Review Article | Published:

Integrating endocannabinoid signaling in the regulation of anxiety and depression

Abstract

Brain endogenous cannabinoid (eCB) signaling seems to harmonize appropriate behavioral responses, which are essential for the organism’s long-term viability and homeostasis. Dysregulation of eCB signaling contributes to negative emotional states and increased stress responses. An understanding of the underlying neural cell populations and neural circuit regulation will enable the development of therapeutic strategies to mitigate behavioral maladaptation and provide insight into the influence of eCB on the neural circuits involved in anxiety and depression. This review focuses on recent evidence that has added a new layer of complexity to the idea of targeting the eCB system for therapeutic benefits in neuropsychiatric disease and on the future research direction of neural circuit modulation.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    Kmietowicz Z. Cannabis based drug is licensed for spasticity in patients with MS. BMJ. 2010;340:c3363.

  2. 2.

    Tart CT. Marijuana intoxication common experiences. Nature. 1970;226:701–4.

  3. 3.

    Volkow ND, Hampson AJ, Baler RD. Don’t worry, be happy: endocannabinoids and cannabis at the intersection of stress and reward. Annu Rev Pharmacol Toxicol. 2017;57:285–308.

  4. 4.

    Gunduz-Cinar O, Hill MN, McEwen BS, Holmes A. Amygdala FAAH and anandamide: mediating protection and recovery from stress. Trends Pharmacol Sci. 2013;34:637–44.

  5. 5.

    McLaughlin RJ, Hill MN, Gorzalka BB. A critical role for prefrontocortical endocannabinoid signaling in the regulation of stress and emotional behavior. Neurosci Biobehav Rev. 2014;42:116–31.

  6. 6.

    Lutz B, Marsicano G, Maldonado R, Hillard CJ. The endocannabinoid system in guarding against fear, anxiety and stress. Nat Rev Neurosci. 2015;16:705–18.

  7. 7.

    Castillo PE, Younts TJ, Chavez AE, Hashimotodani Y. Endocannabinoid signaling and synaptic function. Neuron. 2012;76:70–81.

  8. 8.

    Katona I, Freund TF. Multiple functions of endocannabinoid signaling in the brain. Annu Rev Neurosci. 2012;35:529–58.

  9. 9.

    Han J, Kesner P, Metna-Laurent M, Duan T, Xu L, Georges F, et al. Acute cannabinoids impair working memory through astroglial CB1 receptor modulation of hippocampal LTD. Cell. 2012;148:1039–50.

  10. 10.

    Duan T, Gu N, Wang Y, Wang F, Zhu J, Fang Y, et al. Fatty acid amide hydrolase inhibitors produce rapid anti-anxiety responses through amygdala long-term depression in male rodents. J Psychiatry Neurosci. 2016;42:160116.

  11. 11.

    Mecha M, Feliu A, Carrillo-Salinas FJ, Rueda-Zubiaurre A, Ortega-Gutierrez S, de Sola RG, et al. Endocannabinoids drive the acquisition of an alternative phenotype in microglia. Brain Behav Immun. 2015;49:233–45.

  12. 12.

    Gipson CD, Kupchik YM, Kalivas PW. Rapid, transient synaptic plasticity in addiction. Neuropharmacology. 2014;76 Pt B:276–86.

  13. 13.

    Gonsiorek W, Lunn C, Fan X, Narula S, Lundell D, Hipkin RW. Endocannabinoid 2-arachidonyl glycerol is a full agonist through human type 2 cannabinoid receptor: antagonism by anandamide. Mol Pharmacol. 2000;57:1045–50.

  14. 14.

    Lomazzo E, Bindila L, Remmers F, Lerner R, Schwitter C, Hoheisel U, et al. Therapeutic potential of inhibitors of endocannabinoid degradation for the treatment of stress-related hyperalgesia in an animal model of chronic pain. Neuropsychopharmacology. 2015;40:488–501.

  15. 15.

    Wang J, Ueda N. Biology of endocannabinoid synthesis system. Prostaglandins Other Lipid Mediat. 2009;89:112–9.

  16. 16.

    Huang GZ, Woolley CS. Estradiol acutely suppresses inhibition in the hippocampus through a sex-specific endocannabinoid and mGluR-dependent mechanism. Neuron. 2012;74:801–8.

  17. 17.

    Chevaleyre V, Takahashi KA, Castillo PE. Endocannabinoid-mediated synaptic plasticity in the CNS. Annu Rev Neurosci. 2006;29:37–76.

  18. 18.

    Zhong H, Tong L, Gu N, Gao F, Lu Y, Xie RG, et al. Endocannabinoid signaling in hypothalamic circuits regulates arousal from general anesthesia in mice. J Clin Invest. 2017;127:2295–309.

  19. 19.

    Kaczocha M, Glaser ST, Deutsch DG. Identification of intracellular carriers for the endocannabinoid anandamide. Proc Natl Acad Sci U S A. 2009;106:6375–80.

  20. 20.

    Haj-Dahmane S, Shen RY, Elmes MW, Studholme K, Kanjiya MP, Bogdan D et al. Fatty acid-binding protein 5 controls retrograde endocannabinoid signaling at central glutamate synapses. Proc Natl Acad Sci U S A. 2018; 115:3482–87.

  21. 21.

    Goparaju SK, Ueda N, Taniguchi K, Yamamoto S. Enzymes of porcine brain hydrolyzing 2-arachidonoylglycerol, an endogenous ligand of cannabinoid receptors. Biochem Pharmacol. 1999;57:417–23.

  22. 22.

    Cravatt BF, Giang DK, Mayfield SP, Boger DL, Lerner RA, Gilula NB. Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature. 1996;384:83–7.

  23. 23.

    Freund TF, Katona I, Piomelli D. Role of endogenous cannabinoids in synaptic signaling. Physiol Rev. 2003;83:1017–66.

  24. 24.

    Hua T, Vemuri K, Pu M, Qu L, Han GW, Wu Y, et al. Crystal structure of the human cannabinoid receptor CB1. Cell. 2016;167:750–62 e14.

  25. 25.

    Shao Z, Yin J, Chapman K, Grzemska M, Clark L, Wang J, et al. High-resolution crystal structure of the human CB1 cannabinoid receptor. Nature. 2016; 540: 602-6.

  26. 26.

    Hua T, Vemuri K, Nikas SP, Laprairie RB, Wu Y, Qu L, et al. Crystal structures of agonist-bound human cannabinoid receptor CB1. Nature. 2017;547:468–71.

  27. 27.

    Thibault K, Carrel D, Bonnard D, Gallatz K, Simon A, Biard M, et al. Activation-dependent subcellular distribution patterns of CB1 cannabinoid receptors in the rat forebrain. Cereb Cortex. 2013;23:2581–91.

  28. 28.

    Ladarre D, Roland AB, Biedzinski S, Ricobaraza A, Lenkei Z. Polarized cellular patterns of endocannabinoid production and detection shape cannabinoid signaling in neurons. Front Cell Neurosci. 2014;8:426.

  29. 29.

    Marsicano G, Lutz B. Expression of the cannabinoid receptor CB1 in distinct neuronal subpopulations in the adult mouse forebrain. Eur J Neurosci. 1999;11:4213–25.

  30. 30.

    Hill MN, Kumar SA, Filipski SB, Iverson M, Stuhr KL, Keith JM, et al. Disruption of fatty acid amide hydrolase activity prevents the effects of chronic stress on anxiety and amygdalar microstructure. Mol Psychiatry. 2013;18:1125–35.

  31. 31.

    Haring M, Marsicano G, Lutz B, Monory K. Identification of the cannabinoid receptor type 1 in serotonergic cells of raphe nuclei in mice. Neuroscience. 2007;146:1212–9.

  32. 32.

    Nyiri G, Szabadits E, Cserep C, Mackie K, Shigemoto R, Freund TF. GABAB and CB1 cannabinoid receptor expression identifies two types of septal cholinergic neurons. Eur J Neurosci. 2005;21:3034–42.

  33. 33.

    Soltesz I, Alger BE, Kano M, Lee SH, Lovinger DM, Ohno-Shosaku T, et al. Weeding out bad waves: towards selective cannabinoid circuit control in epilepsy. Nat Rev Neurosci. 2015;16:264–77.

  34. 34.

    Marsicano G, Goodenough S, Monory K, Hermann H, Eder M, Cannich A, et al. CB1 cannabinoid receptors and on-demand defense against excitotoxicity. Science. 2003;302:84–8.

  35. 35.

    Marinelli S, Pacioni S, Cannich A, Marsicano G, Bacci A. Self-modulation of neocortical pyramidal neurons by endocannabinoids. Nat Neurosci. 2009;12:1488–90.

  36. 36.

    Massi P, Valenti M, Bolognini D, Parolaro D. Expression and function of the endocannabinoid system in glial cells. Curr Pharm Des. 2008;14:2289–98.

  37. 37.

    Liu Z, Han J, Jia L, Maillet JC, Bai G, Xu L, et al. Synaptic neurotransmission depression in ventral tegmental dopamine neurons and cannabinoid-associated addictive learning. PLoS One. 2010;5:e15634.

  38. 38.

    Wang F, Han J, Higashimori H, Wang J, Liu J, Tong L, et al. Long-term depression induced by endogenous cannabinoids produces neuroprotection via astroglial CB1R after stroke in rodents. J Cereb Blood Flow Metab. 2018:271678X18755661. [epub ahead of print].

  39. 39.

    Benard G, Massa F, Puente N, Lourenco J, Bellocchio L, Soria-Gomez E, et al. Mitochondrial CB(1) receptors regulate neuronal energy metabolism. Nat Neurosci. 2012;15:558–64.

  40. 40.

    Hebert-Chatelain E, Desprez T, Serrat R, Bellocchio L, Soria-Gomez E, Busquets-Garcia A, et al. A cannabinoid link between mitochondria and memory. Nature. 2016;539:555–9.

  41. 41.

    Stella N. Endocannabinoid signaling in microglial cells. Neuropharmacology. 2009;56:244–53.

  42. 42.

    Mechoulam R, Parker LA. The endocannabinoid system and the brain. Annu Rev Psychol. 2013;64:21–47.

  43. 43.

    Van Sickle MD, Duncan M, Kingsley PJ, Mouihate A, Urbani P, Mackie K, et al. Identification and functional characterization of brainstem cannabinoid CB2 receptors. Science. 2005;310:329–32.

  44. 44.

    Zhang HY, Gao M, Liu QR, Bi GH, Li X, Yang HJ et al. Cannabinoid CB2 receptors modulate midbrain dopamine neuronal activity and dopamine-related behavior in mice. Proc Natl Acad Sci U S A. 2014;111:E5007–15.

  45. 45.

    Avello LM, Pastene NE, Fernandez RP, Cordova MP. [Therapeutic potential of Cannabis sativa]. Rev Med Chil. 2017;145:360–7.

  46. 46.

    Liu QR, Canseco-Alba A, Zhang HY, Tagliaferro P, Chung M, Dennis E, et al. Cannabinoid type 2 receptors in dopamine neurons inhibits psychomotor behaviors, alters anxiety, depression and alcohol preference. Sci Rep. 2017;7:17410.

  47. 47.

    Xi ZX, Peng XQ, Li X, Song R, Zhang HY, Liu QR, et al. Brain cannabinoid CB2 receptors modulate cocaine’s actions in mice. Nat Neurosci. 2011;14:1160–U216.

  48. 48.

    Stempel AV, Stumpf A, Zhang HY, Ozdogan T, Pannasch U, Theis AK, et al. Cannabinoid type 2 receptors mediate a cell type-specific plasticity in the hippocampus. Neuron. 2016;90:795–809.

  49. 49.

    Quraishi SA, Paladini CA. A central move for CB2 receptors. Neuron. 2016;90:670–1.

  50. 50.

    Ishiguro H, Horiuchi Y, Ishikawa M, Koga M, Imai K, Suzuki Y, et al. Brain cannabinoid CB2 receptor in schizophrenia. Biol Psychiatry. 2010;67:974–82.

  51. 51.

    Ortega-Alvaro A, Aracil-Fernandez A, Garcia-Gutierrez MS, Navarrete F, Manzanares J. Deletion of CB2 cannabinoid receptor induces schizophrenia-related behaviors in mice. Neuropsychopharmacology. 2011;36:1489–504.

  52. 52.

    American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington DC (USA): American Psychiatric Press; 2013. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders (DSM-V). p185–95.

  53. 53.

    Collaborators GBoDS. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;386:743–800.

  54. 54.

    Rickels K, Case WG, Downing RW, Winokur A. Long-term diazepam therapy and clinical outcome. JAMA. 1983;250:767–71.

  55. 55.

    Patel S, Hillard CJ. Pharmacological evaluation of cannabinoid receptor ligands in a mouse model of anxiety: further evidence for an anxiolytic role for endogenous cannabinoid signaling. J Pharmacol Exp Ther. 2006;318:304–11.

  56. 56.

    Berrendero F, Maldonado R. Involvement of the opioid system in the anxiolytic-like effects induced by Delta(9)-tetrahydrocannabinol. Psychopharmacol (Berl). 2002;163:111–7.

  57. 57.

    Rubino T, Guidali C, Vigano D, Realini N, Valenti M, Massi P, et al. CB1 receptor stimulation in specific brain areas differently modulate anxiety-related behaviour. Neuropharmacology. 2008;54:151–60.

  58. 58.

    Ruehle S, Remmers F, Romo-Parra H, Massa F, Wickert M, Wortge S, et al. Cannabinoid CB1 receptor in dorsal telencephalic glutamatergic neurons: distinctive sufficiency for hippocampus-dependent and amygdala-dependent synaptic and behavioral functions. J Neurosci. 2013;33:10264–77.

  59. 59.

    Haring M, Kaiser N, Monory K, Lutz B. Circuit specific functions of cannabinoid CB1 receptor in the balance of investigatory drive and exploration. PLoS One. 2011;6:e26617.

  60. 60.

    Lafenetre P, Chaouloff F, Marsicano G. Bidirectional regulation of novelty-induced behavioral inhibition by the endocannabinoid system. Neuropharmacology. 2009;57:715–21.

  61. 61.

    Jacob W, Yassouridis A, Marsicano G, Monory K, Lutz B, Wotjak CT. Endocannabinoids render exploratory behaviour largely independent of the test aversiveness: role of glutamatergic transmission. Genes Brain Behav. 2009;8:685–98.

  62. 62.

    Shonesy BC, Bluett RJ, Ramikie TS, Baldi R, Hermanson DJ, Kingsley PJ, et al. Genetic disruption of 2-arachidonoylglycerol synthesis reveals a key role for endocannabinoid signaling in anxiety modulation. Cell Rep. 2014;9:1644–53.

  63. 63.

    Guggenhuber S, Romo-Parra H, Bindila L, Leschik J, Lomazzo E, Remmers F, et al. Impaired 2-AG signaling in hippocampal glutamatergic neurons: aggravation of anxiety-like behavior and unaltered seizure susceptibility. Int J Neuropsychopharmacol. 2015;19:2.

  64. 64.

    Hermanson DJ, Hartley ND, Gamble-George J, Brown N, Shonesy BC, Kingsley PJ, et al. Substrate-selective COX-2 inhibition decreases anxiety via endocannabinoid activation. Nat Neurosci. 2013;16:1291–8.

  65. 65.

    Bluett RJ, Gamble-George JC, Hermanson DJ, Hartley ND, Marnett LJ, Patel S. Central anandamide deficiency predicts stress-induced anxiety: behavioral reversal through endocannabinoid augmentation. Transl Psychiatry. 2014;4:e408.

  66. 66.

    Dincheva I, Drysdale AT, Hartley CA, Johnson DC, Jing D, King EC, et al. FAAH genetic variation enhances fronto-amygdala function in mouse and human. Nat Commun. 2015;6:6395.

  67. 67.

    Bluett RJ, Baldi R, Haymer A, Gaulden AD, Hartley ND, Parrish WP, et al. Endocannabinoid signalling modulates susceptibility to traumatic stress exposure. Nat Commun. 2017;8:14782.

  68. 68.

    American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington DC (USA): American Psychiatric Press; 2013. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders (DSM-V). p160–8.

  69. 69.

    Briley M, Moret C. Present and future anxiolytics. IDrugs. 2000;3:695–9.

  70. 70.

    Trivedi MH, Rush AJ, Wisniewski SR, Nierenberg AA, Warden D, Ritz L, et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry. 2006;163:28–40.

  71. 71.

    Bambico FR, Gobbi G. The cannabinoid CB1 receptor and the endocannabinoid anandamide: possible antidepressant targets. Expert Opin Ther Targets. 2008;12:1347–66.

  72. 72.

    Hill MN, Patel S. Translational evidence for the involvement of the endocannabinoid system in stress-related psychiatric illnesses. Biol Mood Anxiety Disord. 2013;3:19.

  73. 73.

    Hillard CJ, Liu QS. Endocannabinoid signaling in the etiology and treatment of major depressive illness. Curr Pharm Des. 2014;20:3795–811.

  74. 74.

    Leite CE, Mocelin CA, Petersen GO, Leal MB, Thiesen FV. Rimonabant: an antagonist drug of the endocannabinoid system for the treatment of obesity. Pharmacol Rep. 2009;61:217–24.

  75. 75.

    Griebel G, Stemmelin J, Lopez-Grancha M, Fauchey V, Slowinski F, Pichat P, et al. The selective reversible FAAH inhibitor, SSR411298, restores the development of maladaptive behaviors to acute and chronic stress in rodents. Sci Rep. 2018;8:2416.

  76. 76.

    Hill MN, Hillard CJ, Bambico FR, Patel S, Gorzalka BB, Gobbi G. The therapeutic potential of the endocannabinoid system for the development of a novel class of antidepressants. Trends Pharmacol Sci. 2009;30:484–93.

  77. 77.

    Zhong P, Wang W, Pan B, Liu X, Zhang Z, Long JZ, et al. Monoacylglycerol lipase inhibition blocks chronic stress-induced depressive-like behaviors via activation of mTOR signaling. Neuropsychopharmacology. 2014;39:1763–76.

  78. 78.

    Zhang Z, Wang W, Zhong P, Liu SJ, Long JZ, Zhao L, et al. Blockade of 2-arachidonoylglycerol hydrolysis produces antidepressant-like effects and enhances adult hippocampal neurogenesis and synaptic plasticity. Hippocampus. 2015;25:16–26.

  79. 79.

    Wang Y, Gu N, Duan T, Kesner P, Blaskovits F, Liu J, et al. Monoacylglycerol lipase inhibitors produce pro- or antidepressant responses via hippocampal CA1 GABAergic synapses. Mol Psychiatry. 2017;22:215–26.

  80. 80.

    Gray JM, Vecchiarelli HA, Morena M, Lee TT, Hermanson DJ, Kim AB, et al. Corticotropin-releasing hormone drives anandamide hydrolysis in the amygdala to promote anxiety. J Neurosci. 2015;35:3879–92.

  81. 81.

    Hill MN, McLaughlin RJ, Morrish AC, Viau V, Floresco SB, Hillard CJ, et al. Suppression of amygdalar endocannabinoid signaling by stress contributes to activation of the hypothalamic-pituitary-adrenal axis. Neuropsychopharmacology. 2009;34:2733–45.

  82. 82.

    Dubreucq S, Matias I, Cardinal P, Haring M, Lutz B, Marsicano G, et al. Genetic dissection of the role of cannabinoid type-1 receptors in the emotional consequences of repeated social stress in mice. Neuropsychopharmacology. 2012;37:1885–900.

  83. 83.

    Navarria A, Tamburella A, Iannotti FA, Micale V, Camillieri G, Gozzo L, et al. The dual blocker of FAAH/TRPV1 N-arachidonoylserotonin reverses the behavioral despair induced by stress in rats and modulates the HPA-axis. Pharmacol Res. 2014;87:151–9.

  84. 84.

    McLaughlin RJ, Hill MN, Bambico FR, Stuhr KL, Gobbi G, Hillard CJ, et al. Prefrontal cortical anandamide signaling coordinates coping responses to stress through a serotonergic pathway. Eur Neuropsychopharmacol. 2012;22:664–71.

  85. 85.

    Hill MN, McLaughlin RJ, Pan B, Fitzgerald ML, Roberts CJ, Lee TT, et al. Recruitment of prefrontal cortical endocannabinoid signaling by glucocorticoids contributes to termination of the stress response. J Neurosci. 2011;31:10506–15.

  86. 86.

    Atsak P, Hauer D, Campolongo P, Schelling G, McGaugh JL, Roozendaal B. Glucocorticoids interact with the hippocampal endocannabinoid system in impairing retrieval of contextual fear memory. Proc Natl Acad Sci U S A. 2012;109:3504–9.

  87. 87.

    Bowles NP, Hill MN, Bhagat SM, Karatsoreos IN, Hillard CJ, McEwen BS. Chronic, noninvasive glucocorticoid administration suppresses limbic endocannabinoid signaling in mice. Neuroscience. 2012;204:83–9.

  88. 88.

    Morena M, Patel S, Bains JS, Hill MN. Neurobiological interactions between stress and the endocannabinoid system. Neuropsychopharmacology. 2016;41:80–102.

Download references

Acknowledgements

The project was supported by the Shaanxi Province Natural Science Foundation (No. 2016JQ8024) and by the International Cooperation and Exchange of the National Natural Science Foundation of China (No. 81420108013). We thank LetPub for providing linguistic assistance during the preparation of this manuscript.

Author information

Conflict of interest

The authors declare no conflict of interest.

Correspondence to Feng Wang.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Keywords

  • endocannabinoid (eCB)
  • cannabinoid 1 receptor (CB1R)
  • anxiety
  • depression
  • neural circuits

Further reading

Fig. 1