Abstract
Rational
Several pre-clinical and human-based studies have shown that acutely administered cannabidiol (CBD) can produce anxiolytic-like effects
Objectives
The present study investigated the effects of chronic administration of CBD on rat behaviour and on the expression of brain proteins.
Methods
Male Lister-hooded rats (150–200 g, n = 8 per group) received daily injections of CBD (10 mg/kg, i.p.) for 14 days. The rats were subjected to two behavioural tests: locomotor activity and conditioned emotional response (CER). The expression of brain-derived neurotrophic factor (BDNF), its receptor tyrosine kinase B (Trk B), extracellular signal-regulated kinases (ERK1/2) and phospho-ERK1/2 and the transcription factor cyclic AMP response element binding protein activation (CREB) and phospho-CREB were determined in brain regions such as the frontal cortex and hippocampus using Western immunoblotting.
Results
CBD significantly increased the time spent freezing in the CER test with no effect on locomotor activity. CBD significantly reduced BDNF expression in the hippocampus and frontal cortex with no change in the striatum. In addition, CBD significantly reduced TrkB expression in the hippocampus with a strong trend towards reduction in the striatum but had no effect in the frontal cortex. In the hippocampus, CBD had no effect on ERK1/2 or phospho-ERK2, but in the frontal cortex, CBD significantly reduced phospho-ERK1/2 expression without affecting total ERK.
Conclusion
Chronic administration of CBD produced an anxiogenic-like effect in clear opposition to the acute anxiolytic profile previously reported. In addition, CBD decreased the expression of proteins that have been shown to be enhanced by chronic treatment with antidepressant/anxiolytic drugs.
Similar content being viewed by others
References
Ashton CH (2001) Pharmacology and effects of cannabis: a brief review. Br J Psychiatry 178:101–106
Bergami M, Berninger B, Canossa M (2009) Conditional deletion of TrkB alters adult hippocampal neurogenesis and anxiety-related behavior. Commun Integr Biol 2:14–16
Bisogno T, Hanus L, De Petrocellis L, Tchilibon S, Ponde DE, Brandi I, Moriello AS, Davis JB, Mechoulam R, Di Marzo V (2001) Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. Br J Pharmacol 134:845–852
Bitencourt RM, Pamplona FA, Takahashi RN (2008) Facilitation of contextual fear memory extinction and anti-anxiogenic effects of AM404 and cannabidiol in conditioned rats. Eur Neuropsychopharmacol 18:849–859
Carrier EJ, Auchampach JA, Hillard CJ (2006) Inhibition of an equilibrative nucleoside transporter by cannabidiol: a mechanism of cannabinoid immunosuppression. Proc Natl Acad Sci USA 103:7895–7900
Crippa JA, Zuardi AW, Garrido GE, Wichert-Ana L, Guarnieri R, Ferrari L, Azevedo-Marques PM, Hallak JE, McGuire PK, Filho Busatto G (2004) Effects of cannabidiol (CBD) on regional cerebral blood flow. Neuropsychopharmacology 29:417–426
Dell’Osso B, Buoli M, Baldwin DS, Altamura AC (2010) Serotonin norepinephrine reuptake inhibitors (SNRIs) in anxiety disorders: a comprehensive review of their clinical efficacy. Hum Psychopharmacol 25:17–29
Duman RS, Monteggia LM (2006) A neurotrophic model for stress-related mood disorders. Biol Psychiatr 59:1116–1127
Dunn AJ, Guild AL, Kramarcy NR, Ware MD (1981) Benzodiazepines decrease grooming in response to novelty but not ACTH or beta-endorphin. Pharmacol Biochem Behav 15:605–608
Fanselow MS (1980) Conditioned and unconditional components of post-shock freezing. Pavlov J Biol Sci 15:177–182
Finn DP, Beckett SRG, Richardson D, Kendall DA, Marsden CA, Chapman V (2004a) Evidence for differential modulation of conditioned aversion and fear-conditioned analgesia by CB1 receptors. Eur J Neurosci 20:848–852
Finn DP, Beckett SRG, Roe CH, Madjd A, Fone KCF, Kendall DA, Marsden CA, Chapman V (2004b) Effects of coadministration of cannabinoids and morphine on nociceptive behaviour, brain monoamines and HPA axis activity in a rat model of persistent pain. Eur J Neurosci 19:678–686
Franklin A, Stella N (2003) Arachidonylcyclopropylamide increases microglial cell migration through cannabinoid CB2 and abnormal-cannabidiol-sensitive receptors. Eur J Pharmacol 474:195–198
Gruber AJ, Pope HGJ, Brown ME (1996) Do patients use marijuana as an antidepressant? Depression 4:77–80
Guimaraes FS, Chiaretti TM, Graeff FG, Zuardi AW (1990) Antianxiety effect of cannabidiol in the elevated plus-maze. Psychopharmacology (Berl) 100:558–559
Hashimoto S, Inoue T, Koyama T (1996) Serotonin reuptake inhibitors reduce conditioned fear stress-induced freezing behavior in rats. Psychopharmacology (Berl) 123:182–186
Ignatowska-Jankowska B, Jankowski MM, Swiergiel AH (2011) Cannabidiol decreases body weight gain in rats: Involvement of CB2 receptors. Neurosci Lett 490:82–84
Inoue T, Hashimoto S, Tsuchiya K, Izumi T, Ohmori T, Koyama T (1996) Effect of citalopram, a selective serotonin reuptake inhibitor, on the acquisition of conditioned freezing. Eur J Pharmacol 311:1–6
Jarai Z, Wagner JA, Varga K, Lake KD, Compton DR, Martin BR, Zimmer AM, Bonner TI, Buckley NE, Mezey E, Razdan RK, Zimmer A, Kunos G (1999) Cannabinoid-induced mesenteric vasodilation through an endothelial site distinct from CB1 or CB2 receptors. Proc Natl Acad Sci USA 96:14136–14141
Kennedy SH, Javanmard M, Vaccarino FJ (1997) A review of functional neuroimaging in mood disorders: positron emission tomography and depression. Can J Psychiatry 42:467–475
Kwiatkowska M, Parker LA, Burton P, Mechoulam R (2004) A comparative analysis of the potential of cannabinoids and ondansetron to suppress cisplatin-induced emesis in the Suncus murinus (house musk shrew). Psychopharmacology (Berl) 174:254–259
Lemos JI, Resstel LB, Guimarães FS (2010) Involvement of the prelimbic prefrontal cortex on cannabidiol-induced attenuation of contextual conditioned fear in rats. Behav Brain Res 207:105–111
Li XB, Inoue T, Hashimoto S, Koyama T (2001) Effect of chronic administration of flesinoxan and fluvoxamine on freezing behavior induced by conditioned fear. Eur J Pharmacol 425:43–50
Long LE, Chesworth R, Huang XF, McGregor IS, Arnold JC, Karl T (2009) A behavioural comparison of acute and chronic Delta9-tetrahydrocannabinol and cannabidiol in C57BL/6JArc mice. Int J Neuropsychopharmacol 13:1–16
Lowry OH, Rosebrough NJ, Rarr AL, Randall RJ (1951) Protein measurement with the folin phenol reagent. J Biol Chem 193:265–275
Magen I, Avraham Y, Ackerman Z, Vorobiev L, Mechoulam R, Berry EM (2009) Cannabidiol ameliorates cognitive and motor impairments in mice with bile duct ligation. J Hepatol 51:528–534
Malberg JE, Blendy JA (2005) Antidepressant action: to the nucleus and beyond. Trends Pharmacol Sci 26:631–638
Malfait AM, Gallily R, Sumariwalla PF, Malik AS, Andreakos E, Mechoulam R, Feldmann M (2000) The nonpsychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritis. Proc Natl Acad Sci USA 97:9561–9566
Martinowich K, Manji H, Lu B (2007) New insights into BDNF function in depression and anxiety. Nat Neurosci 10:1089–1093
Mechoulam R, Hanus L (2002) Cannabidiol: an overview of some chemical and pharmacological aspects. Part I: chemical aspects. Chem Phys Lipids 121:35–43
Moody TW, Merali Z, Crawley JN (1988) The effects of anxiolytics and other agents on rat grooming behavior. Ann N Y Acad Sci 525:281–290
Moreira FA, Aguiar DC, Guimaraes FS (2006) Anxiolytic-like effect of cannabidiol in the rat Vogel conflict test. Prog Neuropsychopharmacol Biol Psychiatry 30:1466–1471
Moreira FA, Aguiar DC, Campos AC, Lisboa SF, Terzian AL, Resstel LB, Guimaraes FS (2009) Antiaversive effects of cannabinoids: is the periaqueductal gray involved? Neural Plast 2009:625469
Nestler EJ, Barrot M, DiLeone RJ, Eisch AJ, Gold SJ, Monteggia LM (2002) Neurobiology of depression. Neuron 34:13–25
Nibuya M, Morinobu S, Duman RS (1995) Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. J Neurosci 15:7539–7547
Nibuya M, Nestler EJ, Duman RS (1996) Chronic antidepressant administration increases the expression of cAMP response element binding protein (CREB) in rat hippocampus. J Neurosci 16:2365–2372
Oka S, Nakajima K, Yamashita A, Kishimoto S, Sugiura T (2007) Identification of GPR55 as a lysophosphatidylinositol receptor. Biochem Biophys Res Comm 362:928–934
Oviedo A, Glowa J, Herkenham M (1993) Chronic cannabinoid administration alters cannabinoid receptor binding in rat brain: a quantitative autoradiographic study. Brain Res 616:293–302
Pardon MC, Roberts RE, Marsden CA, Bianchi M, Latif ML, Duxon MS, Kendall DA (2005) Social threat and novel cage stress-induced sustained extracellular-regulated kinase1/2 (ERK1/2) phosphorylation but differential modulation of brain-derived neurotrophic factor (BDNF) expression in the hippocampus of NMRI mice. Neuroscience 132:561–574
Patapoutian A, Reichardt LF (2001) Trk receptors: mediators of neurotrophin action. Curr Opin Neurobiol 11:272–280
Petitet F, Jeantaud B, Reibaud M, Imperato A, Dubroeucq M-C (1998) Complex pharmacology of natural cannabinoids: evidence for partial agonist activity of [Delta]9-tetrahydrocannabinol and antagonist activity of cannabidiol on rat brain cannabinoid receptors. Life Sci 63:PL1–PL6
Potter DJ, Clark P, Brown MB (2008) Potency of delta 9-THC and other cannabinoids in cannabis in England in 2005: implications for psychoactivity and pharmacology. J Forensic Sci 53:90–94
Qin N, Neeper MP, Liu Y, Hutchinson TL, Lubin ML, Flores CM (2008) TRPV2 is activated by cannabidiol and mediates CGRP release in cultured rat dorsal root ganglion neurons. J Neurosci 28:6231–6238
Resstel LBM, Joca SRL, Moreira FA, Correa FMA, Guimaraes FS (2006) Effects of cannabidiol and diazepam on behavioural and cardiovascular responses induced by contextual conditioned fear in rats. Behav Brain research 172:294–298
Resstel LB, Tavares RF, Lisboa SF, Joca SR, Correa FM, Guimaraes FS (2009) 5-HT1A receptors are involved in the cannabidiol-induced attenuation of behavioural and cardiovascular responses to acute restraint stress in rats. Br J Pharmacol 156:181–188
Rock EM, Limebeer CL, Mechoulam R, Piomelli D, Parker LA (2008) The effect of cannabidiol and URB597 on conditioned gaping (a model of nausea) elicited by a lithium-paired context in the rat. Psychopharmacology (Berl) 196:389–395
Rudy JW, Huff NC, Matus-Amat P (2004) Understanding contextual fear conditioning: insights from a two-process model. Neurosci Biobehav Rev 28:675–685
Russo EB, McPartland JM (2003) Cannabis is more than simply ?9-tetrahydrocannabinol. Psychopharmacology 165:431–432
Russo EB, Burnett A, Hall B, Parker KK (2005) Agonistic properties of cannabidiol at 5-HT1a receptors. Neurochem Res 30:1037–1043
Ryberg E, Larsson N, Sjogren S, Hjorth S, Hermansson NO, Leonova J, Elebring T, Nilsson K, Drmota T, Greasley PJ (2007) The orphan receptor GPR55 is a novel cannabinoid receptor. Br J Pharmacol 152:1092–1101
Sheline YI (2000) 3D MRI studies of neuroanatomic changes in unipolar major depression: the role of stress and medical comorbidity. Biol Psychiatry 48:791–800
Thome J, Sakai N, Shin KH, Steffen C, Zhang YJ, Impey S, Storm D, Duman RS (2000) cAMP response element-mediated gene transcription is upregulated by chronic antidepressant treatment. J Neurosci 20:4030–4036
van Erp AMM, Kruk MR, Meelis W, Willekens-Bramer DC (1994) Effect of environmental stressors on time course, variability and form of self-grooming in the rat: handling, social contact, defeat, novelty, restraint and fur moistening. Behav Brain research 65:47–55
Wiley JL, Burston JJ, Leggett DC, Alekseeva OO, Razdan RK, Mahadevan A, Martin BR (2005) CB1 cannabinoid receptor-mediated modulation of food intake in mice. Br J Pharmacol 145:293–300
Williamson EM, Evans FJ (2000) Cannabinoids in clinical practice. Drugs 60:1303–1314
Zanelati TV, Biojone C, Moreira FA, Guimaraes FS, Joca SR (2010) Antidepressant-like effects of cannabidiol in mice: possible involvement of 5-HT1A receptors. Br J Pharmacol 159:122–128
Zuardi AW, Shirakawa I, Finkelfarb E (1982) Action of cannabidiol on the anxiety and other effects produced by delta 9-THC in normal subjects. Psychopharmacology 76:245–250
Zuardi AW, Crippa JAS, Hallak JEC, Moreira FA, Guimarães FS (2006) Cannabidiol, a Cannabis sativa constituent, as an antipsychotic drug. Braz J Med Biol Res 39:421–429
Acknowledgements
We would like to thank GW Pharmaceuticals for kindly supplying the CBD.
Disclosure/conflict of interest
The authors have no conflicts of interest to disclose
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
ElBatsh, M.M., Assareh, N., Marsden, C.A. et al. Anxiogenic-like effects of chronic cannabidiol administration in rats. Psychopharmacology 221, 239–247 (2012). https://doi.org/10.1007/s00213-011-2566-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-011-2566-z