Recruitment of Prefrontal Cortical Endocannabinoid Signaling by Glucocorticoids Contributes to Termination of the Stress Response

Laboratory of Neuroendocrinology, The Rockefeller University, New York, New York 10065, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 07/2011; 31(29):10506-15. DOI: 10.1523/JNEUROSCI.0496-11.2011
Source: PubMed


The mechanisms subserving the ability of glucocorticoid signaling within the medial prefrontal cortex (mPFC) to terminate stress-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis are not well understood. We report that antagonism of the cannabinoid CB(1) receptor locally within the mPFC prolonged corticosterone secretion following cessation of stress in rats. Mice lacking the CB(1) receptor exhibited a similar prolonged response to stress. Exposure of rats to stress produced an elevation in the endocannabinoid 2-arachidonoylglycerol within the mPFC that was reversed by pretreatment with the glucocorticoid receptor antagonist RU-486 (20 mg/kg). Electron microscopic and electrophysiological data demonstrated the presence of CB(1) receptors in inhibitory-type terminals impinging upon principal neurons within layer V of the prelimbic region of the mPFC. Bath application of corticosterone (100 nm) to prefrontal cortical slices suppressed GABA release onto principal neurons in layer V of the prelimbic region, when examined 1 h later, which was prevented by application of a CB(1) receptor antagonist. Collectively, these data demonstrate that the ability of stress-induced glucocorticoid signaling within mPFC to terminate HPA axis activity is mediated by a local recruitment of endocannabinoid signaling. Endocannabinoid activation of CB(1) receptors decreases GABA release within the mPFC, likely increasing the outflow of the principal neurons of the prelimbic region to contribute to termination of the stress response. These data support a model in which endocannabinoid signaling links glucocorticoid receptor engagement to activation of corticolimbic relays that inhibit corticosterone secretion.

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    • "Egoera normaletan sistema endokannabinoideak erregulazio negatibo bat eragiten du HPA ardatzean eta nerbio sistema begetatiboan eta ondorioz, sistema horietako hormonen jariapena inhibitzen da. Estres-egoeretan, endokannabinoide mailak jaisten dira eta horren ondorioz, inhibizioa eteten da eta aipatutako bi sistemak berriro aktibatzen dira (Hill et al., 2011). "
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    ABSTRACT: Laburpena Gaur egun, gero eta ebidentzia gehiago aurkitzen dira sistema endokannabinoideak (eCB) estres-prozesuetan duen ondorioei buruz. Sistema horretan dagoen CB1 hartzailea (CB1R) genetikoki ezabatzeak hipotalamo-hipofisi-adrenal (HPA) ardatzaren aktibitatea areagotzea eragiten du eta animaliak estresera sentsibilizatzen ditu. Are gehiago, ikerketa neurofisiologikoek erakutsi dutenez, CB1 hartzailearen aktibitatean aldaketak gertatzen dira estresaren ondorioz. Aurkikuntza hauek badira ere, ez da oso ezaguna estresaren eragina aipatutako giltzurrun gaineko guruinaren sistema endokannabinoidean. Hitz gakoak: eCB-CB1R-estres-giltzurrun gaineko guruina Abstract Increasing evidence suggests that the endocannabinoid (eCB) system plays a role in stress responses. Genetic disruption of the endocannabinoid signaling by knocking out the cannabinoid 1 receptor (CB1R) increases activity of the hypothalamic-pituitary-adrenal (HPA) axis, sensitizing animals to stress. Furthermore, neurophysiological studies reveal changes in CB1 receptor activity following stress. Despite these findings, little is known about how stress affects the endocannabinoid system in the adrenal gland.
    Ikergazte, Durango; 05/2015
    • "Deletion of CB1 receptors exacerbates stress-induced retraction of mPFC dendrites (Hill et al. 2011a), whereas deletion of a degradative enzyme, fatty acid amide hydrolase, prevents stress induced dendrite expansion in basolateral amygala neurons (Hill et al. 2013). Endocannabinoids also play a role in shut-off of HPA function, as well as basal CORT (cortisol, human; corticosterone, rodent) levels after chronic stress and habituation of the CORT response to chronic stress and they appear to do so via the prefrontal cortex and amygdala (Hill et al. 2011b). With regard to estrogen actions, there are multiple targets of genomic and non-genomic actions of E 2 . "
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    ABSTRACT: The discovery of steroid hormone receptors in brain regions that mediate every aspect of brain function has broadened the definition of "neuroendocrinology" to include the reciprocal communication between the brain and the body via hormonal and neural pathways. The brain is the central organ of stress and adaptation to stress because it perceives and determines what is threatening, as well as the behavioral and physiological responses to the stressor. The adult and developing brain possess remarkable structural and functional plasticity in response to stress, including neuronal replacement, dendritic remodeling, and synapse turnover. Stress causes an imbalance of neural circuitry subserving cognition, decision-making, anxiety and mood that can alter expression of those behaviors and behavioral states. This imbalance, in turn, affects systemic physiology via neuroendocrine, autonomic, immune and metabolic mediators. In the short term, as for increased fearful vigilance and anxiety in a threatening environment, these changes may be adaptive. But, if the danger passes and the behavioral state persists along with the changes in neural circuitry, such maladaptation may need intervention with a combination of pharmacological and behavioral therapies, as is the case for chronic anxiety and depression. There are important sex differences in the brain responses to stressors that are in urgent need of further exploration. Moreover, adverse early-life experience, interacting with alleles of certain genes, produce lasting effects on brain and body over the life-course via epigenetic mechanisms. While prevention is most important, the plasticity of the brain gives hope for therapies that take into consideration brain-body interactions.
    Journal of Endocrinology 05/2015; 226(2). DOI:10.1530/JOE-15-0121 · 3.72 Impact Factor
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    • "Since virtually nothing is known about the function of pepcans in the CNS and the periphery, our data may inspire more detailed work on the CB1 receptor negative allosteric modulating role of these peptides, complementing a recent report on endogenous positive allosteric CB1 modulators (Pamplona et al., 2012). The ECS is an important regulator of neuroendocrine and behavioral adaptation in stress related disorders (Riebe and Wotjak, 2011; Hill et al., 2011). Endocannabinoids are typically released under stress and act via CB1 receptor activation on the HPA-axis, with differentially regulated 2- AG and AEA levels in the brain and elevated levels of AEA being found in the periphery (Hill et al., 2010, 2006; Cota, 2008; Hill et al., 2006; Wenger et al., 2003). "
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    ABSTRACT: The endocannabinoid system (ECS) comprises the cannabinoid receptors CB1 and CB2 and their endogenous arachidonic acid-derived agonists 2-arachidonoyl glycerol and anandamide, which play important neuromodulatory roles. Recently, a novel class of negative allosteric CB1 receptor peptide ligands, hemopressin-like peptides derived from alpha hemoglobin, has been described, with yet unknown origin and function in the CNS. Using monoclonal antibodies we now identified the localization of RVD-hemopressin (pepcan-12) and N-terminally extended peptide endocannabinoids (pepcans) in the CNS and determined their neuronal origin. Immunohistochemical analyses in rodents revealed distinctive and specific staining in major groups of noradrenergic neurons, including the locus coeruleus (LC), A1, A5 and A7 neurons, which appear to be major sites of production/release in the CNS. No staining was detected in dopaminergic neurons. Peptidergic axons were seen throughout the brain (notably hippocampus and cerebral cortex) and spinal cord, indicative of anterograde axonal transport of pepcans. Intriguingly, the chromaffin cells in the adrenal medulla were also strongly stained for pepcans. We found specific co-expression of pepcans with galanin, both in the LC and adrenal gland. Using LC-MS/MS, pepcan-12 was only detected in non-perfused brain (∼40 pmol/g), suggesting that in the CNS it is secreted and present in extracellular compartments. In adrenal glands, significantly more pepcan-12 (400-700 pmol/g) was measured in both non-perfused and perfused tissue. Thus, chromaffin cells may be a major production site of pepcan-12 found in blood. These data uncover important areas of peptide endocannabinoid occurrence with exclusive noradrenergic immunohistochemical staining, opening new doors to investigate their potential physiological function in the ECS. Copyright © 2015. Published by Elsevier Ltd.
    Neuropharmacology 03/2015; DOI:10.1016/j.neuropharm.2015.03.021 · 5.11 Impact Factor
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