.B., Hillard, C.J., 2008c. Serum endocannabinoid content is altered in females with depressive disorders: a preliminary report. Pharmacopsychiatry 41 (2), 48e53. Hill, M.N., Patel, S., Carrier, E.J., Rademacher, D.J., Ormerod, B.K., Hillard, C.J., et al., 2005. Downregulation of endocannabinoid signaling in the hippocampus following chronic unpredictable stress. Neuropsychopharmacology 30 (3), 508e515. Hill, M.N., Tasker, J.G., 2012. Endocannabinoid signaling, glucocorticoid-mediated negative feedback, and regulation of the hypothalamic-pituitary-adrenal axis. Neuroscience 204, 5e16. Hillard, C.J., Edgemond, W.S., Jarrahian, A., Campbell, W.B., 1997. Accumulation of N-arachidonoylethanolamine (anandamide) into cerebellar granule cells occurs via facilitated diffusion. Journal of Neurochemistry 69 (2), 631e638. Howlett, A.C., Barth, F., Bonner, T.I., Cabral, G., Casellas, P., Devane, W.A., et al., 2002. International union of pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacological Reviews 54 (2), 161e202. Karatsoreos, I.N., McEwen, B.S., 2011. Psychobiological allostasis: resistance, resilience and vulnerability. Trends in Cognitive Sciences 15 (12), 576e584. Kathuria, S., Gaetani, S., Fegley, D., Valino, F., Duranti, A., Tontini, A., et al., 2003. Modulation of anxiety through blockade of anandamide hydrolysis. Nature Medicine 9 (1), 76e81. Katona, I., Freund, T.F., 2012. Multiple functions of endocannabinoid signaling in the brain. Annual Review of Neuroscience 35, 529e558. Lomazzo, E., Bindila, L., Remmers, F., Lerner, R., Schwitter, C., Hoheisel, U., et al., 2015. Therapeutic potential of inhibitors of endocannabinoid degradation for the treatment of stress-related hyperalgesia in an animal model of chronic pain. Neuropsychopharmacology 40 (2), 488e501. Long, J.Z., Nomura, D.K., Cravatt, B.F., 2009. Characterization of monoacylglycerol lipase inhibition reveals differences in central and peripheral endocannabinoid metabolism. Chemical Biology 16 (7), 744e753. Marco, E.M., Viveros, M.P., 2009. The critical role of the endocannabinoid system in emotional homeostasis: avoiding excess and deficiencies. Mini Reviews in Medicinal Chemistry 9 (12), 1407e1415. Marrs, W.R., Blankman, J.L., Horne, E.A., Thomazeau, A., Lin, Y.H., Coy, J., et al., 2010. The serine hydrolase ABHD6 controls the accumulation and efficacy of 2-AG at cannabinoid receptors. Nature Neuroscience 13 (8), 951e957. Martin, M., Ledent, C., Parmentier, M., Maldonado, R., Valverde, O., 2002. Involvement of CB1 cannabinoid receptors in emotional behaviour. Psychopharmacology (Berl) 159 (4), 379e387. Matsuda, L.A., Lolait, S.J., Brownstein, M.J., Young, A.C., Bonner, T.I., 1990. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346 (6284), 561e564. McEwen, B.S., Gianaros, P.J., 2011. Stress- and allostasis-induced brain plasticity. Annual Review of Medicine 62, 431e445.

References

361

McLaughlin, R.J., Hill, M.N., Bambico, F.R., Stuhr, K.L., Gobbi, G., Hillard, C.J., et al., 2012. Prefrontal cortical anandamide signaling coordinates coping responses to stress through a serotonergic pathway. European Neuropsychopharmacology 22 (9), 664e671. McPartland, J.M., Glass, M., Pertwee, R.G., 2007. Meta-analysis of cannabinoid ligand binding affinity and receptor distribution: interspecies differences. British Journal of Pharmacology 152 (5), 583e593. Mechoulam, R., Parker, L.A., 2013. The endocannabinoid system and the brain. Annual Review of Psychology 64, 21e47. Metna-Laurent, M., Marsicano, G., 2015. Rising stars: modulation of brain functions by astroglial type 1 cannabinoid receptors. Glia 63 (3), 353e364. Morena, M., Patel, S., Bains, J.S., Hill, M.N., 2016. Neurobiological interactions between stress and the endocannabinoid system. Neuropsychopharmacology 41 (1), 80e102. Morgan, A.J., Kingsley, P.J., Mitchener, M.M., Altemus, M., Patrick, T.A., Gaulden, A.D., et al., 2018. Detection of cyclo-oxygenase-2 derived oxygenation products of the endogenous cannabinoid 2-arachidonoylglycerol in mouse brain. ACS Chemical Neuroscience 9 (7), 1552e1559. Naidu, P.S., Varvel, S.A., Ahn, K., Cravatt, B.F., Martin, B.R., Lichtman, A.H., 2007. Evaluation of fatty acid amide hydrolase inhibition in murine models of emotionality. Psychopharmacology (Berl) 192 (1), 61e70. Natividad, L.A., Buczynski, M.W., Herman, M.A., Kirson, D., Oleata, C.S., Irimia, C., et al., 2017. Constitutive increases in amygdalar corticotrophin-releasing factor and fatty acid amide hydrolase drive an anxious phenotype. Biological Psychiatry 82 (7), 500e510. Navarette, M., Diez, A., Araque, A., 2014. Astrocytes in endocannabinoid signaling. Philosophical Transactions of the Royal Society of London B Biological Sciences 369 (1654), 20130599. Neumeister, A., Normandin, M.D., Pietrzak, R.H., Piomelli, D., Zheng, M.Q., Gujarro-Anton, A., Potenza, M.N., Bailey, C.R., Lin, S.F., Najafzadeh, S., Ropchan, J., Henry, S., Corsi-Travali, S., Carson, R.E., Huang, Y., 2013. Elevated brain cannabinoid CB1 receptor availability in post-traumatic stress disorder: a positron emission tomography study. Mol Psychiatry 18 (9), 1034e1040. Newsom, R.J., Osterlund, C., Masini, C.V., Day, H.E., Spencer, R.L., Campeau, S., 2012. Cannabinoid receptor type 1 antagonism significantly modulates basal and loud noise induced neural and hypothalamic-pituitary-adrenal axis responses in male Sprague-Dawley rats. Neuroscience 204, 64e73. Patel, S., Hillard, C.J., 2008. Adaptations in endocannabinoid signaling in response to repeated homotypic stress: a novel mechanism for stress habituation. European Journal of Neuroscience 27 (11), 2821e2829. Patel, S., Kingsley, P.J., Mackie, K., Marnett, L.J., Winder, D.G., 2009. Repeated homotypic stress elevates 2-arachidonoylglycerol levels and enhances short-term endocannabinoid signaling at inhibitory synapses in basolateral amygdala. Neuropsychopharmacology 34 (13), 2699e2709. Patel, S., Roelke, C.T., Rademacher, D.J., Cullinan, W.E., Hillard, C.J., 2004. Endocannabinoid signaling negatively modulates stress-induced activation of the hypothalamic-pituitary-adrenal axis. Endocrinology 145 (12), 5431e5438. Patel, S., Roelke, C.T., Rademacher, D.J., Hillard, C.J., 2005. Inhibition of restraint stress-induced neural and behavioural activation by endogenous cannabinoid signalling. European Journal of Neuroscience 21 (4), 1057e1069. Pertwee, R.G., 2005. Pharmacological actions of cannabinoids. Handbook of Experimental Pharmacology 168, 1e51. Qin, Z., Zhou, X., Pandey, N.R., Vecchiarelli, H.A., Stewart, C.A., Zhang, X., et al., 2015. Chronic stress induces anxiety via an amygdalar intracellular cascade that impairs endocannabinoid signaling. Neuron 85 (6), 1319e1331. Rademacher, D.J., Meier, S.E., Shi, L., Ho, W.S., Jarrahian, A., Hillard, C.J., 2008. Effects of acute and repeated restraint stress on endocannabinoid content in the amygdala, ventral striatum, and medial prefrontal cortex in mice. Neuropharmacology 54 (1), 108e116. Ramikie, T.S., Nyilas, R., Bluett, R.J., Gamble-George, J.C., Hartley, N.D., Mackie, K., et al., 2014. Multiple mechanistically distinct modes of endocannabinoid mobilization at central amygdala glutamatergic synapses. Neuron 81 (5), 1111e1125. Ramikie, T.S., Patel, S., 2012. Endocannabinoid signaling in the amygdala: anatomy, synaptic signaling, behavior, and adaptations to stress. Neuroscience 204, 38e52. Roberts, C.J., Stuhr, K.L., Hutz, M.J., Raff, H., Hillard, C.J., 2014. Endocannabinoid signaling in hypothalamicpituitary-adrenocortical axis recovery following stress: effects of indirect agonists and comparison of male and female mice. Pharmacology Biochemistry and Behavior 117, 17e24.

362

22. Endocannabinoid signaling and stress resilience

Rossi, S., De Chiara, V., Musella, A., Sacchetti, L., Cantarella, C., Castelli, M., et al., 2010. Preservation of striatal cannabinoid CB1 receptor function correlates with the antianxiety effects of fatty acid amide hydrolase inhibition. Molecular Pharmacology 78 (2), 260e268. Rubino, T., Realini, N., Castiglioni, C., Guidali, C., Vigano, D., Marras, E., et al., 2008. Role in anxiety behavior of the endocannabinoid system in the prefrontal cortex. Cerebral Cortex 18 (6), 1292e1301. Russo, S.J., Murrough, J.W., Han, M.H., Charney, D.S., Nestler, E.J., 2012. Neurobiology of resilience. Nature Neuroscience 15 (11), 1475e1484. Sciolino, N.R., Zhou, W., Hohmann, A.G., 2011. Enhancement of endocannabinoid signaling with JZL184, an inhibitor of the 2-arachidonoylglycerol hydrolyzing enzyme monoacylglycerol lipase, produces anxiolytic effects under conditions of high environmental aversiveness in rats. Pharmacological Research 64 (3), 226e234. Sugiura, T., Kondo, S., Sukagawa, A., Nakane, S., Shinoda, A., Itoh, K., et al., 1995. 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochemical and Biophysical Research Communications 215 (1), 89e97. Sumislawski, J.J., Ramikie, T.S., Patel, S., 2011. Reversible gating of endocannabinoid plasticity in the amygdala by chronic stress: a potential role for monoacylglycerol lipase inhibition in the prevention of stress-induced behavioral adaptation. Neuropsychopharmacology 36 (13), 2750e2761. Surkin, P.N., Gallino, S.L., Luce, V., Correa, F., Fernandez-Solari, J., De Laurentiis, A., 2018. Pharmacological augmentation of endocannabinoid signaling reduces the neuroendocrine response to stress. Psychoneuroendocrinology 87, 131e140. Van Sickle, M.D., Duncan, M., Kingsley, P.J., Mouihate, A., Urbani, P., Mackie, K., et al., 2005. Identification and functional characterization of brainstem cannabinoid CB2 receptors. Science 310 (5746), 329e332. Wamsteeker, J.I., Kuzmiski, J.B., Bains, J.S., 2010. Repeated stress impairs endocannabinoid signaling in the paraventricular nucleus of the hypothalamus. Journal of Neuroscience 30 (33), 11188e11196. Wamsteeker Cusulin, J.I., Senst, L., Teskey, G.C., Bains, J.S., 2014. Experience salience gates endocannabinoid signaling at hypothalamic synapses. Journal of Neuroscience 34 (18), 6177e6181. Wang, M., Hill, M.N., Zhang, L., Gorzalka, B.B., Hillard, C.J., Alger, B.E., 2012. Acute restraint stress enhances hippocampal endocannabinoid function via glucocorticoid receptor activation. Journal of Psychopharmacology 26 (1), 56e70. Wang, W., Sun, D., Pan, B., Roberts, C.J., Sun, X., Hillard, C.J., et al., 2010. Deficiency in endocannabinoid signaling in the nucleus accumbens induced by chronic unpredictable stress. Neuropsychopharmacology 35 (11), 2249e2261. Yi, B., Nichoporuk, I., Nicolas, M., Schneider, S., Feuerecker, M., Vassilieva, G., et al., 2016. Reductions in circulating endocannabinoid 2-arachidonoyly glycerol levels in healthy humans subjects exposed to chronic stressors. Progress In Neuro-Psychopharmacology and Biological Psychiatry 67, 92e97. Zhong, P., Wang, W., Pan, B., Liu, X., Zhang, Z., Long, J.Z., et al., 2014. Monoacylglycerol lipase inhibition blocks chronic stress-induced depressive-like behaviors via activation of mTOR signaling. Neuropsychopharmacology 39 (7), 1763e1776.