Adaptations in endocannabinoid signaling in response to repeated homotypic stress: a novel mechanism for stress habituation

“…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 systems-level habituation to stress (Hill et al, 2010b; Patel and Hillard, 2008 ).”

“Stress habituation can be viewed as a special form of learning, in which not only the glucocorticoids, but also the endocannabinoids play a central role (Hill et al., 2010; Patel and Hillard, 2008).”

“A growing body of evidence suggests that endocannabinoid signaling also contributes to the process of stress habituation (8).”

“An emerging paradigm from cannabinoid research is that the eCB system constitutes an allostatic signalling system that contributes to cellular plasticity responses in adaptation to stress-induced alterations (Patel and Hillard, 2008).”

“Recent preclinical evidence indicates that stress also mobilizes the endocannabinoid (eCB) system in both the brain and the periphery, and that the eCB system can modulate behavioral and endocrine responses to both acute and chronic stress (Hill et al, 2010; Patel and Hillard, 2008).”

“This is consistent with the finding that stress habituation mediated by the ECS also crucially involves the modulation of glutamatergic neurotransmission (Patel and Hillard, 2008).”

“Studies have generally shown a bidirectional effect of stress on endocannabinoid levels, AEA levels decreasing and 2-AG levels increasing compared to controls [228,229].”

“Despite the abovementioned diversity in central and peripheral functions, recent studies in animals [9] and humans [10] point to a major role of EC signaling in both the periphery [10] and central nervous system [11] in controlling adaptive processes to aversive situations and regulating and limiting stress reactions.”

“Patel et al. (2005) showed that the endocannabinoid system mediates habituation to repeated restraint stress and suggested that pharmacological augmentation of endocannabinoid signaling is a good target for the treatment of affective disorders (Patel and Hillard, 2008).”

“Furthermore, the nature or type of stressor is also crucial, with habituation known to occur when animals are repeatedly exposed to the same type of stressor, a phenomenon thought to be mediated via oxytocin (470) and endocannabinoid pathways (471).”

“With regard to measures of anxiety, DAGLa / mice showed increased anxiety-like behavior in the open-field, L-D-box, and NIH assay, thus supporting a primary role for 2-AG signaling in the regulation of anxiety-like behavior (Patel and Hillard, 2008).”

“We have shown earlier that repeated stress increases 2-AG in the amygdaloid region, an effect that shows sensitization such that maximal increases are seen after 10 consecutive days of restraint (Patel and Hillard, 2008; Rademacher et al, 2008).”

“, 2002) might be explained by an involvement of the endocannabinoid system in habituation to homotypic stressors (Patel and Hillard, 2008).”

“Neurochemical, biochemical, and electrophysiological tools have indicated that the actions of the ECS are stress sensitive (Patel and Hillard, 2008; Hill et al, 2010b; Riebe and Wotjak, 2011).”

“The presence of functional eCB signaling at large has been mechanistically implicated in the extinction of conditioned stress responses (Marsicano et al., 2002) and the habituation of HPA responses resulting from homotypic stress (Patel and Hillard, 2008).”

“2-AG is known to be more selective for CB1 receptors which play an important role in stress recovery reactions [35].”

“Although some controversy exists in the literature, stress has been shown tomobilize 2-AGwhile concurrently decreasing AEA levels in the hippocampus (30, 31).”

“Endocannabinoids (eCBs) are a class of bioactive lipids that have been demonstrated to have important roles in stress-response physiology (Lutz, 2009; Patel and Hillard, 2008; Viveros et al, 2005).”

“Of very high relevance is the concept that eCBs and CB1 receptors employ their functions in order to adjust the behaviour to repeated homotypic stress [13 ].”

“Interactions with this circuit occur via stress-induced regulation of the endocannabinoid ligands Narachidonylethanolamide (anandamide; AEA) and 2-arachidonoylglycerol (2-AG) (Hill and McEwen, 2010; Patel and Hillard, 2008).”

“The cannabinoid system and the stress system are highly interconnected [44–49] and it may be that the effects of WIN on performance in a stressful learning”

“…of AS subjects at the time of death is unknown, the alterations in the CB1 receptor function might also be due to stress or anxiety related disorders (Kamprath et al., 2009; Mangieri and Piomelli, 2007; Patel et al., 2004; Patel and Hillard, 2008; Steiner et al., 2008a; Vinod and Hungund, 2006).”

“stressful conditions [138]; however, the mechanisms subserving these effects are not well understood.”

“In contrast to AEA, stress generally increases 2-AG levels (32), which contributes to termination and adaptation to stress, as well as potentially contributing to changes in pain perception and emotional memory (13, 33).”

“Recently, Patel and Hillard (2008) proposed a mechanism for endocannabinoid-mediated stress habituation, which cen- trally involves the modulation of glutamatergic signaling.”

“…concentration of the major endocannabinoids, activities of their degrading enzymes, agonist binding properties of receptors, and receptor-mediated control of neurotransmitter release (Bortolato et al., 2007; Dubreucq et al., 2012; Hill et al., 2005; Patel and Hillard, 2008; Reich et al., 2009).”

“…of endogenous cannabinoid ligands fluctuate in response to environmental challenges in both developing and adult rodents (Gorzalka et al., 2008; Patel and Hillard, 2008; Lee and Gorzalka, 2012; Marco and Laviola, 2012), and, notably, changes in endocannabinoid-related gene expression have also…”

“Because the endocannabinoid system was shown to mediate habituation to homotypic stressors (Patel et al. 2005; Patel & Hillard 2008), including adaptation to aversive tones (Kamprath et al. 2006), and to play a particular role during re-exposure to exploration-based anxiety tests, such as the…”

“Specifically, eCBs are involved in stress habituation processes (Hill et al. 2010a; Patel & Hillard 2008) that likely facilitate the ability to distinguish between stimuli that are worthy of memory consolidation from those that are rather forgotten.”

“These changes were interpreted as a unique adaptive response of the endocannabinoid system to repeated homotypic stress [162].”

“In general, the cannabinoid system and the stress system are highly interconnected (Gorzalka et al, 2008; Hill and McEwen, 2010; Hill et al, 2010; Patel et al, 2004; Patel and Hillard, 2008), and it has been suggested that the eCB system might become activated specifically in highly aversive situations but not in non-…”

“A brief overview of the literature supporting a role for the endocannabinoid system in the pathophysiology of depression and as a target for development of novel antidepressants will be provided but for more detailed considerations, please refer to recent reviews covering this topic (Bambico and Gobbi, 2008; Gorzalka…”

“When the suppression after 10 s depolarization was plotted against the change produced by AM251 application, a strong correlation between both parameters on either DSE (R¼ 0.8984) or DSI (R¼ 0.8905) (Figure 4b and d, respectively) was found, indicating the presence of an endocannabinoid tone.”

“This suggestion is consistent with a growing body of literature supporting a role of the ECS in habituation of the behavioral and endocrine responses to stress (Patel and Hillard 2008).”

“In general, the cannabinoid system and the stress system are highly interconnected (Gorzalka et al, 2008; Hill and McEwen, 2010; Hill et al, 2010; Patel et al, 2004; Patel and Hillard, 2008), and it has been suggested that the endocannabinoid system might become activated specifically in highly aversive situations but…”

“Furthermore, AEA synthesis in the hypothalamus, a central relay structure for the integration of endocrine signaling involved in the control of feeding and stress, might be more sensitive to hormonal regulation than to precursor availability compared with other brain regions (56).”

“…capacity of 2-AG becomes progressively increased under conditions of repeated stress, where it is thought to mediate changes in synaptic transmission and neural excitability (Patel et al., 2005b, 2009; Patel and Hillard, 2008; Hill et al., 2010; Sumislawski et al., 2011; Dubreucq et al., 2012).”

“Here we review the perspective that stress responses, emotional memories and fear extinction are mediated by endocannabinoids (Morena et al., 2016; Patel and Hillard, 2008).”

“Changes in eCB content in specific brain areas have been reported in response to a number of environmental stimuli (Gorzalka et al., 2008; Patel and Hillard, 2008).”

“…STRESS-INDUCED ADAPTATIONS IN eCB SIGNALING IN THE AMYGDALA 1.4.1 Biochemical adaptations We initially investigated the effects of acute and repeated restraint stress on levels of 2-AG and AEA in the amygdala of mice (Patel et al., 2004; Patel et al., 2005; Patel and Hillard, 2008).”

“symptoms during abstinence (Rothwell et al, 2012) and the view that amygdaloid 2-AG is recruited during chronic stressful events to promote habituation to stress (Patel and Hillard, 2008).”

“Animal experiments indicate that stress also mobilizes the endocannabinoid (eCB) system in both the brain and the periphery and that the eCB system can modulate behavioral and endocrine responses to stress (Hill et al., 2010; Ramikie and Patel, 2012; Patel and Hillard, 2008).”

“Moreover, evidence shows that stressful experiences increased central levels of 2-AG, and that this increase is directly proportional to the level of stress exposure (Hill et al., 2010; Patel and Hillard, 2008; Patel et al., 2009; Rademacher et al., 2008; Sumislawski et al., 2011).”

“Studies in animals (Patel & Hillard, 2008) and humans point to a major additional role of endocannabinoid signaling in both the periphery (Chouker et al., 2010) and central nervous system (Hill et al., 2010), namely, controlling adaptive processes to aversive situations and regulating and limiting…”

“In accordance with this last finding, MAGL expression has been found to decrease over time, in response to persistent stress [494].”

“The endocannabinoid system (ECS), formed by cannabinoid receptors (CB1 and CB2), their endogenous lipid ligands (endocannabinoids, ECBs), and the machinery for synthesis and degradation of ECBs plays a key role in the psychoneuroendocrine responses to stress (Patel and Hillard, 2008; Steiner and Wotjak, 2008; Hill et…”

“Endocannabinoids are present in stress-responsive neural circuits and a growing body of evidence indicates that eCB tone provides negative feedback to attenuate stress responses and re-establish homeostasis [94,95].”

“These studies support the overall hypothesis that eCBs serve to buffer anxiety and stress responses in an “on demand” basis under challenging environmental conditions (Hill et al. 2010; Lutz 2009; Patel and Hillard 2008).”

“The Role of the Endocannabinoid System and the CB1 Receptor in Stress, Depression, and Anxiety Modulation of the stress response and stress adaptation is one of the major roles and effects of the central nervous endocannabinoid system (Patel and Hillard, 2008).”

“Also, endocannabinoid (neuroactive lipids) signaling and changes in its receptor density play a role in adaptation of the hypothalamic–pituitary–adrenal (HPA) axis to repeated restraint stress (Patel and Hillard, 2008; Hill et al., 2010).”

“Consistent with this idea, results from previous studies have shown that chronic exposure to stress enhances the release of 2-AG in various brain regions (Patel and Hillard, 2008; Patel et al., 2009).”

“Moreover, the endocannabinoids exert negative fine-tuning control over the hypothalamus–hypophysis–adrenal stress axis and their levels are altered in certain brain regions in response to stress (Patel et al., 2004; Gorzalka et al., 2008; Patel and Hillard, 2008; Finn, 2010).”

“…are vital for stress adaptation processes in the brain (Marsicano et al., 2002; Kamprath et al., 2006), including habituation of HPA responses (Patel & Hillard, 2008). eCB function and CB1R signalling are also labile in many limbic regions in response to chronic stress or CORT (Rossi et al.,…”

“CB1 receptor agonists may suppress these types of adverse memories and the anxiety that coexists (116-118).”

“9,12,15,19,41,42 Our data here refine the temporal specificity for stress-induced elevations in BLA eCBs by revealing phasic increases in eCB production and release at vHPC-BLA synapses that closely parallel increases in BLA activity.”

“It has been suggested that EC signaling is required for stress adaptation and that a dysfunction of the EC system or an inability to upregulate its activity during stressful conditions could predispose individuals to the development of depression or other stress-related disorders (Gorzalka et al., 2008; Patel and Hill…”

“With respect to endocannabinoid signaling, it has also been proposed that cannabinoids could represent a therapeutic target for the treatment of psychiatric diseases such as post-traumatic stress disorders (Patel and Hillard, 2008; Marsicano et al., 2002).”

“…receptors signaling to constrain HPA axis activity under acute conditions (Hill et al., 2011; Marsicano et al., 2002; Rademacher et al., 2008), whereas chronic corticosterone or chronic unpredictable stress leads to a functional down-regulation in CB1 receptors signaling (Patel & Hillard, 2008).”

“…and NAc DA release (at least in CD rats) may be mediated by region-specific changes in endocannabinoid signaling, specifically via 2-AG production (Patel & Hillard, 2008) In order to test whether hypothalamic indices of HPA axis activation after acute stress were modified by early diet exposure,…”

“On the one hand, eCB levels seem to fluctuate in response to environmental challenges (Gorzalka et al., 2008; Patel and Hillard, 2008).”

“Stress exposure also alters brain concentrations of endocannabinoids such as 2-AG and anandamide in the amygdala, prefrontal cortices and hippocampus (Hill and McEwen, 2010; Hill et al., 2004; Hillard, 2014; McLaughlin et al., 2014; Patel and Hillard, 2008; Patel et al., 2009; Patel et al., 2005; Rademacher et al., 20…”

“Relevantly, immobilization paradigms have the great advantage of being relatively simple and standardizable, although construct validity is limited as it only recapitulates the immobilization phase of a natural catastrophe such as an earthquake, consequently featuring high habituation rates [86].”

“In contrast, chronic stress in rodents results in reduced eCB-mediated CB1 receptor signaling, and poor adaptation and excessive stress responses (47).”

“More importantly, it has been demonstrated that during chronic stress the endocannabinoid signalling changes gradually leading to stress habituation (Patel & Hillard 2008), which is impaired in migraine patients (Afra et al. 2000).”

“The roles of the endocannabinoid system in mediating neurological responses to stress have been reviewed elsewhere (Hill and Gorzalka, 2009; Patel and Hillard, 2008).”