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Endocannabinoid Signaling and the Hypothalamic‐Pituitary‐Adrenal Axis

Cecilia J. Hillard, Margaret Beatka, Jenna Sarvaideo

10.1002/cphy.c160005

Source: Volume 7, Issue 1, January 2017

Published online: December 2016

Full Article on Wiley Online Library



ABSTRACT

The elucidation of Δ9‐tetrahydrocannabinol as the active principal of Cannabis sativa in 1963 initiated a fruitful half‐century of scientific discovery, culminating in the identification of the endocannabinoid signaling system, a previously unknown neuromodulatory system. A primary function of the endocannabinoid signaling system is to maintain or recover homeostasis following psychological and physiological threats. We provide a brief introduction to the endocannabinoid signaling system and its role in synaptic plasticity. The majority of the article is devoted to a summary of current knowledge regarding the role of endocannabinoid signaling as both a regulator of endocrine responses to stress and as an effector of glucocorticoid and corticotrophin‐releasing hormone signaling in the brain. We summarize data demonstrating that cannabinoid receptor 1 (CB1R) signaling can both inhibit and potentiate the activation of the hypothalamic‐pituitary‐adrenal axis by stress. We present a hypothesis that the inhibitory arm has high endocannabinoid tone and also serves to enhance recovery to baseline following stress, while the potentiating arm is not tonically active but can be activated by exogenous agonists. We discuss recent findings that corticotropin‐releasing hormone in the amygdala enables hypothalamic‐pituitary‐adrenal axis activation via an increase in the catabolism of the endocannabinoid N‐arachidonylethanolamine. We review data supporting the hypotheses that CB1R activation is required for many glucocorticoid effects, particularly feedback inhibition of hypothalamic‐pituitary‐adrenal axis activation, and that glucocorticoids mobilize the endocannabinoid 2‐arachidonoylglycerol. These features of endocannabinoid signaling make it a tantalizing therapeutic target for treatment of stress‐related disorders but to date, this promise is largely unrealized. © 2017 American Physiological Society. Compr Physiol 7:1‐15, 2017.

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Figure 1. Figure 1. Two eCBs act at CB1 and CB2 receptors with differing affinities and efficacies. AEA, N‐arachidonylethanolamine; CB1R, subtype 1 of the cannabinoid receptor; CB2R, subtype 2 of the cannabinoid receptor; 2‐AG, 2‐arachidonoylglycerol. Affinity refers to the ability of the eCB and receptor to form a bound complex and efficacy refers to the ability of the eCB to induce signaling via the receptor.
Figure 2. Figure 2. (A) Biosynthetic and catabolic pathways for AEA. (B) Biosynthetic and catabolic pathways for 2‐AG. AA, arachidonic acid; Abhd, alpha‐beta‐hydrolase domain protein; DAG, diacylglycerol; DAGL, diacylglycerol lipase; EA, ethanolamine; FAAH, fatty acid amide hydrolase; GDE1, glycerophosphodiesterase 1; GP‐AEA, glycerophospho‐AEA; NAAA, N‐acylethanolamine‐hydrolyzing acid amidase; NAPE‐PLD, N‐acyl phosphatidylethanolamine‐specific phospholipase D; NAT, N‐acyltransferase; PA, phosphatidic acid; PAP, phosphatidic acid phosphatase; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PIP2, phosphatidylinositol bis phosphate; PI‐PLC, phosphatidylinositol‐specific phospholipase C; PLA/AT, phospholipase A/acyltransferase; PLA2, phospholipase A2; PLC, phospholipase C; PLD, phospholipase D; PTPN22, protein tyrosine phosphatase, nonreceptor type 22; SHIP1, Src homology 2‐containing inositol phosphatase‐1.
Figure 3. Figure 3. (A) Components of eCB signaling are expressed at the synapse. Shown is the common pattern of distribution of the CB1R and the proteins involved in the synthesis and degradation of the eCBs AEA and 2‐AG. See the legend to Figure 2 for abbreviations. (B) CB1R, via Gαi/0, inhibit neurotransmitter release via multiple mechanisms. Inhibition of the opening of voltage‐gated calcium channels results in the short‐term changes in synaptic plasticity of depolarization‐induced suppression of inhibition (DSI) or excitation (DSE). Inhibition of cAMP generation and the subsequent reduction in activation of protein kinase A results in long term depression of inhibition (iLTD) and long term depression of excitation (LTD).
Figure 4. Figure 4. mGluR and 2‐AG regulation of synaptic activity. (A) In this scenario, the CB1R are present on glutamatergic terminals so increased 2‐AG synthesis in response to mGluR receptor activation results in inhibition of glutamate release. As a result, the synaptic balance is shifted to reduced excitation and increased inhibition (A1). (B) In this scenario, the CB1R are present on GABA terminals and increased 2‐AG synthesis results in inhibition of GABA release. As a result, the synaptic balance is shifted to greater excitation and reduced inhibition. 2‐AG, 2‐arachidonoylglycerol; CB1R, subtype 1 of the cannabinoid receptor; Glu, glutamate; mGluR, metabotropic glutamate receptor. Other abbreviations are in the legend to Figure 2.
Figure 5. Figure 5. Hypothesized expression and function of CB1R along the HPA axis. Data described in the text support the expression and hypothesized inhibitory roles of the CB1R at all three levels of the HPA axis. In the paraventricular nucleus, CB1R have been identified on both glutamatergic and GABAergic terminals. Corticotropes of the anterior pituitary express CB1R, which we hypothesize, could inhibit CRH‐induced activation of adenylyl cyclase (AC), thereby reducing cAMP concentrations. In the adrenal gland, CB1R have been identified on cortical cells, where we hypothesize they could oppose the elevation of cAMP induced by ACTH acting through melanocortin 2 receptors (MC2R). CB1R have also been proposed to be present on medullary cells of the adrenal gland and to inhibit the release of epinephrine (EPI) from these cells. This would result in reduced activation of ß‐adrenergic receptors (ßAR) on the cortical cells.
Figure 6. Figure 6. High‐efficacy cannabinoid agonists have biphasic effects on HPA axis activation by stress, while the partial agonist, THC, and antagonists increase HPA axis activation. Our hypothesis for these findings is displayed in this figure. The CB1R‐mediated inhibition of HPA axis activation by stress has high eCB tone (as is shown in Fig. 7). As a result, only high efficacy agonists can increase this tone further. Low‐efficacy agonists and antagonists will inhibit this tone and “uncover” the HPA axis potentiating CB1R function. We hypothesize based on the data available that the HPA axis potentiating CB1R has low eCB tone.
Figure 7. Figure 7. Depiction of the amygdalar AEA gate hypothesis. According to this hypothesis, AEA concentrations are high at rest, resulting in tonic activation of CB1R on glutamatergic terminals in the basolateral amygdala. This prevents glutamate release. Increased CRH as occurs during stress results in activation of FAAH by an as‐yet unidentified mechanism, resulting in reduced AEA and relief of AEA/CB1R‐mediated inhibition of glutamate release.
Figure 8. Figure 8. In both the prefrontal cortex and hippocampus, studies demonstrate that 2‐AG synthesis is enhanced by glucocorticoid (CORT) through activation of GRs. CB1R on GABAergic terminals are subsequently activated, resulted in reduced GABA release and disinhibition of glutamatergic projection neurons. These neurons project onto GABAergic neurons in other areas of the brain which ultimately inhibit CRH release.


Figure 1. Two eCBs act at CB1 and CB2 receptors with differing affinities and efficacies. AEA, N‐arachidonylethanolamine; CB1R, subtype 1 of the cannabinoid receptor; CB2R, subtype 2 of the cannabinoid receptor; 2‐AG, 2‐arachidonoylglycerol. Affinity refers to the ability of the eCB and receptor to form a bound complex and efficacy refers to the ability of the eCB to induce signaling via the receptor.


Figure 2. (A) Biosynthetic and catabolic pathways for AEA. (B) Biosynthetic and catabolic pathways for 2‐AG. AA, arachidonic acid; Abhd, alpha‐beta‐hydrolase domain protein; DAG, diacylglycerol; DAGL, diacylglycerol lipase; EA, ethanolamine; FAAH, fatty acid amide hydrolase; GDE1, glycerophosphodiesterase 1; GP‐AEA, glycerophospho‐AEA; NAAA, N‐acylethanolamine‐hydrolyzing acid amidase; NAPE‐PLD, N‐acyl phosphatidylethanolamine‐specific phospholipase D; NAT, N‐acyltransferase; PA, phosphatidic acid; PAP, phosphatidic acid phosphatase; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PIP2, phosphatidylinositol bis phosphate; PI‐PLC, phosphatidylinositol‐specific phospholipase C; PLA/AT, phospholipase A/acyltransferase; PLA2, phospholipase A2; PLC, phospholipase C; PLD, phospholipase D; PTPN22, protein tyrosine phosphatase, nonreceptor type 22; SHIP1, Src homology 2‐containing inositol phosphatase‐1.


Figure 3. (A) Components of eCB signaling are expressed at the synapse. Shown is the common pattern of distribution of the CB1R and the proteins involved in the synthesis and degradation of the eCBs AEA and 2‐AG. See the legend to Figure 2 for abbreviations. (B) CB1R, via Gαi/0, inhibit neurotransmitter release via multiple mechanisms. Inhibition of the opening of voltage‐gated calcium channels results in the short‐term changes in synaptic plasticity of depolarization‐induced suppression of inhibition (DSI) or excitation (DSE). Inhibition of cAMP generation and the subsequent reduction in activation of protein kinase A results in long term depression of inhibition (iLTD) and long term depression of excitation (LTD).


Figure 4. mGluR and 2‐AG regulation of synaptic activity. (A) In this scenario, the CB1R are present on glutamatergic terminals so increased 2‐AG synthesis in response to mGluR receptor activation results in inhibition of glutamate release. As a result, the synaptic balance is shifted to reduced excitation and increased inhibition (A1). (B) In this scenario, the CB1R are present on GABA terminals and increased 2‐AG synthesis results in inhibition of GABA release. As a result, the synaptic balance is shifted to greater excitation and reduced inhibition. 2‐AG, 2‐arachidonoylglycerol; CB1R, subtype 1 of the cannabinoid receptor; Glu, glutamate; mGluR, metabotropic glutamate receptor. Other abbreviations are in the legend to Figure 2.


Figure 5. Hypothesized expression and function of CB1R along the HPA axis. Data described in the text support the expression and hypothesized inhibitory roles of the CB1R at all three levels of the HPA axis. In the paraventricular nucleus, CB1R have been identified on both glutamatergic and GABAergic terminals. Corticotropes of the anterior pituitary express CB1R, which we hypothesize, could inhibit CRH‐induced activation of adenylyl cyclase (AC), thereby reducing cAMP concentrations. In the adrenal gland, CB1R have been identified on cortical cells, where we hypothesize they could oppose the elevation of cAMP induced by ACTH acting through melanocortin 2 receptors (MC2R). CB1R have also been proposed to be present on medullary cells of the adrenal gland and to inhibit the release of epinephrine (EPI) from these cells. This would result in reduced activation of ß‐adrenergic receptors (ßAR) on the cortical cells.


Figure 6. High‐efficacy cannabinoid agonists have biphasic effects on HPA axis activation by stress, while the partial agonist, THC, and antagonists increase HPA axis activation. Our hypothesis for these findings is displayed in this figure. The CB1R‐mediated inhibition of HPA axis activation by stress has high eCB tone (as is shown in Fig. 7). As a result, only high efficacy agonists can increase this tone further. Low‐efficacy agonists and antagonists will inhibit this tone and “uncover” the HPA axis potentiating CB1R function. We hypothesize based on the data available that the HPA axis potentiating CB1R has low eCB tone.


Figure 7. Depiction of the amygdalar AEA gate hypothesis. According to this hypothesis, AEA concentrations are high at rest, resulting in tonic activation of CB1R on glutamatergic terminals in the basolateral amygdala. This prevents glutamate release. Increased CRH as occurs during stress results in activation of FAAH by an as‐yet unidentified mechanism, resulting in reduced AEA and relief of AEA/CB1R‐mediated inhibition of glutamate release.


Figure 8. In both the prefrontal cortex and hippocampus, studies demonstrate that 2‐AG synthesis is enhanced by glucocorticoid (CORT) through activation of GRs. CB1R on GABAergic terminals are subsequently activated, resulted in reduced GABA release and disinhibition of glutamatergic projection neurons. These neurons project onto GABAergic neurons in other areas of the brain which ultimately inhibit CRH release.
References
 1. Achterberg EJ , Trezza V , Vanderschuren LJ . Glucocorticoid receptor antagonism disrupts the reconsolidation of social reward‐related memories in rats. Behav Pharmacol 25: 216‐225, 2014.
 2. Azad SC , Monory K , Marsicano G , Cravatt BF , Lutz B , Zieglgansberger W , Rammes G . Circuitry for associative plasticity in the amygdala involves endocannabinoid signaling. J Neurosci 24: 9953‐9961, 2004.
 3. Bitencourt RM , Alpar A , Cinquina V , Ferreira SG , Pinheiro BS , Lemos C , Ledent C , Takahashi RN , Sialana FJ , Lubec G , Cunha RA , Harkany T , Kofalvi A . Lack of presynaptic interaction between glucocorticoid and CB1 cannabinoid receptors in GABA‐ and glutamatergic terminals in the frontal cortex of laboratory rodents. Neurochem Int 90: 72‐84, 2015.
 4. Block RI , Farinpour R , Schlechte JA . Effects of chronic marijuana use on testosterone, luteinizing hormone, follicle stimulating hormone, prolactin and cortisol in men and women. Drug Alcohol Depend 28: 121‐128, 1991.
 5. Bloom AS , Kiernan CJ . Interaction of ambient temperature with the effects of delta 9‐tetrahydrocannabinol on brain catecholamine synthesis and plasma corticosterone levels. Psychopharmacology (Berl) 67: 215‐219, 1980.
 6. Bortolato M , Mangieri RA , Fu J , Kim JH , Arguello O , Duranti A , Tontini A , Mor M , Tarzia G , Piomelli D . Antidepressant‐like activity of the fatty acid amide hydrolase inhibitor URB597 in a rat model of chronic mild stress. Biol Psychiatry 62: 1103‐1110, 2007.
 7. Bouaboula M , Rinaldi M , Carayon P , Carillon C , Delpech B , Shire D , Le Fur G , Casellas P . Cannabinoid‐receptor expression in human leukocytes. Eur J Biochem 214: 173‐180, 1993.
 8. Boulware MI , Kordasiewicz H , Mermelstein PG . Caveolin proteins are essential for distinct effects of membrane estrogen receptors in neurons. J Neurosci 27: 9941‐9950, 2007.
 9. Bowles NP , Hill MN , Bhagat SM , Karatsoreos IN , Hillard CJ , McEwen BS . Chronic, noninvasive glucocorticoid administration suppresses limbic endocannabinoid signaling in mice. Neuroscience 204: 83‐89, 2012.
 10. Bowles NP , Karatsoreos IN , Li X , Vemuri VK , Wood JA , Li Z , Tamashiro KL , Schwartz GJ , Makriyannis AM , Kunos G , Hillard CJ , McEwen BS , Hill MN . A peripheral endocannabinoid mechanism contributes to glucocorticoid‐mediated metabolic syndrome. Proc Natl Acad Sci U S A 112: 285‐290, 2015.
 11. Buckley NE , Hansson S , Harta G , Mezey E . Expression of the CB1 and CB2 receptor messenger RNAs during embryonic development in the rat. Neurosci 82: 1131‐1149, 1998.
 12. Buckner JD , Zvolensky MJ , Ecker AH , Jeffries ER . Cannabis craving in response to laboratory‐induced social stress among racially diverse cannabis users: The impact of social anxiety disorder. J Psychopharmacol 30: 363‐369, 2016.
 13. Bujarski SJ , Feldner MT , Lewis SF , Babson KA , Trainor CD , Leen‐Feldner E , Badour CL , Bonn‐Miller MO . Marijuana use among traumatic event‐exposed adolescents: Posttraumatic stress symptom frequency predicts coping motivations for use. Addict Behav 37: 53‐59, 2012.
 14. Campolongo P , Roozendaal B , Trezza V , Hauer D , Schelling G , McGaugh JL , Cuomo V . Endocannabinoids in the rat basolateral amygdala enhance memory consolidation and enable glucocorticoid modulation of memory. Proc Natl Acad Sci U S A 106: 4888‐4893, 2009.
 15. Campos AC , Ferreira FR , da Silva WA, Jr. , Guimaraes FS . Predator threat stress promotes long lasting anxiety‐like behaviors and modulates synaptophysin and CB1 receptors expression in brain areas associated with PTSD symptoms. Neurosci Lett 533: 34‐38, 2013.
 16. Caulfield MP , Brown DA . Cannabinoid receptor agonists inhibit Ca current in NG108‐15 neuroblastoma cells via a pertussis toxin‐sensitive mechanism. Br J Pharmacol 106: 231‐232, 1992.
 17. Christensen R , Kristensen PK , Bartels EM , Bliddal H , Astrup A . Efficacy and safety of the weight‐loss drug rimonabant: A meta‐analysis of randomised trials. Lancet 370: 1706‐1713, 2007.
 18. Cone EJ , Johnson RE , Moore JD , Roache JD . Acute effects of smoking marijuana on hormones, subjective effects and performance in male human subjects. Pharmacol Biochem Behav 24: 1749‐1754, 1986.
 19. Cota D , Steiner MA , Marsicano G , Cervino C , Herman JP , Grubler Y , Stalla J , Pasquali R , Lutz B , Stalla GK , Pagotto U . Requirement of cannabinoid receptor type 1 for the basal modulation of hypothalamic‐pituitary‐adrenal axis function. Endocrinology 148: 1574‐1581, 2007.
 20. Coutts AA , Irving AJ , Mackie K , Pertwee RG , Anavi‐Goffer S . Localisation of cannabinoid CB(1) receptor immunoreactivity in the guinea pig and rat myenteric plexus. J Comp Neurol 448: 410‐422, 2002.
 21. Craft RM , Marusich JA , Wiley JL . Sex differences in cannabinoid pharmacology: A reflection of differences in the endocannabinoid system? Life Sci 92: 476‐481, 2012.
 22. Cravatt BF , Demarest K , Patricelli MP , Bracey MH , Giang DK , Martin BR , Lichtman AH . Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase. Proc Natl Acad Sci U S A 98: 9371‐9376, 2001.
 23. Cravatt BF , Giang DK , Mayfield SP , Boger DL , Lerner RA , Gilula NB . Molecular characterization of an enzyme that degrades neuromodulatory fatty‐acid amides. Nature 384: 83‐87, 1996.
 24. D'Souza DC , Perry E , MacDougall L , Ammerman Y , Cooper T , Wu YT , Braley G , Gueorguieva R , Krystal JH . The psychotomimetic effects of intravenous delta‐9‐tetrahydrocannabinol in healthy individuals: Implications for psychosis. Neuropsychopharmacology 29: 1558‐1572, 2004.
 25. D'Souza DC , Ranganathan M , Braley G , Gueorguieva R , Zimolo Z , Cooper T , Perry E , Krystal J . Blunted psychotomimetic and amnestic effects of delta‐9‐tetrahydrocannabinol in frequent users of cannabis. Neuropsychopharmacology 33: 2505‐2516, 2008.
 26. de Kloet ER , Sibug RM , Helmerhorst FM , Schmidt MV . Stress, genes and the mechanism of programming the brain for later life. Neurosci Biobehav Rev 29: 271‐281, 2005.
 27. de Quervain DJ , Aerni A , Schelling G , Roozendaal B . Glucocorticoids and the regulation of memory in health and disease. Front Neuroendocrinol 30: 358‐370, 2009.
 28. Di S , Malcher‐Lopes R , Halmos KC , Tasker JG . Nongenomic glucocorticoid inhibition via endocannabinoid release in the hypothalamus: A fast feedback mechanism. J Neurosci 23: 4850‐4857, 2003.
 29. Di S , Malcher‐Lopes R , Marcheselli VL , Bazan NG , Tasker JG . Rapid glucocorticoid‐mediated endocannabinoid release and opposing regulation of glutamate and GABA inputs to hypothalamic magnocellular neurons. Endocrinology 146: 4292‐4301, 2005.
 30. Dinh TP , Carpenter D , Leslie FM , Freund TF , Katona I , Sensi SL , Kathuria S , Piomelli D . Brain monoglyceride lipase participating in endocannabinoid inactivation. Proc Natl Acad Sci U S A 99: 10819‐10824, 2002.
 31. Diorio D , Viau V , Meaney MJ . The role of the medial prefrontal cortex (cingulate gyrus) in the regulation of hypothalamic‐pituitary‐adrenal responses to stress. J Neurosci 13: 3839‐3847, 1993.
 32. Evanson NK , Herman JP . Metabotropic glutamate receptor‐mediated signaling dampens the HPA axis response to restraint stress. Physiol Behav 150: 2‐7, 2015.
 33. Evanson NK , Tasker JG , Hill MN , Hillard CJ , Herman JP . Fast feedback inhibition of the HPA axis by glucocorticoids is mediated by endocannabinoid signaling. Endocrinology 151: 4811‐4819, 2010.
 34. Fernandez‐Ruiz JJ , Munoz RM , Romero J , Villanua MA , Makriyannis A , Ramos JA . Time course of the effects of different cannabimimetics on prolactin and gonadotrophin secretion: Evidence for the presence of CB1 receptors in hypothalamic structures and their involvement in the effects of cannabimimetics. Biochem Pharmacol 53: 1919‐1927, 1997.
 35. Forray MI , Gysling K . Role of noradrenergic projections to the bed nucleus of the stria terminalis in the regulation of the hypothalamic‐pituitary‐adrenal axis. Brain Res Brain Res Rev 47: 145‐160, 2004.
 36. Fox CL , Towe SL , Stephens RS , Walker DD , Roffman RA . Motives for cannabis use in high‐risk adolescent users. Psychol Addict Behav 25: 492‐500, 2011.
 37. Freund TF , Katona I , Piomelli D . Role of endogenous cannabinoids in synaptic signaling. Physiol Rev 83: 1017‐1066, 2003.
 38. Frick KM . Molecular mechanisms underlying the memory‐enhancing effects of estradiol. Horm Behav 74: 4‐18, 2015.
 39. Ganon‐Elazar E , Akirav I . Cannabinoid receptor activation in the basolateral amygdala blocks the effects of stress on the conditioning and extinction of inhibitory avoidance. J Neurosci 29: 11078‐11088, 2009.
 40. Gobbi G , Bambico FR , Mangieri R , Bortolato M , Campolongo P , Solinas M , Cassano T , Morgese MG , Debonnel G , Duranti A , Tontini A , Tarzia G , Mor M , Trezza V , Goldberg SR , Cuomo V , Piomelli D . Antidepressant‐like activity and modulation of brain monoaminergic transmission by blockade of anandamide hydrolysis. Proc Natl Acad Sci U S A 102: 18620‐18625, 2005.
 41. Gray JM , Vecchiarelli HA , Morena M , Lee TT , Hermanson DJ , Kim AB , McLaughlin RJ , Hassan KI , Kuhne C , Wotjak CT , Deussing JM , Patel S , Hill MN . Corticotropin‐releasing hormone drives anandamide hydrolysis in the amygdala to promote anxiety. J Neurosci 35: 3879‐3892, 2015.
 42. Gray JM , Wilson CD , Lee TT , Pittman QJ , Deussing JM , Hillard CJ , McEwen BS , Schulkin J , Karatsoreos IN , Patel S , Hill MN . Sustained glucocorticoid exposure recruits cortico‐limbic CRH signaling to modulate endocannabinoid function. Psychoneuroendocrinology 66: 151‐158, 2016.
 43. Gulyas AI , Cravatt BF , Bracey MH , Dinh TP , Piomelli D , Boscia F , Freund TF . Segregation of two endocannabinoid‐hydrolyzing enzymes into pre‐ and postsynaptic compartments in the rat hippocampus, cerebellum and amygdala. Eur J Neurosci 20: 441‐458, 2004.
 44. Hartmann K , Koenen M , Schauer S , Wittig‐Blaich S , Ahmad M , Baschant U , Tuckermann JP . Molecular actions of glucocorticoids in cartilage and bone during health, disease, and steroid therapy. Physiol Rev 96: 409‐447, 2016.
 45. Herkenham M , Groen BG , Lynn AB , De Costa BR , Richfield EK . Neuronal localization of cannabinoid receptors and second messengers in mutant mouse cerebellum. Brain Res 552: 301‐310, 1991.
 46. Herkenham M , Lynn AB , Johnson MR , Melvin LS , de Costa BR , Rice KC . Characterization and localization of cannabinoid receptors in rat brain: A quantitative in vitro autoradiographic study. J Neurosci 11: 563‐583, 1991.
 47. Herman JP , Figueiredo H , Mueller NK , Ulrich‐Lai Y , Ostrander MM , Choi DC , Cullinan WE . Central mechanisms of stress integration: Hierarchical circuitry controlling hypothalamo‐pituitary‐adrenocortical responsiveness. Front Neuroendocrinol 24: 151‐180, 2003.
 48. Herman JP , McKlveen JM , Ghosal S , Kopp B , Wulsin A , Makinson R , Scheimann J , Myers B . Regulation of the hypothalamic‐pituitary‐adrenocortical stress response. Compr Physiol 6: 603‐621, 2016.
 49. Herman JP , Ostrander MM , Mueller NK , Figueiredo H . Limbic system mechanisms of stress regulation: Hypothalamo‐pituitary‐adrenocortical axis. Prog Neuropsychopharmacol Biol Psychiatry 29: 1201‐1213, 2005.
 50. Hermann H , Marsicano G , Lutz B . Coexpression of the cannabinoid receptor type 1 with dopamine and serotonin receptors in distinct neuronal subpopulations of the adult mouse forebrain. Neuroscience 109: 451‐460, 2002.
 51. Hermanson DJ , Gamble‐George JC , Marnett LJ , Patel S . Substrate‐selective COX‐2 inhibition as a novel strategy for therapeutic endocannabinoid augmentation. Trends Pharmacol Sci 35: 358‐367, 2014.
 52. Hill MN , Carrier EJ , Ho WS , Shi L , Patel S , Gorzalka BB , Hillard CJ . Prolonged glucocorticoid treatment decreases cannabinoid CB1 receptor density in the hippocampus. Hippocampus 18: 221‐226, 2008.
 53. Hill MN , Karatsoreos IN , Hillard CJ , McEwen BS . Rapid elevations in limbic endocannabinoid content by glucocorticoid hormones in vivo. Psychoneuroendocrinology 35: 1333‐1338, 2010.
 54. Hill MN , McEwen BS . Endocannabinoids: The silent partner of glucocorticoids in the synapse. Proc Natl Acad Sci U S A 106: 4579‐4580, 2009.
 55. Hill MN , McLaughlin RJ , Bingham B , Shrestha L , Lee TT , Gray JM , Hillard CJ , Gorzalka BB , Viau V . Endogenous cannabinoid signaling is essential for stress adaptation. Proc Natl Acad Sci U S A 107: 9406‐9411, 2010.
 56. Hill MN , McLaughlin RJ , Morrish AC , Viau V , Floresco SB , Hillard CJ , Gorzalka BB . Suppression of amygdalar endocannabinoid signaling by stress contributes to activation of the hypothalamic‐pituitary‐adrenal axis. Neuropsychopharmacology 34: 2733‐2745, 2009.
 57. Hill MN , McLaughlin RJ , Pan B , Fitzgerald ML , Roberts CJ , Lee TT , Karatsoreos IN , Mackie K , Viau V , Pickel VM , McEwen BS , Liu QS , Gorzalka BB , Hillard CJ . Recruitment of prefrontal cortical endocannabinoid signaling by glucocorticoids contributes to termination of the stress response. J Neurosci 31: 10506‐10515, 2011.
 58. Hillard C , Liu Q‐S , Liu X , Pan B , Roberts C , Shi L . Cannabinoids, endocannabinoids and stress. In: DiMarzo V , editor. Cannabinoids. Hoboken, NJ: Wiley‐Blackwell, 2014.
 59. Hillard CJ . Biochemistry and pharmacology of the endocannabinoids arachidonylethanolamide and 2‐arachidonylglycerol. Prostaglandins Other Lipid Mediat 61: 3‐18, 2000.
 60. Hillard CJ . The endocannabinoid signaling system in the CNS: A primer. Int Rev Neurobiol 125: 1‐47, 2015.
 61. Hillard CJ , Manna S , Greenberg MJ , DiCamelli R , Ross RA , Stevenson LA , Murphy V , Pertwee RG , Campbell WB . Synthesis and characterization of potent and selective agonists of the neuronal cannabinoid receptor (CB1). J Pharmacol Exp Ther 289: 1427‐1433, 1999.
 62. Hong S , Zheng G , Wiley JW . Epigenetic regulation of genes that modulate chronic stress‐induced visceral pain in the peripheral nervous system. Gastroenterology 148: 148‐157 e147, 2015.
 63. Hong S , Zheng G , Wu X , Snider NT , Owyang C , Wiley JW . Corticosterone mediates reciprocal changes in CB 1 and TRPV1 receptors in primary sensory neurons in the chronically stressed rat. Gastroenterology 140: 627‐637, 2011.
 64. Howlett AC . Cannabinoid inhibition of adenylate cyclase. Biochemistry of the response in neuroblastoma cell membranes. Mol Pharmacol 27: 429‐436, 1985.
 65. Huang GZ , Woolley CS . Estradiol acutely suppresses inhibition in the hippocampus through a sex‐specific endocannabinoid and mGluR‐dependent mechanism. Neuron 74: 801‐808, 2012.
 66. Huizink AC , Mulder EJ . Maternal smoking, drinking or cannabis use during pregnancy and neurobehavioral and cognitive functioning in human offspring. Neurosci Biobehav Rev 30: 24‐41, 2006.
 67. Hyman SM , Sinha R . Stress‐related factors in cannabis use and misuse: Implications for prevention and treatment. J Subst Abuse Treat 36: 400‐413, 2009.
 68. Idris AI , Sophocleous A , Landao‐Bassonga E , Canals M , Milligan G , Baker D , van't Hof RJ , Ralston SH . Cannabinoid receptor type 1 protects against age‐related osteoporosis by regulating osteoblast and adipocyte differentiation in marrow stromal cells. Cell Metab 10: 139‐147, 2009.
 69. Idris AI , van ‘t Hof RJ , Greig IR , Ridge SA , Baker D , Ross RA , Ralston SH . Regulation of bone mass, bone loss and osteoclast activity by cannabinoid receptors. Nat Med 11: 774‐779, 2005.
 70. Jin XC , Lu YF , Yang XF , Ma L , Li BM . Glucocorticoid receptors in the basolateral nucleus of amygdala are required for postreactivation reconsolidation of auditory fear memory. Eur J Neurosci 25: 3702‐3712, 2007.
 71. Joels M , Sarabdjitsingh RA , Karst H . Unraveling the time domains of corticosteroid hormone influences on brain activity: Rapid, slow, and chronic modes. Pharmacol Rev 64: 901‐938, 2012.
 72. Kamprath K , Marsicano G , Tang J , Monory K , Bisogno T , Di Marzo V , Lutz B , Wotjak CT . Cannabinoid CB1 receptor mediates fear extinction via habituation‐like processes. J Neurosci 26: 6677‐6686, 2006.
 73. Kamprath K , Plendl W , Marsicano G , Deussing JM , Wurst W , Lutz B , Wotjak CT . Endocannabinoids mediate acute fear adaptation via glutamatergic neurons independently of corticotropin‐releasing hormone signaling. Genes Brain Behav 8: 203‐211, 2009.
 74. Kamprath K , Romo‐Parra H , Haring M , Gaburro S , Doengi M , Lutz B , Pape HC . Short‐term adaptation of conditioned fear responses through endocannabinoid signaling in the central amygdala. Neuropsychopharmacology 36: 652‐663, 2011.
 75. Kano M . Control of synaptic function by endocannabinoid‐mediated retrograde signaling. Proc Jpn Acad Ser B Phys Biol Sci 90: 235‐250, 2014.
 76. Kaplan HB , Martin SS , Johnson RJ , Robbins CA . Escalation of marijuana use: Application of a general theory of deviant behavior. J Health Soc Behav 27: 44‐61, 1986.
 77. Karst H , Berger S , Erdmann G , Schutz G , Joels M . Metaplasticity of amygdalar responses to the stress hormone corticosterone. Proc Natl Acad Sci U S A 107: 14449‐14454, 2010.
 78. Karst H , Berger S , Turiault M , Tronche F , Schutz G , Joels M . Mineralocorticoid receptors are indispensable for nongenomic modulation of hippocampal glutamate transmission by corticosterone. Proc Natl Acad Sci U S A 102: 19204‐19207, 2005.
 79. Katona I , Rancz EA , Acsady L , Ledent C , Mackie K , Hajos N , Freund TF . Distribution of CB1 cannabinoid receptors in the amygdala and their role in the control of GABAergic transmission. J Neurosci 21: 9506‐9518, 2001.
 80. Katona I , Sperlagh B , Sik A , Kafalvi A , Vizi ES , Mackie K , Freund TF . Presynaptically located CB1 cannabinoid receptors regulate GABA release from axon terminals of specific hippocampal interneurons. J Neurosci 19: 4544‐4558, 1999.
 81. Kearn CS , Greenberg MJ , DiCamelli R , Kurzawa K , Hillard CJ . Relationships between ligand affinities for the cerebellar cannabinoid receptor CB1 and the induction of GDP/GTP exchange. J Neurochem 72: 2379‐2387, 1999.
 82. King GR , Ernst T , Deng W , Stenger A , Gonzales RM , Nakama H , Chang L . Altered brain activation during visuomotor integration in chronic active cannabis users: Relationship to cortisol levels. J Neurosci 31: 17923‐17931, 2011.
 83. Kleinloog D , Liem‐Moolenaar M , Jacobs G , Klaassen E , de Kam M , Hijman R , van Gerven J . Does olanzapine inhibit the psychomimetic effects of Delta(9)‐tetrahydrocannabinol? J Psychopharmacol 26: 1307‐1316, 2012.
 84. Klumpers LE , Cole DM , Khalili‐Mahani N , Soeter RP , Te Beek ET , Rombouts SA , van Gerven JM . Manipulating brain connectivity with delta(9)‐tetrahydrocannabinol: A pharmacological resting state FMRI study. Neuroimage 63: 1701‐1711, 2012.
 85. Ko JY , Wu RW , Kuo SJ , Chen MW , Yeh DW , Ke HC , Wu SL , Wang FS . Cannabinoid receptor 1 mediates glucocorticoid‐induced bone loss in rats by perturbing bone mineral acquisition and marrow adipogenesis. Arthritis Rheum 64: 1204‐1214, 2012.
 86. Konturek PC , Brzozowski T , Konturek SJ . Stress and the gut: Pathophysiology, clinical consequences, diagnostic approach and treatment options. J Physiol Pharmacol 62: 591‐599, 2011.
 87. Kreitzer AC , Regehr WG . Retrograde inhibition of presynaptic calcium influx by endogenous cannabinoids at excitatory synapses onto Purkinje cells. Neuron 29: 717‐727, 2001.
 88. Kulkarni‐Narla A , Brown DR . Localization of CB1‐cannabinoid receptor immunoreactivity in the porcine enteric nervous system. Cell Tissue Res 302: 73‐80, 2000.
 89. Lightman SL . The neuroendocrinology of stress: A never ending story. J Neuroendocrinol 20: 880‐884, 2008.
 90. Lowette K , Tack J , Vanden Berghe P . Role of corticosterone in the murine enteric nervous system during fasting. Am J Physiol Gastrointest Liver Physiol 307: G905‐913, 2014.
 91. Mackie K . Cannabinoid receptors: Where they are and what they do. J Neuroendocrinol 20(Suppl 1): 10‐14, 2008.
 92. Mackie K , Hille B . Cannabinoids inhibit N‐type calcium channels in neuroblastoma‐glioma cells. Proc Natl Acad Sci 89: 3825‐3829, 1992.
 93. Mailleux P , Vanderhaeghen JJ . Glucocorticoid regulation of cannabinoid receptor messenger RNA levels in the rat caudate‐putamen. An in situ hybridization study. Neurosci Lett 156: 51‐53, 1993.
 94. Malcher‐Lopes R , Franco A , Tasker JG . Glucocorticoids shift arachidonic acid metabolism toward endocannabinoid synthesis: A non‐genomic anti‐inflammatory switch. Eur J Pharmacol 583: 322‐339, 2008.
 95. Malfitano AM , Basu S , Maresz K , Bifulco M , Dittel BN . What we know and do not know about the cannabinoid receptor 2 (CB2). Semin Immunol 26: 369‐379, 2014.
 96. Manzanares J , Corchero J , Fuentes JA . Opioid and cannabinoid receptor‐mediated regulation of the increase in adrenocorticotropin hormone and corticosterone plasma concentrations induced by central administration of delta(9)‐tetrahydrocannabinol in rats. Brain Res 839: 173‐179, 1999.
 97. Marrs WR , Blankman JL , Horne EA , Thomazeau A , Lin YH , Coy J , Bodor AL , Muccioli GG , Hu SS , Woodruff G , Fung S , Lafourcade M , Alexander JP , Long JZ , Li W , Xu C , Moller T , Mackie K , Manzoni OJ , Cravatt BF , Stella N . The serine hydrolase ABHD6 controls the accumulation and efficacy of 2‐AG at cannabinoid receptors. Nat Neurosci 13: 951‐957, 2010.
 98. Matthews L , Berry A , Ohanian V , Ohanian J , Garside H , Ray D . Caveolin mediates rapid glucocorticoid effects and couples glucocorticoid action to the antiproliferative program. Mol Endocrinol 22: 1320‐1330, 2008.
 99. McEwen BS . Steroid hormone actions on the brain: When is the genome involved? Horm Behav 28: 396‐405, 1994.
 100. McLaughlin RJ , Hill MN , Bambico FR , Stuhr KL , Gobbi G , Hillard CJ , Gorzalka BB . Prefrontal cortical anandamide signaling coordinates coping responses to stress through a serotonergic pathway. Eur Neuropsychopharmacol 22: 664‐671, 2012.
 101. McLaughlin RJ , Hill MN , Gorzalka BB . Monoaminergic neurotransmission contributes to cannabinoid‐induced activation of the hypothalamic‐pituitary‐adrenal axis. Eur J Pharmacol 624: 71‐76, 2009.
 102. McReynolds JR , Doncheck EM , Vranjkovic O , Ganzman GS , Baker DA , Hillard CJ , Mantsch JR . CB1 receptor antagonism blocks stress‐potentiated reinstatement of cocaine seeking in rats. Psychopharmacology (Berl) 233: 99‐109, 2016.
 103. McReynolds JR , Pena DF , Blacktop JM , Mantsch JR . Neurobiological mechanisms underlying relapse to cocaine use: Contributions of CRF and noradrenergic systems and regulation by glucocorticoids. Stress 17: 22‐38, 2014.
 104. Nahar J , Haam J , Chen C , Jiang Z , Glatzer NR , Muglia LJ , Dohanich GP , Herman JP , Tasker JG . Rapid nongenomic glucocorticoid actions in male mouse hypothalamic neuroendocrine cells are dependent on the nuclear glucocorticoid receptor. Endocrinology 156: 2831‐2842, 2015.
 105. Newsom RJ , Osterlund C , Masini CV , Day HE , Spencer RL , Campeau S . 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: 64‐73, 2012.
 106. Niederhoffer N , Hansen HH , Fernandez‐Ruiz JJ , Szabo B . Effects of cannabinoids on adrenaline release from adrenal medullary cells. Br J Pharmacol 134: 1319‐1327, 2001.
 107. Nieman LK . Cushing's syndrome: Update on signs, symptoms and biochemical screening. Eur J Endocrinol 173: M33‐38, 2015.
 108. Nomura DK , Morrison BE , Blankman JL , Long JZ , Kinsey SG , Marcondes MC , Ward AM , Hahn YK , Lichtman AH , Conti B , Cravatt BF . Endocannabinoid hydrolysis generates brain prostaglandins that promote neuroinflammation. Science 334: 809‐813, 2011.
 109. Oropeza VC , Mackie K , Van Bockstaele EJ . Cannabinoid receptors are localized to noradrenergic axon terminals in the rat frontal cortex. Brain Res 1127: 36‐44, 2007.
 110. Pagotto U , Marsicano G , Fezza F , Theodoropoulou M , Grubler Y , Stalla J , Arzberger T , Milone A , Losa M , Di Marzo V , Lutz B , Stalla GK . Normal human pituitary gland and pituitary adenomas express cannabinoid receptor type 1 and synthesize endogenous cannabinoids: First evidence for a direct role of cannabinoids on hormone modulation at the human pituitary level. J Clin Endocrinol Metab 86: 2687‐2696, 2001.
 111. Pan B , Wang W , Long JZ , Sun D , Hillard CJ , Cravatt BF , Liu QS . Blockade of 2‐arachidonoylglycerol hydrolysis by selective monoacylglycerol lipase inhibitor 4‐nitrophenyl 4‐(dibenzo[d][1,3]dioxol‐5‐yl(hydroxy)methyl)piperidine‐1‐carboxylate (JZL184) Enhances retrograde endocannabinoid signaling. J Pharmacol Exp Ther 331: 591‐597, 2009.
 112. Patel S , Carrier EJ , Ho WS , Rademacher DJ , Cunningham S , Reddy DS , Falck JR , Cravatt BF , Hillard CJ . The postmortal accumulation of brain N‐arachidonylethanolamine (anandamide) is dependent upon fatty acid amide hydrolase activity. J Lipid Res 46: 342‐349, 2005.
 113. Patel S , Roelke CT , Rademacher DJ , Cullinan WE , Hillard CJ . Endocannabinoid signaling negatively modulates stress‐induced activation of the hypothalamic‐pituitary‐adrenal axis. Endocrinology 145: 5431‐5438, 2004.
 114. Patel S , Roelke CT , Rademacher DJ , Hillard CJ . Inhibition of restraint stress‐induced neural and behavioural activation by endogenous cannabinoid signalling. Eur J Neurosci 21: 1057‐1069, 2005.
 115. Pereira MJ , Palming J , Svensson MK , Rizell M , Dalenback J , Hammar M , Fall T , Sidibeh CO , Svensson PA , Eriksson JW . FKBP5 expression in human adipose tissue increases following dexamethasone exposure and is associated with insulin resistance. Metabolism 63: 1198‐1208, 2014.
 116. Pertwee RG . Tolerance to the effect of delta1‐tetrahydrocannabinol on corticosterone levels in mouse plasma produced by repeated administration of cannabis extract or delta1‐tetrahydrocannabinol. Br J Pharmacol 51: 391‐397, 1974.
 117. Pertwee RG . Ligands that target cannabinoid receptors in the brain: From THC to anandamide and beyond. Addict Biol 13: 147‐159, 2008.
 118. Pertwee RG , Howlett AC , Abood ME , Alexander SP , Di Marzo V , Elphick MR , Greasley PJ , Hansen HS , Kunos G , Mackie K , Mechoulam R , Ross RA . International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: Beyond CB and CB. Pharmacol Rev 62: 588‐631, 2010.
 119. Pickel VM , Shobin ET , Lane DA , Mackie K . Cannabinoid‐1 receptors in the mouse ventral pallidum are targeted to axonal profiles expressing functionally opposed opioid peptides and contacting N‐acylphosphatidylethanolamine‐hydrolyzing phospholipase D terminals. Neuroscience 227C: 10‐21, 2012.
 120. Qin Z , Zhou X , Pandey NR , Vecchiarelli HA , Stewart CA , Zhang X , Lagace DC , Brunel JM , Beique JC , Stewart AF , Hill MN , Chen HH . Chronic stress induces anxiety via an amygdalar intracellular cascade that impairs endocannabinoid signaling. Neuron 85: 1319‐1331, 2015.
 121. Rademacher DJ , Hillard CJ . Interactions between endocannabinoids and stress‐induced decreased sensitivity to natural reward. Prog Neuropsychopharmacol Biol Psychiatry 31: 633‐641, 2007.
 122. Rademacher DJ , Meier SE , Shi L , Ho W‐SV , Jarrahian A , HIllard CJ . Effects of acute and repeated restraint stress on endocannabinoid content in the amygdala, ventral striatum and medial prefrontal cortex in mice. Neuropharmacol 54: 108‐116, 2008.
 123. Ranganathan M , Braley G , Pittman B , Cooper T , Perry E , Krystal J , D'Souza DC . The effects of cannabinoids on serum cortisol and prolactin in humans. Psychopharmacology (Berl) 203: 737‐744, 2009.
 124. Rauch A , Seitz S , Baschant U , Schilling AF , Illing A , Stride B , Kirilov M , Mandic V , Takacz A , Schmidt‐Ullrich R , Ostermay S , Schinke T , Spanbroek R , Zaiss MM , Angel PE , Lerner UH , David JP , Reichardt HM , Amling M , Schutz G , Tuckermann JP . Glucocorticoids suppress bone formation by attenuating osteoblast differentiation via the monomeric glucocorticoid receptor. Cell Metab 11: 517‐531, 2010.
 125. Reich CG , Taylor ME , McCarthy MM . Differential effects of chronic unpredictable stress on hippocampal CB1 receptors in male and female rats. Behav Brain Res 203: 264‐269, 2009.
 126. Rice W , Shannon JM , Burton F , Fiedeldey D . Expression of a brain‐type cannabinoid receptor (CB1) in alveolar Type II cells in the lung: Regulation by hydrocortisone. Eur J Pharmacol 327: 227‐232, 1997.
 127. Roberts CJ , Stuhr KL , Hutz MJ , Raff H , Hillard CJ . Endocannabinoid signaling in hypothalamic‐pituitary‐adrenocortical axis recovery following stress: Effects of indirect agonists and comparison of male and female mice. Pharmacol Biochem Behav 117: 17‐24, 2014.
 128. Robinson SA , Loiacono RE , Christopoulos A , Sexton PM , Malone DT . The effect of social isolation on rat brain expression of genes associated with endocannabinoid signalling. Brain Res 1343: 153‐167, 2010.
 129. Rodriguez de Fonseca F , Cebeira M , Martin M , Fernandez‐Ruiz JJ . Cannabinoid receptors in rat brain areas: Sexual differences, fluctuations during estrous cycle and changes after gonadectomy and sex steroid replacement. Life Sci 54: 159‐170, 1994.
 130. Roozendaal B , de Quervain DJ , Ferry B , Setlow B , McGaugh JL . Basolateral amygdala‐nucleus accumbens interactions in mediating glucocorticoid enhancement of memory consolidation. J Neurosci 21: 2518‐2525, 2001.
 131. Roozendaal B , Schelling G , McGaugh JL . Corticotropin‐releasing factor in the basolateral amygdala enhances memory consolidation via an interaction with the beta‐adrenoceptor‐cAMP pathway: Dependence on glucocorticoid receptor activation. J Neurosci 28: 6642‐6651, 2008.
 132. Roozendaal B , Williams CL , McGaugh JL . Glucocorticoid receptor activation in the rat nucleus of the solitary tract facilitates memory consolidation: Involvement of the basolateral amygdala. Eur J Neurosci 11: 1317‐1323, 1999.
 133. Sadie‐Van Gijsen H , Crowther NJ , Hough FS , Ferris WF . The interrelationship between bone and fat: From cellular see‐saw to endocrine reciprocity. Cell Mol Life Sci 70: 2331‐2349, 2013.
 134. Samir SM , Malek HA . Effect of cannabinoid receptors 1 modulation on osteoporosis in a rat model of different ages. J Physiol Pharmacol 65: 687‐694, 2014.
 135. Shen M , Piser TM , Seybold VS , Thayer SA . Cannabinoid receptor agonists inhibit glutamatergic synaptic transmission in rat hippocampal cultures. J Neurosci 16: 4322‐4334, 1996.
 136. Solomon MB , Loftspring M , de Kloet AD , Ghosal S , Jankord R , Flak JN , Wulsin AC , Krause EG , Zhang R , Rice T , McKlveen J , Myers B , Tasker JG , Herman JP . Neuroendocrine function After hypothalamic depletion of glucocorticoid receptors in male and female mice. Endocrinology 156: 2843‐2853, 2015.
 137. Somaini L , Manfredini M , Amore M , Zaimovic A , Raggi MA , Leonardi C , Gerra ML , Donnini C , Gerra G . Psychobiological responses to unpleasant emotions in cannabis users. Eur Arch Psychiatry Clin Neurosci 262: 47‐57, 2012.
 138. Steiner MA , Wotjak CT . Role of the endocannabinoid system in regulation of the hypothalamic‐pituitary‐adrenocortical axis. Prog Brain Res 170: 397‐432, 2008.
 139. Sumislawski JJ , Ramikie TS , Patel S . 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: 2750‐2761, 2011.
 140. Szallasi A , Di Marzo V . New perspectives on enigmatic vanilloid receptors. Trends Neurosci 23: 491‐497, 2000.
 141. Tabatadze N , Huang G , May RM , Jain A , Woolley CS . Sex differences in molecular signaling at inhibitory synapses in the hippocampus. J Neurosci 35: 11252‐11265, 2015.
 142. Tasker JG , Herman JP . Mechanisms of rapid glucocorticoid feedback inhibition of the hypothalamic‐pituitary‐adrenal axis. Stress 14: 398‐406, 2011.
 143. Tsou K , Nogueron MI , Muthian S , Sanudo‐Pena MC , Hillard CJ , Deutsch DG , Walker JM . Fatty acid amide hydrolase is located preferentially in large neurons in the rat central nervous system as revealed by immunohistochemistry. Neurosci Lett 254: 137‐140, 1998.
 144. Ueda N , Tsuboi K , Uyama T . N‐acylethanolamine metabolism with special reference to N‐acylethanolamine‐hydrolyzing acid amidase (NAAA). Prog Lipid Res 49: 299‐315, 2010.
 145. van Leeuwen AP , Verhulst FC , Reijneveld SA , Vollebergh WA , Ormel J , Huizink AC . Can the gateway hypothesis, the common liability model and/or, the route of administration model predict initiation of cannabis use during adolescence? A survival analysis–the TRAILS study. J Adolesc Health 48: 73‐78, 2011.
 146. Van Sickle MD , Duncan M , Kingsley PJ , Mouihate A , Urbani P , Mackie K , Stella N , Makriyannis A , Piomelli D , Davison JS , Marnett LJ , Di Marzo V , Pittman QJ , Patel KD , Sharkey KA . Identification and functional characterization of brainstem cannabinoid CB2 receptors. Science 310: 329‐332, 2005.
 147. Vaughn LK , Mantsch JR , Vranjkovic O , Stroh G , Lacourt M , Kreutter M , Hillard CJ . Cannabinoid receptor involvement in stress‐induced cocaine reinstatement: Potential interaction with noradrenergic pathways. Neuroscience 204: 117‐124, 2012.
 148. Verkuyl JM , Karst H , Joels M . GABAergic transmission in the rat paraventricular nucleus of the hypothalamus is suppressed by corticosterone and stress. Eur J Neurosci 21: 113‐121, 2005.
 149. Wade MR , Degroot A , Nomikos GG . Cannabinoid CB1 receptor antagonism modulates plasma corticosterone in rodents. Eur J Pharmacol 551: 162‐167, 2006.
 150. Waleh NS , Cravatt BF , Apte‐Deshpande A , Terao A , Kilduff TS . Transcriptional regulation of the mouse fatty acid amide hydrolase gene. Gene 291: 203‐210, 2002.
 151. Wang J , Shen RY , Haj‐Dahmane S . Endocannabinoids mediate the glucocorticoid‐induced inhibition of excitatory synaptic transmission to dorsal raphe serotonin neurons. J Physiol 590: 5795‐5808, 2012.
 152. Wang M , Hill MN , Zhang L , Gorzalka BB , Hillard CJ , Alger BE . Acute restraint stress enhances hippocampal endocannabinoid function via glucocorticoid receptor activation. J Psychopharmacol 26: 56‐70, 2012.
 153. Wang S , Lim G , Mao J , Sung B , Yang L . Central glucocorticoid receptors regulate the upregulation of spinal cannabinoid‐1 receptors after peripheral nerve injury in rats. Pain 131: 96‐105, 2007.
 154. Watts AG . The impact of physiological stimuli on the expression of corticotropin‐releasing hormone (CRH) and other neuropeptide genes. Front Neuroendocrinol 17: 281‐326, 1996.
 155. Wittmann G , Deli L , Kallo I , Hrabovszky E , Watanabe M , Liposits Z , Fekete C . Distribution of type 1 cannabinoid receptor (CB1)‐immunoreactive axons in the mouse hypothalamus. J Comp Neurol 503: 270‐279, 2007.
 156. Wu RW , Lin TP , Ko JY , Yeh DW , Chen MW , Ke HC , Wu SL , Wang FS . Cannabinoid receptor 1 regulates ERK and GSK‐3beta‐dependent glucocorticoid inhibition of osteoblast differentiation in murine MC3T3‐E1 cells. Bone 49: 1255‐1263, 2011.
 157. Yoshida T , Fukaya M , Uchigashima M , Miura E , Kamiya H , Kano M , Watanabe M . Localization of diacylglycerol lipase‐alpha around postsynaptic spine suggests close proximity between production site of an endocannabinoid, 2‐arachidonoyl‐glycerol, and presynaptic cannabinoid CB1 receptor. J Neurosci 26: 4740‐4751, 2006.
 158. Zheng Y , Wang XL , Mo FF , Li M . Dexamethasone alleviates motion sickness in rats in part by enhancing the endocannabinoid system. Eur J Pharmacol 727: 99‐105, 2014.
 159. Zias J , Stark H , Sellgman J , Levy R , Werker E , Breuer A , Mechoulam R . Early medical use of cannabis. Nature 363: 215, 1993.
 160. Ziegler CG , Mohn C , Lamounier‐Zepter V , Rettori V , Bornstein SR , Krug AW , Ehrhart‐Bornstein M . Expression and function of endocannabinoid receptors in the human adrenal cortex. Horm Metab Res 42: 88‐92, 2010.
 161. Zoppi S , Madrigal JL , Perez‐Nievas BG , Marin‐Jimenez I , Caso JR , Alou L , Garcia‐Bueno B , Colon A , Manzanares J , Gomez‐Lus ML , Menchen L , Leza JC . Endogenous cannabinoid system regulates intestinal barrier function in vivo through cannabinoid type 1 receptor activation. Am J Physiol Gastrointest Liver Physiol 302: G565‐571, 2012.

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Article Title: Endocannabinoid Signaling and the Hypothalamic‐Pituitary‐Adrenal Axis
 

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Cecilia J. Hillard, Margaret Beatka, Jenna Sarvaideo. Endocannabinoid Signaling and the Hypothalamic‐Pituitary‐Adrenal Axis. Compr Physiol 2016, 7: 1-15. doi: 10.1002/cphy.c160005