Abstract
Exposure to stress elicits excitoxicity and neuroinflammation in the brain, contributing to cell death and damage in stress-related neurological and neuropsychiatric diseases. The endocannabinoid system is present in stress-responsive neural circuits and has been proposed as an endogenous neuroprotective system activated in some neuropathological scenarios to restore homeostasis. To elucidate the possible regulatory role of cannabinoid receptor 1 (CB1) in stress-induced excitotoxicity and neuroinflammation, both genetic and pharmacological approaches were used alternatively: (1) wild-type (WT) and CB1 knockout mice (CB1-KO) were exposed to immobilization/acoustic stress (2 h/day for 4 days) and (2) to specifically activate CB1, the selective CB1 agonist Arachidonyl-2′-chloroethylamide (ACEA) (2.5 mg/kg) was intraperitoneally administered daily to some groups of animals. Stress exposure increased CB1 mRNA and protein expression in the prefrontal cortex of WT mice in a mechanism related to N-methyl-D-aspartate glutamate receptor activation. Daily ACEA pretreatment prevented stress-induced: (1) upregulation of CB1 mRNA and protein, (2) decrease in glutamate uptake and glutamate astroglial transporter excitatory amino acid transporter 2 expression, (3) increase in consecutive proinflammatory molecules, such as cytokines (tumor necrosis factor-α and MCP-1), nuclear factor kappa B, and enzymatic sources, such as inducible nitric oxide synthase (NOS-2) and cyclooxygenase-2 (COX-2), (4) increase in lipid peroxidation; although having no effect on plasma corticosterone. Interestingly, a possible related mechanism could be the positive ACEA modulation of the antiinflammatory pathway deoxyprostaglandin/peroxisome proliferator-activated receptor γ (15d-PGJ2/PPARγ). Conversely, KO animal experiments indicated that a lack of CB1 produces hypothalamic/pituitary/adrenal (HPA) axis dysregulation and exacerbates stress-induced excitotoxic/neuroinflammatory responses. These multifaceted neuroprotective effects suggest that CB1 activation could be a new therapeutic strategy against neurological/neuropsychiatric pathologies with HPA axis dysregulation and an excitotoxic/neuroinflammatory component in their pathophysiology.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Arévalo-Martín A, García-Ovejero D, Gómez O, Rubio-Araiz A, Navarro-Galve B, Guaza C et al (2008). CB2 cannabinoid receptors as an emerging target for demyelinating diseases: from neuroimmune interactions to cell replacement strategies. Br J Pharmacol 153: 216–225.
Arévalo-Martín A, Vela JM, Molina-Holgado E, Borrell J, Guaza C (2003). Therapeutic action of cannabinoids in a murine model of multiple sclerosis. J Neurosci 23: 2511–2516.
Ashton JC, Glass M (2007). The cannabinoid CB2 receptor as a target for inflammation-dependent neurodegeneration. Curr Neuropharmacol 5: 73–80.
Aso E, Ozaita A, Valdizán EM, Ledent C, Pazos A, Maldonado R et al (2008). BDNF impairment in the hippocampus is related to enhanced despair behavior in CB1 knockout mice. J Neurochem 105: 565–572.
Bambico FR, Duranti A, Tontini A, Tarzia G, Gobbi G (2009). Endocannabinoids in the treatment of mood disorders: evidence from animal models. Curr Pharm Des 15: 1623–1646.
Barna I, Zelena D, Arszovszki AC, Ledent C (2004). The role of endogenous cannabinoids in the hypothalamo-pituitary-adrenal axis regulation: in vivo and in vitro studies in CB1 receptor knockout mice. Life Sci 75: 2959–2970.
Baum A, Posluszny DM (1999). Health psychology: mapping biobehavioral contributions to health and illness. Annu Rev Psychol 50: 137–163.
Begley JG, Butterfield DA, Keller JN, Koppal T, Drake J, Mattson MP (1998). Cryopreservation of rat cortical synaptosomes and analysis of glucose and glutamate transporter activities, and mitochondrial function. Brain Res Brain Res Protoc 3: 76–82.
Bierhaus A, Wolf J, Andrassy M, Rohleder N, Humpert PM, Petrov D et al (2003). A mechanism converting psychosocial stress into mononuclear cell activation. Proc Natl Acad Sci USA 100: 1920–1925.
Bradford MM (1976). A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72: 248–254.
Bremner JD, Randall P, Scott TM, Bronen RA, Seibyl JP, Southwick SM et al (1995). MRI-based measurement of hippocampal volume in patients with combat-related posttraumatic stress disorder. Am J Psychiatry 152: 973–981.
Burns KA, Vanden Heuvel JP (2007). Modulation of PPAR activity via phosphorylation. Biochim Biophys Acta 1771: 952–960.
Cabral GA, Griffin-Thomas L (2009). Emerging role of the cannabinoid receptor CB2 in immune regulation: therapeutic prospects for neuroinflammation. Expert Rev Mol Med 11: e3.
Castaldo P, Magi S, Gaetani S, Cassano T, Ferraro L, Antonelli T et al (2007). Prenatal exposure to the cannabinoid receptor agonist WIN 55,212-2 increases glutamate uptake through overexpression of GLT1 and EAAC1 glutamate transporter subtypes in rat frontal cerebral cortex. Neuropharmacology 53: 369–378.
Centonze D, Battistini L, Maccarrone M (2008). The endocannabinoid system in peripheral lymphocytes as a mirror of neuroinflammatory diseases. Curr Pharm Des 14: 2370–2442.
Chan GC, Hinds TR, Impey S, Storm DR (1998). Hippocampal neurotoxicity of delta 9-tetrahydrocannabinol. J Neurosci 18: 5322–5332.
Chang YH, Lee ST, Lin WW (2001). Effects of cannabinoids on LPS-stimulated inflammatory mediator release from macrophages: involvement of eicosanoids. J Cell Biochem 81: 715–723.
Chevaleyre V, Takahashi KA, Castillo PE (2006). Endocannabinoid-mediated synaptic plasticity in the CNS. Annu Rev Neurosci 29: 37–76.
Cota D (2008). The role of the endocannabinoid system in the regulation of hypothalamic pituitary-adrenal axis activity. J Neuroendocrinol 20 (Suppl 1): 35–38.
Das NP, Ratty AK (1987). Studies on the effects of the narcotic alkaloids, cocaine, morphine and codeine on nonenzymatic lipid peroxidation in rat brain mitochondria. Biochem Med Metab Biol 37: 256–264.
Daynes RA, Jones DC (2002). Emerging roles of PPARs in inflammation and immunity. Nat Rev Immunol 2: 748–759.
Depke M, Fusch G, Domanska G, Geffers R, Völker U, Schuett C et al (2008). Hypermetabolic syndrome as a consequence of repeated psychological stress in mice. Endocrinology 149: 2714–2723.
Esposito G, De Filippis D, Steardo L, Scuderi C, Savani C, Cuomo V et al (2006). CB1 receptor selective activation inhibits beta-amyloid-induced iNOS protein expression in C6 cells and subsequently blunts tau protein hyperphosphorylation in co-cultured neurons. Neurosci Lett 404: 342–346.
Fernández-López D, Martínez-Orgado J, Nuñez E, Romero J, Lorenzo P, Moro MA et al (2006). Characterization of the neuroprotective effect of the cannabinoid agonist WIN-55212 in an in vitro model of hypoxic-ischemic brain damage in newborn rats. Pediatr Res 60: 169–173.
Freund TF, Katona I, Piomelli D (2003). Role of endogenous cannabinoids in synaptic signaling. Physiol Rev 83: 1017–1066.
Galve-Roperh I, Aguado T, Palazuelos J, Guzmán M (2008). Mechanisms of control of neuron survival by the endocannabinoid system. Curr Pharm Des 14: 2279–2288.
García-Bueno B, Caso JR, Leza JC (2008a). Stress as a neuroinflammatory condition in brain: damaging and protective mechanisms. Neurosci Biobehav Rev 32: 1136–1151.
García-Bueno B, Caso JR, Pérez-Nievas BG, Lorenzo P, Leza JC (2007). Effects of peroxisome proliferator-activated receptor gamma agonists on brain glucose and glutamate transporters after stress in rats. Neuropsychopharmacology 32: 1251–1260.
García-Bueno B, Madrigal JL, Pérez-Nievas BG, Leza JC (2008b). Stress mediators regulate brain prostaglandin synthesis and peroxisome proliferator-activated receptor gamma activation after stress in rats. Endocrinology 149: 1969–1978.
Gilbert GL, Kim HJ, Waataja JJ, Thayer SA (2007). Delta 9-tetrahydrocannabinol protects hippocampal neurons from excitotoxicity. Brain Res 1128: 61–69.
Hampson AJ, Grimaldi M, Lolic M, Wink D, Rosenthal R, Axelrod J (2000). Neuroprotective antioxidants from marijuana. Ann N Y Acad Sci 899: 274–282.
Hertz L, Bender AS, Richardson JS (1983). Benzodiazepines and beta-adrenergic binding to primary cultures of astrocytes and neurons. Prog Neuropsychopharmacol Biol Psychiatry 7: 681–686.
Jean-Gilles L, Gran B, Constantinescu CS (2010). Interaction between cytollines cannabinoids and the nervous system. Immunobiology 215: 606–610.
Jeon YJ, Yang KH, Pulaski JT, Kaminski NE (1996). Attenuation of inducible nitric oxide synthase gene expression by delta 9-tetrahydrocannabinol is mediated through the inhibition of nuclear factor- kappa B/Rel activation. Mol Pharmacol 50: 334–341.
Jezova D, Tokarev D, Rusnak M (1995). Endogenous excitatory amino acids are involved in stress-induced adrenocorticotropin and catecholamine release. Neuroendocrinology 62: 326–333.
Jin K, Xie L, Kim SH, Parmentier-Batteur S, Sun Y, Mao XO et al (2004). Defective adult neurogenesis in CB1 cannabinoid receptor knockout mice. Mol Pharmacol 66: 204–208.
Kiank C, Holtfreter B, Starke A, Mundt A, Wilke C, Schütt C (2006). Stress susceptibility predicts the severity of immune depression and the failure to combat bacterial infections in chronically stressed mice. Brain Behav Immun 20: 359–368.
Kim JJ, Yoon KS (1998). Stress: metaplastic effects in the hippocampus. Trends Neurosci 21: 505–509.
Kim SH, Won SJ, Mao XO, Jin K, Greenberg DA (2006). Molecular mechanisms of cannabinoid protection from neuronal excitotoxicity. Mol Pharmacol 69: 691–696.
Kozela E, Pietr M, Juknat A, Rimmerman N, Levy R, Vogel Z (2010). Cannabinoids delta (9)-tetrahydrocannabinol and cannabidiol differentially inhibit the lipopolysaccharide-activated NF-kappaB and interferon-beta/STAT proinflammatory pathways in BV-2 microglial cells. J Biol Chem 285: 1616–1626.
Ledent C, Valverde O, Cossu G, Petitet F, Aubert JF, Beslot F et al (1999). Unresponsiveness to cannabinoids and reduced addictive effects of opiates in CB1 receptor knockout mice. Science 283: 401–404.
Lee YL, Choi B, Lee EH, Choi KS, Sohn S (2006). Immobilization stress induces cell death through production of reactive oxygen species in the mouse cerebral cortex. Neurosci Lett 392: 27–31.
Lépicier P, Bibeau-Poirier A, Lagneux C, Servant MJ, Lamontagne D (2006). Signaling pathways involved in the cardioprotective effects of cannabinoids. J Pharmacol Sci 102: 155–166.
Loría F, Petrosino S, Hernangómez M, Mestre L, Spagnolo A, Correa F et al (2010). An endocannabinoid tone limits excitotoxicity in vitro and in a model of multiple sclerosis. Neurobiol Dis 37: 166–176.
Lowy MT, Gault L, Yamamoto BK (1993). Adrenalectomy attenuates stress-induced elevations in extracellular glutamate concentrations in the hippocampus. J Neurochem 61: 1957–1960.
Madrigal JL, García-Bueno B, Caso JR, Pérez-Nievas BG, Leza JC (2006). Stress-induced oxidative changes in brain. CNS Neurol Disord Drug Targets 5: 561–568.
Madrigal JL, Hurtado O, Moro MA, Lizasoain I, Lorenzo P, Castrillo A et al (2002). The increase in TNF-alpha levels is involved in NF-kappaB activation and inducible nitric oxide synthase expression in brain cortex after immobilization stress. Neuropsychopharmacology 26: 155–163.
Madrigal JL, Moro MA, Lizasoain I, Lorenzo P, Castrillo A, Boscá L et al (2001a). Inducible nitric oxide synthase expression in brain cortex after acute restraint stress is regulated by nuclear factor kappaB-mediated mechanisms. J Neurochem 76: 532–538.
Madrigal JL, Moro MA, Lizasoain I, Lorenzo P, Fernández AP, Rodrigo J et al (2003). Induction of cyclooxygenase-2 accounts for restraint stress-induced oxidative status in rat brain. Neuropsychopharmacology 28: 1579–1588.
Madrigal JL, Olivenza R, Moro MA, Lizasoain I, Lorenzo P, Rodrigo J et al (2001b). Glutathione depletion, lipid peroxidation and mitochondrial dysfunction are induced by chronic stress in rat brain. Neuropsychopharmacology 24: 420–429.
Manzanares J, Corchero J, Fuentes JA (1999). Opioid and cannabinoid receptormediated 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.
Marchalant Y, Brothers HM, Norman GJ, Karelina K, DeVries AC, Wenk GL (2009). Cannabinoids attenuate the effects of aging upon neuroinflammation and neurogenesis. Neurobiol Dis 34: 300–307.
Maresz K, Pryce G, Ponomarev ED, Marsicano G, Croxford JL, Shriver LP et al (2007). Direct suppression of CNS autoimmune inflammation via the cannabinoid receptor CB1 on neurons and CB2 on autoreactive T cells. Nat Med 13: 492–497.
Marsicano G, Goodenough S, Monory K, Hermann H, Eder M, Cannich A et al (2003). CB1 cannabinoid receptors and on-demand defense against excitotoxicity. Science 302: 84–88.
Marsicano G, Moosmann B, Hermann H, Lutz B, Behl C (2002). Neuroprotective properties of cannabinoids against oxidative stress: role of the cannabinoid receptor CB1. J Neurochem 80: 448–456.
McEwen BS (1998). Protective and damaging effects of stress mediators. N Engl J Med 338: 171–179.
McLeod TM, Lopez-Figueroa AL, Lopez-Figueroa MO (2001). Nitric oxide, stress, and depression. Psychopharmacol Bull 35: 24–41.
Mechoulam R, Shohami E (2007). Endocannabinoids and traumatic brain injury. Mol Neurobiol 36: 68–74.
Mikics E, Vas J, Aliczki M, Halasz J, Haller J (2009). Interactions between the anxiogenic effects of CB1 gene disruption and 5-HT3 neurotransmission. Behav Pharmacol 20: 265–272.
Moghaddam B (1993). Stress preferentially increases extraneuronal levels of excitatory amino acids in the prefrontal cortex: comparison to hippocampus and basal ganglia. J Neurochem 60: 1650–1657.
Olfe J, Domanska G, Schuett C, Kiank C (2010). Different stress-related phenotypes of BALB/c mice from in-house or vendor: alterations of the sympathetic and HPA axis responsiveness. BMC Physiol 10: 2.
O’Sullivan SE (2007). Cannabinoids go nuclear: evidence for activation of peroxisome proliferator-activated receptors. Br J Pharmacol 152: 576–582.
Panikashvili D, Mechoulam R, Beni SM, Alexandrovich A, Shohami E (2005). CB1 cannabinoid receptors are involved in neuroprotection via NF-kappa B inhibition. J Cereb Blood Flow Metab 25: 477–484.
Parmentier-Batteur S, Jin K, Mao XO, Xie L, Greenberg DA (2002). Increased severity of stroke in CB1 cannabinoid receptor knock-out mice. J Neurosci 22: 9771–9775.
Patel S, Roelke CT, Rademacher DJ, Cullinan WE, Hillard CJ (2004). Endocannabinoid signaling negatively modulates stress-induced activation of the hypothalamic-pituitaryadrenal axis. Endocrinology 145: 5431–5438.
Pérez-Rial S, García-Gutiérrez MS, Molina JA, Pérez-Nievas BG, Ledent C, Leiva C et al (2009). Increased vulnerability to 6-hydroxydopamine lesion and reduced development of dyskinesias in mice lacking CB1 cannabinoid receptors. Neurobiol Aging. (Epub ahead of print 4 May 2009).
Pryce G, Ahmed Z, Hankey DJ, Jackson SJ, Croxford JL, Pocock JM et al (2003). Cannabinoids inhibit neurodegeneration in models of multiple sclerosis. Brain 126 (Part 10): 2191–2202.
Qiu BS, Vallance BA, Blennerhassett PA, Collins SM (1999). The role of CD4+ lymphocytes in the susceptibility of mice to stress-induced reactivation of experimental colitis. Nat Med 5: 1178–1182.
Radley JJ, Arias CM, Sawchenko PE (2006). Regional differentiation of the medial prefrontal cortex in regulating adaptive responses to acute emotional stress. J Neurosci 26: 12967–12976.
Robinson MB, Hunter-Ensor M, Sinor J (1991). Pharmacologically distinct sodium-dependent L-[3H]glutamate. Brain Res 544: 196–202.
Rajesh M, Mukhopadhyay P, Haskó G, Huffman JW, Mackie K, Pacher P (2008). CB2 cannabinoid receptor agonists attenuate TNF-alpha-induced human vascular smooth muscle cell proliferation and migration. Br J Pharmacol 153: 347–357.
Rockwell CE, Snider NT, Thompson JT, Vanden Heuvel JP, Kaminski NE (2006). Interleukin-2 suppression by 2-arachidonyl glycerol is mediated through peroxisome proliferator-activated receptor gamma independently of cannabinoid receptors 1 and 2. Mol Pharmacol 70: 101–111.
Romera C, Hurtado O, Mallolas J, Pereira MP, Morales JR, Romera A et al (2007). Ischemic preconditioning reveals that GLT1/EAAT2 glutamate transporter is a novel PPARgamma target gene involved in neuroprotection. J Cereb Blood Flow Metab 27: 1327–1338.
Schreiber E, Matthias P, Müller MM, Schaffner W (1989). Rapid detection of octamer binding proteins with ‘mini-extracts’, prepared from a small number of cells. Nucleic Acid Res 17: 6419.
Sheng WS, Hu S, Min X, Cabral GA, Lokensgard JR, Peterson PK (2005). Synthetic cannabinoid WIN55,212-2 inhibits generation of inflammatory mediators by IL-1beta stimulated human astrocytes. Glia 49: 211–219.
Slimmer LM, Lyness JM, Caine ED (2001). Stress, medical illness, and depression. Semin Clin Neuropsychiatry 6: 12–26.
Stebulis JA, Johnson DR, Rossetti RG, Burstein SH, Zurier RB (2008). Ajulemic acid, a synthetic cannabinoid acid, induces an antiinflammatory profile of eicosanoids in human synovial cells. Life Sci 83: 666–670.
Stein-Behrens BA, Lin WJ, Sapolsky RM (1994). Physiological elevations of glucocorticoids potentiate glutamate accumulation in the hippocampus. J Neurochem 63: 596–602.
Steiner MA, Wotjak CT (2008). Role of the endocannabinoid system in regulation of the hypothalamic-pituitary-adrenocortical axis. Prog Brain Res 170: 397–432.
Sun Y, Bennett A (2007). Cannabinoids: a new group of Agonists of PPARs. PPAR Res 2007: 23513.
Urigüen L, Pérez-Rial S, Ledent C, Palomo T, Manzanares J (2004). Impaired action of anxiolytic drugs in mice deficient in cannabinoid CB1 receptors. Neuropharmacology 46: 966–973.
Veldhuis WB, van der Stelt M, Wadman MW, van Zadelhoff G, Maccarrone M, Fezza F et al (2003). Neuroprotection by the endogenous cannabinoid anandamide and arvanil against in vivo excitotoxicity in the rat: role of vanilloid receptors and lipoxygenases. J Neurosci 23: 4127–4133.
Wolf SA, Tauber S, Ullrich O (2008). CNS immune surveillance and neuroinflammation: endocannabinoids keep control. Curr Pharm Des 14: 2266–2278.
Zhang J, Chen CJ (2008). Endocannabinoid 2-arachidonoylglycerol protects neurons by limiting COX-2 elevation. Biol Chem 283: 22601–22611.
Acknowledgements
This research was supported by the Regional Government of Madrid (S-SAL/0261/2006), the Spanish Ministeries of Science and Innovation (SAF07-63138 and CIBERSAM), and Universidad Complutense-Santander (2878-920140). The research was also funded by Red Temática de Investigación Cooperativa en Salud (RETICS, Instituto de Salud Carlos III, MICINN/FEDER): Red de Trastornos Adictivos, RD06/0001/1004 (JM).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Rights and permissions
About this article
Cite this article
Zoppi, S., Pérez Nievas, B., Madrigal, J. et al. Regulatory Role of Cannabinoid Receptor 1 in Stress-Induced Excitotoxicity and Neuroinflammation. Neuropsychopharmacol 36, 805–818 (2011). https://doi.org/10.1038/npp.2010.214
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/npp.2010.214
Keywords
This article is cited by
-
How depression and antidepressant drugs affect endocannabinoid system?—review of clinical and preclinical studies
Naunyn-Schmiedeberg's Archives of Pharmacology (2024)
-
The semantics of microglia activation: neuroinflammation, homeostasis, and stress
Journal of Neuroinflammation (2021)
-
Cannabinoid receptor 1 signalling modulates stress susceptibility and microglial responses to chronic social defeat stress
Translational Psychiatry (2021)
-
Cognitive behavioral therapy program for cannabis use cessation in first-episode psychosis patients: study protocol for a randomized controlled trial
Trials (2016)
-
Neurobiological Interactions Between Stress and the Endocannabinoid System
Neuropsychopharmacology (2016)
