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. Author manuscript; available in PMC: 2013 Mar 1.
Published in final edited form as: Neuroscience. 2011 Dec 24;204:5–16. doi: 10.1016/j.neuroscience.2011.12.030

Endocannabinoid Signaling, Glucocorticoid-Mediated Negative Feedback and Regulation of the HPA Axis

M N Hill 1,2,3,*, J G Tasker 4
PMCID: PMC3288468  NIHMSID: NIHMS351601  PMID: 22214537

Abstract

The hypothalamic-pituitary-adrenal (HPA) axis regulates the outflow of glucocorticoid hormones under basal conditions and in response to stress. Within the last decade, a large body of evidence has mounted indicating that the endocannabinoid system is involved in the central regulation of the stress response; however, the specific role endocannabinoid signalling plays in phases of HPA axis regulation, or the neural sites of action mediating this regulation, was not mapped out until recently. This review aims to collapse the current state of knowledge regarding the role of the endocannabinoid system in the regulation of the HPA axis to put together a working model of how and where endocannabinoids act within the brain to regulate outflow of the HPA axis. Specifically, we discuss the role of the endocannabinoid system in the regulation of the HPA axis under basal conditions, activation in response to acute stress and glucocorticoid-mediated negative feedback. Interestingly, there appears to be some anatomical specificity to the role of the endocannabinoid system in each phase of HPA axis regulation, as well as distinct roles of both anandamide and 2-arachidonoylglycerol in these phases. Ultimately, the current level of information indicates that endocannabinoid signalling acts to suppress HPA axis activity through concerted actions within the prefrontal cortex, amygdala and hypothalamus.

Stress, the HPA Axis and Glucocorticoid Feedback

The stress response to disruption of physiological homeostasis or to a perceived threat to homeostasis involves a coordinated activation of a constellation of physiological systems designed to increase the survival of the organism. The common stress response to both physiological and psychological stressors can be summarized generally as the concerted activation of a two-pronged physiological defense mechanism, an autonomic response and a neuroendocrine response. The autonomic response involves stimulation of sympathetic motor and hormonal outputs via descending neural circuits originating in hypothalamic preautonomic control centers. The neuroendocrine stress response is mediated by activation of the hypothalamic-pituitary-adrenal (HPA) axis, which results in an increase in circulating corticosteroids and corticosteroid coordination of activity in multiple target organ systems (Pecoraro et al., 2006).

In the HPA response to stress, stressful stimuli cause the activation of neural inputs to corticotropin releasing hormone (CRH) neurons in the hypothalamic paraventricular nucleus (PVN), which leads to CRH and, under some conditions, vasopressin neurosecretion from axon terminals in the basal hypothalamus into the pituitary portal circulation. Portal blood-borne CRH and vasopressin act to stimulate cells of the anterior pituitary that produce adrenocorticotropic hormone (ACTH), which causes ACTH release into the systemic circulation. Circulating ACTH then stimulates the synthesis of corticosteroids in the cortex of the adrenal glands, which causes an increase in corticosteroid secretion into the blood. Systemic corticosteroids then elicit both rapid and protracted actions in target tissues throughout the organism, including in the brain. Both long-lasting corticosteroid effects, induced by activation of the “classical” intracellular corticosteroid receptors and transcriptional steroid actions, and rapid corticosteroid actions, mediated by putative membrane-associated glucocorticoid receptors and non-genomic steroid actions, have been described in the brain (Tasker and Herman, 2011, Pecoraro et al., 2006).

The HPA axis is under negative feedback control by circulating glucocorticoids. Glucocorticoid feedback regulation of the HPA axis can occur directly at the level of the hypothalamus (Evanson et al., 2010, Jones et al., 1977, Keller-Wood and Dallman, 1984) and pituitary (Russell et al., 2010, Cole et al., 2000), as well as at upstream limbic structures such as the hippocampus (Sapolsky et al., 1984, Jacobson and Sapolsky, 1991, Furay et al., 2008), paraventricular thalamus (PVT; Jaferi et al., 2003; Jaferi and Bhatnagar, 2006) and prefrontal cortex (Hill et al., 2011, Radley and Sawchenko, 2011). Outputs from the PFC and hippocampus/subiculum comprise excitatory projections from principal neurons that transit to the PVN, and reverse their sign, via inhibitory relays in the bed nucleus of the stria terminalis (BNST) and peri-PVN hypothalamic regions (Radley and Sawchenko, 2011, Ulrich-Lai and Herman, 2009). Glucocorticoid actions in these structures, therefore, should be excitatory in order to exert an inhibitory influence on PVN CRH neurons and the HPA axis. In contrast, the direct negative feedback actions of glucocorticoids in the PVN and pituitary are inhibitory (Evanson et al., 2010, Di et al., 2003). Interestingly, the involvement of higher limbic structures in the negative glucocorticoid feedback control of the HPA axis appears to be specific to the HPA response to psychological stressors, and not physiological stressors, based on lesion studies and studies in mice with conditional forebrain cortical and limbic knockout of the glucocorticoid receptor (Diorio et al., 1993; Furay et al., 2008). Rapid glucocorticoid regulation of hypothalamic CRH neurons (Di et al., 2003) as well as hippocampal pyramidal neurons (Hu et al., 2010, Karst et al., 2005), prefrontal cortical pyramidal neurons (Hill et al., 2011, Yuen et al., 2009), and principal neurons of the basolateral amygdala (Karst et al., 2010) is mediated largely by modulation of excitatory and/or inhibitory synaptic inputs to these neurons. In several cases, rapid glucocorticoid actions have been demonstrated to include stimulation of endocannabinoid synthesis and engagement of the endocannabinoid system in the modulation of synaptic inputs (Hill et al. 2010a, Karst et al., 2010, Di et al., 2003); for review, see Tasker and Herman, 2011).

Endocannabinoid Signaling

The endocannabinoid system is a lipid signaling system throughout the brain and body that was first discovered as the biochemical target of delta9-tetrahydrocannabinol (THC), the psychoactive constituent of cannabis (Pertwee, 2008). The endocannabinoid system is composed of two G-protein coupled receptors, denoted CB1 and CB2 receptors, which exhibit distinct patterns of distribution (Matsuda et al., 1990, Munro et al., 1993). The CB1 receptors are widely expressed throughout the brain, but is also found in many cell types and organ systems of the periphery as well, including all major endocrine glands (Herkenham et al., 1991, Bellocchio et al., 2008). The CB2 receptors are traditionally viewed as exhibiting peripheral expression patterns exclusively, particularly on organs involved in the immune response such as leukocytes and the spleen (Atwood and Mackie, 2010, Patel et al., 2010); however, recent evidence has questioned this view and there is emerging evidence for the expression of CB2 receptors in the brain (Onaivi et al., 2011, Xi et al., 2011, Van Sickle et al., 2005). Given that all of the research examining the endocannabinoid system and the HPA axis has focused on the CB1 receptor, this review will focus exclusively on the CB1 receptor.

Within the brain, the CB1 receptor is predominately expressed on axon terminals of a variety of neuronal populations, including glutamatergic, GABAergic and monoaminergic neurons (Freund et al., 2003). Activation of the CB1 receptor results in a suppression of adenylate cyclase activity and calcium influx into the axon terminal; thus, CB1 receptor signaling functions to suppress neurotransmitter release into the synapse (Freund et al., 2003). In addition to the ability of THC to activate CB1 receptors, there are at least two endogenous ligands that activate the CB1 receptor (termed endocannabinoids). The two ligands that are widely accepted as endocannabinoids, N-arachidonylethanolamine (anandamide; AEA; Devane et al., 1992) and 2-arachidonoylglycerol (2-AG; Sugiura et al., 1995), are arachidonate-derived signaling lipids, which in the brain are synthesized in the post-synaptic membrane and released in a retrograde fashion to activate presynaptically located CB1 receptors (Alger, 2002, Wilson and Nicoll, 2002). The synthesis of AEA and 2-AG is believed to be driven by the cleavage of membrane-associated phospholipid head groups by activation of specific enzymes. The activation of these biosynthetic enzymes can be driven by activity-dependent depolarization and increased intracellular calcium signaling or through metabotropic receptor activation (Freund et al., 2003). The biosynthesis of 2-AG is mediated by the generation of diacylglycerol, via the actions of either phospholipase C (PLC) or phospholipase D (PLD), which is subsequently converted to 2-AG via the actions of DAG lipase (Hillard, 2000, Sugiura et al., 2002, Di Marzo, 2008). The pathways mediating AEA synthesis are less well understood. To date, three distinct and independent mechanisms have been found to generate AEA (Okamoto et al., 2004, Liu et al., 2006, Simon and Cravatt, 2006); however, the pathway that is primarily responsible for neuronal AEA synthesis is not currently known (see Ahn et al., 2008, Bisogno, 2008 for details on putative biosynthetic pathways of AEA). The functional lifespan of endocannabinoids in the synapse is determined by their metabolism by specific enzymatic pathways. Fatty acid amide hydrolase (FAAH) is the primary catabolic enzyme of AEA, and hydrolyzes AEA into ethanolamine and arachidonic acid (Deutsch et al., 2002, Ueda, 2002). 2-AG is primarily metabolized by monoacylglyceride lipase (MAG lipase) to form glycerol and arachidonic acid (Dinh et al., 2002, Ueda, 2002).

While the physiological function of AEA and 2-AG are very similar, based upon differences in binding affinity, pharmacokinetics and signaling efficacy, we and others have proposed that AEA represents a “tonic” signal that gates and regulates transmitter release under steady-state conditions, while 2-AG represents a “phasic” signal that is brought on-line during sustained neuronal depolarization and is involved in many forms of synaptic plasticity (Ahn et al., 2008, Gorzalka et al., 2008). This concept is highlighted by the fact that AEA and 2-AG possess distinct biosynthetic and metabolic pathways, and pharmacological or genetic modulation of their signaling produces distinct behavioural and physiological responses (Ahn et al., 2008, Long et al., 2009a, Long et al., 2009b)

With respect to regulation of the HPA axis, the endocannabinoid system is widely distributed throughout the cortico-limbic and hypothalamic circuitry that regulates activation of the HPA axis (Hill and McEwen, 2010, Gorzalka et al., 2008). Within this circuitry, endocannabinoid signaling has been found to regulate both excitatory and inhibitory transmitter release, and in general, the predominant effects of endocannabinoid signaling are to constrain activation of the HPA axis (Hill et al., 2010c). However, research has identified site-specific roles, and divergent functions of AEA and 2-AG, with respect to HPA axis regulation in the context of basal function, activation in response to stress and termination during the HPA recovery phase. Each of these phases will be discussed independently.

Endocannabinoid Signaling and Basal Regulation of the HPA Axis

Studies employing mice deficient in CB1 receptors (CB1 KO mice) or treated with a CB1 receptor antagonist generally indicate that a disruption of CB1 receptor function increases basal drive on the HPA axis. Specifically, acute treatment with a CB1 receptor antagonist to an otherwise unstressed rodent has been reliably found to increase circulating levels of ACTH and corticosterone in a dose-dependent manner during the nadir of the diurnal cycle (Atkinson et al., 2010, Hill et al., 2010b, Manzanares et al., 1999, Gonzalez et al., 2004, Patel et al., 2004, Wade et al., 2006, Steiner et al., 2008, Newsom et al., 2011). These data suggest that there is an endocannabinoid tone, which, under steady-state conditions, constrains activation of the HPA axis and, when disrupted, increases HPA axis outflow. More detailed studies have revealed that this effect is likely due to basal endocannabinoid suppression of the peak amplitudes in the pulsatility of ACTH and corticosterone release and not to a regulation of the frequency of pulses (Atkinson et al., 2010). Furthermore, the ability of CB1 receptor antagonism to increase HPA axis activity appears to be greater during the daily nadir, suggesting that endocannabinoids may contribute more to the decrease in HPA axis outflow during the diurnal trough, than to regulating basal activity during the diurnal peak (Atkinson et al., 2010). Consistent with these findings, CB1 KO mice have generally been found to exhibit increased basal HPA axis activity. Specifically, CB1 KO mice have increased CRH mRNA within the PVN (Cota et al., 2003, Cota et al., 2007) and, consistent with the pharmacological studies, several studies have similarly demonstrated that CB1 KO mice have increased circulating levels of ACTH and corticosterone during the daily nadir (Barna et al., 2004, Haller et al., 2004, Steiner et al., 2008), but also during the diurnal peak (Cota et al.,2007). Some studies have reported no difference between wild-type and CB1 KO mice in basal ACTH and/or corticosterone levels (Fride et al., 2005, Wade et al., 2006, Aso et al., 2008); however, these discrepancies could be due to differences in strain, breeding/outbreeding protocols and ambient laboratory conditions. Regardless, the general consensus in this area is that there is an endocannabinoid tone that acts to constrain HPA axis under basal conditions, particularly during the nadir of the diurnal cycle and to some degree during the diurnal peak, and disruption of this tone increases HPA axis activity.

With respect to the site of action of tonic endocannabinoid suppression of HPA axis activity, the current body of evidence suggests that this effect is centrally mediated. While there is evidence that CB1 receptors are present in the pituitary and adrenal glands, where they may regulate the synthesis and/or release of ACTH and corticosterone (Ziegler et al., 2010, Pagotto et al., 2001, Cota et al., 2007), the HPA stimulating effects of CB1 receptor antagonism can be replicated by intra-cerebroventricular administration (Manzanares et al., 1999), indicating a central site of action. Consistent with this hypothesis, systemic administration of a CB1 receptor antagonist increases neuronal activation (as indicated by the induction of the immediate early gene c-fos) in the PVN (Patel et al., 2004, Doyon et al., 2006, Newsom et al., 2011), suggesting that the increase in HPA axis activity is mediated by an activation of CRH neurosecretory cells in the PVN, although the site of endocannabinoid action may be in upstream excitatory neural circuits.

Within the PVN, CB1 receptors are localized to glutamatergic terminals impinging upon CRH neurosecretory neurons, and CB1 receptor activation decreases glutamate release onto these neurons (Wamsteeker et al., 2010, Di et al., 2003). Theoretically, these excitatory synapses would be an ideal site for endocannabinoid gating of basal HPA axis activity; however, there does not appear to be an endocannabinoid tone within this micro-circuit that contributes to the regulation of basal HPA axis activity, as CB1 receptor antagonism in PVN slices does not increase excitatory synaptic inputs to CRH neurons (Di et al., 2003) and local administration of a CB1 receptor antagonist in the PVN does not increase basal HPA axis drive (Evanson et al., 2010). These data suggest, therefore, that tonic regulation of the HPA axis by endocannabinoids occurs at an extrahypothalamic site that communicates with the PVN.

In addition to the PVN, c-fos studies have indicated that acute administration of a CB1 receptor antagonist increases neuronal activation in limbic circuits that feed into the PVN, particularly the amygdala and the prefrontal cortex (Newsom et al., 2011, Alonso et al., 1999, Singh et al., 2004, Patel et al., 2005a). Local administration of a CB1 receptor antagonist into the medial prefrontal cortex, however, has no effect on basal HPA axis function (Hill et al., 2011), indicating that the medial prefrontal cortex is also not the location by which endocannabinoid signaling tonically regulates basal HPA axis activity. Interestingly, administration of a CB1 receptor antagonist in the basolateral nucleus of the amygdala (BLA; Ganon-Elazar and Akirav, 2009, Hill et al., 2009a), but not in the medial or central nuclei of the amygdala (Hill et al., 2009a), increases HPA axis activity in non-stressed animals. These data would indicate that an endocannabinoid tone within the BLA tonically gates excitation of this structure, and that disruption of CB1 receptor function in the BLA increases its intrinsic excitability, which ultimately results in the activation of the PVN. While the BLA does not anatomically project directly to the PVN, it does regulate PVN activity through a series of trans-synaptic pathways including the central and medial nuclei of the amygdala, the bed nucleus of the stria terminalis and neighbouring hypothalamic nuclei (Herman et al., 2005, Ulrich-Lai and Herman, 2009), and activation of the BLA is sufficient to increase HPA axis activity (Feldman et al., 1982). Consistent with this, CB1 receptors in the BLA are located on both glutamatergic and GABAergic terminals (Marsicano and Lutz, 1999, Katona et al., 2001, McDonald and Mascagni, 2001, Azad et al., 2003, Domenici et al., 2006), but electrophysiological work has demonstrated that the ability of CB1 receptor signaling to suppress glutamate signaling in this nucleus overrides the suppression of GABA signaling, as the net effect of CB1 receptor activation in the BLA is a reduction in the firing activity of principal neurons (Azad et al., 2003). As such, our current working model is that, under steady-state conditions, there is an endocannabinoid tone that gates excitatory inputs to principal neurons in the BLA and thus constrains the excitability of the BLA under non-stressed conditions. Disruption of this endocannabinoid tone increases excitation in the BLA, and the increased outflow of projection neurons from the BLA stimulates the activation of the PVN and results in an increase in HPA activity. As AEA is believed to represent the “tonic” signaling molecule of the endocannabinoid system, our current hypothesis is that AEA signaling within the BLA is a distal “gatekeeper” of basal HPA axis activity.

Endocannabinoid Signaling and Stress-induced Activation of the HPA Axis

Consistent with the hypothesis that AEA signaling within the BLA represents a “gatekeeper” over HPA axis activity, evidence has also mounted that a rapid loss of this AEA signal in the BLA is involved in the natural activation of the HPA axis in response to stress. Specifically, exposure to stress results in a reduction in the tissue content of AEA in the amygdala (Patel et al., 2005b, Rademacher et al., 2008, Hill et al., 2009a), possibly through a rapid induction of FAAH-mediated AEA hydrolysis (Hill et al., 2009a). The magnitude of the decline in AEA content within the amygdala negatively correlates with the extent of HPA axis activation, such that larger reductions in amygdala AEA levels in response to stress are related to greater increases in corticosterone secretion (Hill et al., 2009a). Furthermore, local administration of a FAAH inhibitor in the BLA, but not in the central or medial nuclei of the amygdala, attenuates stress-induced activation of the HPA axis, indicating that AEA hydrolysis in the BLA in response to stress contributes to activation of the HPA axis (Hill et al., 2009a). These data are consistent with the aforementioned hypothesis, and suggest that this “gatekeeper” role of AEA signaling in the BLA is modified by exposure to stress to facilitate the neuroendocrine response to stress. Additionally, local administration of a CB1 receptor agonist directly into the BLA similarly suppresses stress-induced activation of the HPA axis (Ganon-Elazar and Akirav, 2009, Hill et al., 2009a), supporting the hypothesis that CB1 receptor signaling in the BLA counters HPA axis activity. Taken together, these data demonstrate that AEA signaling in the BLA plays an important role in the regulation of the HPA axis (see Figure 1). Under steady-state conditions, there is an AEA tone within the BLA that gates incoming excitatory neurotransmission. Disruption of this AEA tone following exposure to stress, either through the blockade of CB1 receptor signaling or a reduction in AEA content, increases the activation of principal neurons in the BLA and results in an increase in HPA axis activation and in the release of glucocorticoid hormones into the circulation.

Figure 1.

Figure 1

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Under basal conditions (left panel), there is an anandamide (AEA) tone within the basolateral nucleus of the amygdala (BLA) which gates the presynaptic release of glutamate, through activation of CB1 receptors on glutamatergic terminals, and thus constrains the excitability of projection neurons of the BLA. In response to stress (right panel), hydrolysis of AEA by fatty acid amide hydrolase (FAAH) increases reducing signalling levels of AEA. This loss of AEA signalling at the CB1 receptor disinhibits glutamatergic inputs to projection neurons of the BLA, resulting in an increase in the firing activity and outflow of BLA projection neurons. Increased activation of the amygdala will contribute to activation of a stress response, which ultimately increases activation of the HPA axis.

Endocannabinoid Signaling and Glucocorticoid-mediated Negative Feedback

Once glucocorticoids are released into the circulation, they activate multiple negative feedback loops both within central and peripheral components of the HPA axis and within extrahypothalamic regions in the brain. This feedback process occurs within distinct temporal windows (Keller-Wood and Dallman, 1984; Pecoraro et al., 2006). Rapid negative feedback processes occur within a few minutes (typically under 10 min), are not sensitive to protein synthesis inhibition and appear to be mediated by non-classical glucocorticoid actions at the membrane level (Keller-Wood and Dallman, 1984; Dallman, 2005). Delayed negative feedback occurs over a longer duration (minutes to hours), is driven by changes in gene expression and is mediate by classical actions of glucocorticoids within the nucleus (Keller-Wood and Dallman, 1984; Pecoraro et al., 2006). At the adrenal and pituitary levels, there is negative feedback initiated by glucocorticoids that acts to suppress the release of both ACTH from the pituitary and corticosteroids from the adrenal cortex to limit the release of HPA hormones. Within the brain, there is a complex process of glucocorticoid feedback that involves both rapid and delayed components at multiple sites (Tasker and Herman, 2011, Pecoraro et al., 2006). As discussed previously, within the PVN of the hypothalamus there is both a rapid and delayed feedback process that involves a suppression of the excitatory drive to CRH neurosecretory cells and a down-regulation of CRH and vasopressin mRNA transcription in these same neurons, respectively. The down-regulation of CRH and vasopressin mRNA transcription is directly mediated by genomic actions of glucocorticoids and occurs over a period of a couple of hours. The rapid feedback component, however, is driven by non-genomic actions of glucocorticoids interacting with membrane-associated glucocorticoid receptors located on the extracellular surface of CRH neurosecretory cells within the PVN. Activation of these membrane glucocorticoid receptors results in the generation of a retrograde signal that traverses back across the synaptic cleft to axon terminals of excitatory afferents and suppresses the release of glutamate onto CRH neurons, suppressing the excitation of these cells and the release of CRH. Multiple lines of evidence have demonstrated that this fast feedback inhibition of glucocorticoids locally within the PVN is mediated by an endocannabinoid signal (for detailed discussion of this phenomenon please refer to Tasker and Herman, 2011).

First, bath application of glucocorticoids to PVN slices results in a rapid suppression of glutamate-mediated excitatory synaptic currents in CRH neurons, which is completely abrogated by co-application of a CB1 receptor antagonist (Wamsteeker et al., 2010, Di et al., 2003, Malcher-Lopes et al., 2006). This indicates that glucocorticoids act to mobilize endocannabinoids within the PVN to dampen excitatory synaptic input to CRH neurons. Consistent with this hypothesis, glucocorticoids have been found to increase the content of both AEA and 2-AG in PVN slices in vitro (Malcher-Lopes et al., 2006) and in whole hypothalamic sections in vivo (Hill et al., 2010a). Furthermore, 30-min exposure to restraint stress similarly increases 2-AG content within the hypothalamus in vivo (Evanson et al., 2010). At the systems level, while local administration of a CB1 receptor antagonist does not affect basal drive on the HPA axis, it is capable of completely preventing the ability of intra-PVN glucocorticoid administration to dampen stress-induced activation of the HPA axis (Evanson et al., 2010). Furthermore, CB1 receptor KO mice exhibit a larger peak ACTH and corticosterone response following acute stress, suggesting that a loss of CB1 receptors reduces the fast feedback inhibition and increases the magnitude and duration of the HPA axis response to acute stress (Hill et al., 2011, Barna et al., 2004, Haller et al., 2004, Uriguen et al., 2004, Aso et al., 2008, Steiner et al., 2008). As such, these data create a compelling argument that endocannabinoids mediate fast-feedback inhibition of the HPA axis by glucocorticoids locally within the PVN through a non-genomic mechanism by which glucocorticoids induce endocannabinoid mobilization to suppress excitatory input to CRH neurons.

Outside of the PVN, there is also evidence that endocannabinoids are involved in glucocorticoid-feedback inhibition of the HPA axis. Within the amygdala for example, as it has been established that AEA signaling in the BLA is an important component of basal HPA axis activity and its activation in response to stress, it is interesting to note that glucocorticoids and stress exposure exert oppositional effects on AEA content. Specifically, as mentioned previously, acute exposure to stress reduces AEA content in the basolateral nucleus of the amygdala (Patel et al., 2005b, Rademacher et al., 2008, Hill et al., 2009a), however administration of glucocorticoids in the absence of stress actually causes a rapid increase in AEA content within the amygdala (Hill et al., 2010a). One interpretation of these data is that stress, through a non-glucocorticoid pathway (possibly CRH or norepinephrine), rapidly suppresses AEA signaling within the BLA to facilitate activation of the HPA axis, and once glucocorticoid levels begin to rise they act to increase AEA content in the amygdala and thus normalize the reduction produced by stress exposure. While this process remains to be determined experimentally, a recent report showed that exposure of BLA slices from stressed animals to corticosterone in vitro results in a suppression of afferent glutamateric input through an endocannabinoid mechanism (Karst et al., 2010). As such, the ability of glucocorticoids to rapidly increase AEA content within the BLA may be one of the mechanisms by which glucocorticoids reduce neuronal activity within the amygdala (Henckens et al., 2010) and contribute to termination of the stress response.

In addition to these rapid, non-genomic effects of glucocorticoids to suppress activation of the HPA axis, the medial prefrontal cortex and hippocampus also represent two neuroanatomical sites integral for delayed feedback inhibition of the HPA axis. Glucocorticoid receptors are abundantly expressed in both the prefrontal cortex and hippocampus, and activation of these receptors inhibits activation of the HPA axis, while lesioning of either of these structures impairs normative recovery of the HPA axis following exposure to stress (Radley and Sawchenko, 2011, Diorio et al., 1993, Herman and Mueller, 2006, Radley et al., 2006). An elegant series of anatomical studies has demonstrated that both of these structures suppress HPA axis activity through activation of glutamatergic projection neurons to inhibitory relays to the PVN within the bed nucleus of the stria terminalis (BNST; Radley and Sawchenko, 2011). As such, glucocorticoids facilitate neuronal activity within the medial prefrontal cortex (Hill et al., 2011, Yuen et al., 2009) and hippocampus (Karst et al., 2005) to increase the outflow of projection neurons in these structures to suppress HPA axis activity and terminate the stress response.

In the prefrontal cortex, a clear role of endocannabinoid signaling in the glucocorticoid-mediated negative feedback inhibition of the HPA axis has been demonstrated. Specifically, exposure to stress was found to increase 2-AG content, but not AEA, within the prefrontal cortex in a glucocorticoid-dependent manner (Hill et al., 2011). Unlike what was seen in the PVN (Di et al., 2003), however, this ability of glucocorticoids to increase endocannabinoid content was not rapid and involved genomic actions of glucocorticoids, as it was blocked by the classical intracellular glucocorticoid receptor antagonist RU-486 (Hill et al., 2011). Whereas local administration of a CB1 receptor antagonist did not change the peak corticosterone responses to acute stress, it did prolong the duration of elevated corticosterone secretion following termination of the stress, indicating that the recruitment of 2-AG by glucocorticoids in the mPFC contributes to termination of the stress response (Hill et al., 2011). The ability of endocannabinoids in the prefrontal cortex to contribute to the termination of the stress response appears to be due to modulation of local excitability, as CB1 receptors were found on GABAergic terminals clustered around pyramidal neurons in the prefrontal cortex, and bath application of corticosterone to prefrontal cortical slices resulted in a CB1 receptor-dependent reduction of inhibitory tone in these cells (Hill et al., 2011). Again, unlike in the hypothalamus, this effect appeared to be mediated by genomic actions of glucocorticoids, as it was seen following 1 h of glucocorticoid application (Hill et al., 2011). While the exact nature of how glucocorticoids may interact with the endocannabinoid system at a genomic level has yet to be determined, preliminary evidence indicates that glucocorticoids can downregulate MAG lipase activity (Shrestha and Hillard, 2010), so it is possible that glucocorticoids may act to suppress 2-AG metabolism and thus increase the synaptic availability of 2-AG. As such, these data demonstrate that endocannabinoid system is also recruited in the prefrontal cortex by glucocorticoids following exposure to stress, and that the endocannabinoid-induced increase in endocannabinoid signaling increases the activity of prefrontal cortical outputs and contributes to termination of the stress response and glucocorticoid-mediated negative feedback.

In the hippocampus, it is possible that a similar phenomenon is occurring, however this remains to be fully determined. Currently, it has been shown that exposure to acute stress increases 2-AG content within the hippocampus through activation of genomic glucocorticoid receptors (Wang et al., 2011). Furthermore, both stress and corticosterone exposure (in vivo and in vitro) increase endocannabinoid-mediated suppression of GABAergic transmission within the hippocampus (Wang et al., 2011). However, it has yet to be determined if this increase in endocannabinoid signaling can influence the excitability of projection neurons from the hippocampus to the BNST that are involved in the termination of the stress response (Radley and Sawchenko, 2011), or if local antagonism of CB1 receptors in the hippocampus can modulate stress-induced HPA axis activity or glucocorticoid-mediated negative feedback. Future research should examine if a similar endocannabinoid-mechanism of glucocorticoid feedback inhibition is occurring in the hippocampus as what has been determined in the prefrontal cortex (Hill et al., 2011).

Taken together, these data demonstrate that endocannabinoids play an important role in glucocorticoid-mediated negative feedback (see Figure 2). In addition to the data detailed above, it has also been reported that CB1 receptor knockout mice also exhibit deficits in dexamethasone-mediated suppression of HPA axis activity (Cota et al., 2007), further demonstrating an important role of the endocannabinoid system in glucocorticoid feedback inhibition of the HPA axis. Interestingly, the current data indicate that the endocannabinoid system appears to contribute to both the short and long feedback loops of glucocorticoid feedback inhibition, and does so through distinct mechanisms. Within the PVN, and possibly in the amygdala, a rapid induction of endocannabinoid activity through a non-genomic glucocorticoid mechanism contributes to the fast feedback inhibition of the HPA axis, while in the prefrontal cortex, and possibly in the hippocampus, a delayed increase in endocannabinoid activity, through a genomic glucocorticoid mechanism, contributes to the long-loop glucocorticoid feedback inhibition pathway. As such, the endocannabinoid system appears to represent one of the synaptic workhorses of glucocorticoids, bridging postsynaptic effects of glucocorticoids to presynaptic regulation of excitability within a given circuit (Hill and McEwen, 2009).

Figure 2.

Figure 2

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(1) Exposure to stress causes activation of CRH neurosecretory cells within the paraventricular nucleus of the hypothalamus (PVN); (2) CRH stimulates the release of ACTH into the general circulation where it acts on the adrenal gland to induce the synthesis and release of glucocorticoid hormones; (3) Glucocorticoid hormones enter the circulation and penetrate the brain where they activate negative feedback pathways; (4) Within the PVN glucocorticoids cause a rapid release of endocannabinoids which suppress excitatory inputs to the CRH cells in the PVN to contribute to fast-feedback inhibition of the HPA axis. Within the prefrontal cortex (PFC), glucocorticoids cause a delayed increase in endocannabioid mobilization, which suppresses local inhibitory circuits and increases the outflow of projection neurons from the PFC. (5) These projection neurons from the PFC activate inhibitory relay neurons to the PVN to turn off neuronal activation of the PVN and contribute to delayed glucocorticoid negative feedback of the HPA axis. Combined, the recruitment of endocannabinoid signalling acts at both short (PVN) and long (PFC) loops of the negative feedback pathway in the brain.

Model of Endocannabinoid Actions in HPA Axis Regulation and Glucocorticoid-Mediated Negative Feedback

The body of research detailed herein demonstrates a critical and complex role of the endocannabinoid system in the regulation of HPA axis activity and glucocorticoid-mediated negative feedback. When looking at the complete picture of the role of endocannabinoid signaling in HPA axis regulation, a ying-yang role of AEA and 2-AG emerges and suggests a fluid model of how this system integrates into the HPA axis (Figure 3). Under steady-state conditions, there is an AEA tone in the BLA that gates excitation of BLA principal neurons and suppresses BLA activity in the absence of stress. Following exposure to stress, AEA content within the BLA rapidly decreases, which disinhibits the BLA and results in an activation of the HPA axis and glucocorticoid hormone secretion into the circulation. As glucocorticoid hormone concentrations rise and penetrate the brain, they bind to membrane-associated receptors in the PVN, and possibly in the amygdala, to rapidly induce endocannabinoid synthesis. Within the PVN, this increase in endocannabinoid signaling suppresses excitatory synaptic drive to the CRH neurons and acts to mediate the fast feedback inhibition of the HPA axis. Within the amygdala, this increase in endocannabinoid signaling functions to decrease the excitatory drive to principal neurons of the BLA and decrease the facilitatory influence this nuclei has on the HPA axis. In the prefrontal cortex, and possibly in the hippocampus, glucocorticoids produce a delayed increase in 2-AG content by activating genomic receptors, possibly through a down-regulation of MAG lipase activity. This delayed increase in 2-AG acts to increase the excitability of projection neurons by suppressing local inhibitory tone on these neurons. This increase in outflow of the prefrontal cortex and hippocampus activates inhibitory relays in the BNST that suppress neuronal activation in the PVN. Collectively, this multi-site process results in the termination of the HPA axis and limits the duration and magnitude of glucocorticoid secretion in response to stress. In addition, this model also reveals a divergent pattern of endocannabinoid regulation which indicates putatively distinct role of AEA and 2-AG. AEA signalling exerts a tonic suppression over the HPA axis, while 2-AG is recruited by glucocorticoids to turn off the HPA axis following cessation of stress. As such, this hypothetical model reveals multiple sites of action by which a disruption in endocannabinoid signaling could result in an increase in HPA axis activity and illustrates how endocannabinoid activity can regulate the HPA axis at multiple levels and in distinct phases of the stress response.

Figure 3.

Figure 3

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AEA and 2-AG exhibit a ying-yang relationship with HPA axis activity. Under basal conditions, AEA tonically suppresses HPA axis activity. In response to stress, AEA levels rapidly decline within the amygdala, disinhibiting HPA axis activity and resulting in an increase in glucocorticoid hormone secretion. Glucocorticoid hormones act to increase 2-AG production, which then acts to suppress HPA axis activity through actions in both the hypothalamus (rapid) and prefrontal cortex (delayed). In addition, glucocorticoids also act to normalize AEA levels within the amygdala, and thus remove the disinhibition on the HPA axis and help return HPA function to basal levels.

Conclusions and Future Directions

From this overview, we are able to determine multiple areas of research that are required to fully understand the interaction between endocannabinoids and the HPA axis. First, it remains to be determined what the mechanism is through which stress reduces AEA content. This phenomenon does not appear to be mediated by glucocorticoids, and happens upstream of HPA axis activation (Hill et al., 2009a), thus likely involves local signaling systems that are activated by stress stimulation prior to the activation of the HPA axis, such as CRH or norepinephrine release within the amygdala. Second, in addition to the identified structures, it is important to determine if endocannabinoid signaling operates at additional sites to regulate HPA axis function. As mentioned, there is no evidence to date that shows that manipulation of endocannabinoid signaling in the hippocampus modulates HPA axis function. One study has demonstrated that CB1 receptor knockout mice exhibit a downregulation of glucocorticoid receptors within the hippocampus (a condition that is associated with impaired feedback inhibition of the HPA axis; Sapolsky et al., 1984, Liu et al., 1997, Mizoguchi et al., 2003); however, whether this downregulation is secondary to glucocorticoid hypersecretion or a contributing factor to HPA axis hyperactivity in CB1 receptor knockout mice is not known. In addition to the hippocampus, there is no evidence regarding the role of endocannabinoid signaling in many structures known to be integral for HPA axis regulation, such as in the BNST (Radley and Sawchenko, 2011, Choi et al., 2007), in midline thalamic nuclei such as the paraventricular nucleus of the thalamus (Bhatnagar et al., 2000, Jaferi and Bhatnagar, 2006, Jaferi et al., 2003), in the lateral septum (Singewald et al., 2011) and in hypothalamic nuclei such as the medial preoptic area (Viau and Meaney, 1996) and dorsomedial hypothalamic nucleus (Keim and Shekhar, 1996, Bailey and Dimicco, 2001). Third, there is little information regarding the role of endocannabinoid signaling in different forms of stress induction. To date, all of the studies examining the role of the endocannabinoid system in HPA axis regulation have focused on psychogenic stressors and not physiological stressors. One recent study reported that inhibition of FAAH did not modulate HPA axis activation in response to an immunological challenge (Kerr et al., 2011), but there is no information regarding the role of endocannabinoids in HPA activation by other forms of physiological stress such as osmotic dysregulation or pain. Finally, neuroanatomical studies are required to adequately understand where the molecular components of the endocannabinoid system exist within known circuits regulating the HPA axis. In the PVN, CB1 receptors are known to exist on glutamatergic inputs to CRH neurons (Di et al., 2003) and in the prefrontal cortex, CB1 receptors are clustered on GABAergic terminals impinging on layer V neurons of the prelimbic region, the output neurons that project to subcortical structures such as the BNST (Hill et al., 2011); however, more work is required to understand where CB1 receptors are located in stress-sensitive neurons that that have been widely mapped using c-fos induction to comprise the circuitry that regulates HPA axis function (Radley and Sawchenko, 2011, Cullinan et al., 1995, Herman et al., 2005, Spencer et al., 2005).

Finally, there is emerging evidence that stress also recruits the endocannabinoid system in humans, implying a translational validity to the animal studies. Exposure of individuals to a fifteen minute social stressor (the Trier Social Stress Test) resulted in an increase in the circulating levels of 2-AG (Hill et al., 2009b) that was similar to the increase in central 2-AG content seen in rodents following exposure to stress (Evanson et al., 2010, Hill et al., 2011, Wang et al., 2011). These data suggest that endocannabinoid signaling is engaged by stress in humans; however, it remains to be determined whether this increase in 2-AG content in the blood reflects central changes in endocannabinoid signaling, and whether this increase in 2-AG content is involved in glucocorticoid-mediated feedback inhibition of the HPA axis. A separate study has also found that individuals who carry the C385A polymorphism of the FAAH gene, which increases the proteolytic degradation of FAAH and elevates AEA content (Sipe et al., 2010, Sipe et al., 2002), exhibit a reduction in activation of the amygdala in response to threatening stimuli (Hariri et al., 2009). This finding is consistent with the idea that there is an AEA inhibitory tone within the amygdala that regulates its excitability, and that loss of this tone in response to stress facilitates activation of the amygdala. These data in humans complement and corroborate the preclinical studies demonstrating that local inhibition of FAAH within the amygdala can attenuate the stress response (Hill et al., 2009a). Finally, a recent report has found that administration of a CB1 receptor antagonist in humans may increase cortisol levels when delivered at high doses (Goodwin et al., 2011), suggesting that endocannabinoid signaling may constrain basal activation of the HPA axis in humans, similar to what has been found in rodents. Taken together, these data provide some initial evidence that endocannabinoid signaling may operate to regulate the HPA axis in a similar fashion in humans as what has been described in rodents (for further review, see the article in this issue by Hillard et al., 2011). This conserved ability of endocannabinoid signaling to regulate HPA axis activity may represent one of the mechanisms by which inhibition of CB1 receptor signaling in humans can contribute to the incidence of depression in humans (de Mattos Viana et al., 2009, Hill and Gorzalka, 2009), a disease that is often associated with excessive activation or perturbed circadian rhythms of the HPA axis (Stetler and Miller, 2011, Holsboer, 2000).

In addition to the information detailed herein regarding the role of the endocannabinoid system in the regulation of basal HPA activity, stress-evoked activation of the HPA axis, and termination of the HPA response under conditions of acute stress, there is evidence that the endocannabinoid system also contributes to multiple forms of HPA axis regulation under conditions of chronic stress, such as reduced negative feedback inhibition of the PVN parvocellular neurons (Wamsteeker et al., 2010), habituation of stress-induced HPA axis activity (Hill et al., 2010b, Patel et al., 2005b) and increased basal excitatory drive of the HPA axis (Hill et al., 2010b). Similar to the data described for acute stress, these processes also seem to involve endocannabinoid signaling in the amygdala, hypothalamus and prefrontal cortex (Hill et al., 2010b, Wamsteeker et al., 2010, Patel et al., 2004, Patel et al., 2005b). Therefore, the role of the endocannabinoid system in HPA axis regulation extends beyond the acute stress phase to chronic stress plasticity, and the endocannabinoid system plays an integral part in the changing expression of the HPA response to a continually fluctuating and often challenging environment. It remains to be determined whether plasticity of the endocannabinoid system plays an adaptive or maladaptive role in the chronic stress induction of stress-related pathologies.

Acknowledgements

The authors would like to thank Caitlin Riebe for her excellent technical assistance in the designing and rendering of the figures in this manuscript. JGT is the recipient of a National Institute of Mental Health Grant 2R01 MH066958. Additionally, funding support was provided by the Catherine and Hunter Pierson Chair in Neuroscience, Tulane University Research Enhancement Fund to JGT.

Footnotes

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