Psychopharmacology

, Volume 231, Issue 15, pp 3009–3017 | Cite as

Chronic cannabidiol treatment improves social and object recognition in double transgenic APPswe/PS1∆E9 mice

  • David Cheng
  • Jac Kee Low
  • Warren Logge
  • Brett Garner
  • Tim Karl
Original Investigation

Abstract

Rationale

Patients suffering from Alzheimer’s disease (AD) exhibit a decline in cognitive abilities including an inability to recognise familiar faces. Hallmark pathological changes in AD include the aggregation of amyloid-β (Aβ), tau protein hyperphosphorylation as well as pronounced neurodegeneration, neuroinflammation, neurotoxicity and oxidative damage.

Objectives

The non-psychoactive phytocannabinoid cannabidiol (CBD) exerts neuroprotective, anti-oxidant and anti-inflammatory effects and promotes neurogenesis. CBD also reverses Aβ-induced spatial memory deficits in rodents.

Materials and methods

Thus we determined the therapeutic-like effects of chronic CBD treatment (20 mg/kg, daily intraperitoneal injections for 3 weeks) on the APPswe/PS1∆E9 (APPxPS1) transgenic mouse model for AD in a number of cognitive tests, including the social preference test, the novel object recognition task and the fear conditioning paradigm. We also analysed the impact of CBD on anxiety behaviours in the elevated plus maze.

Results

Vehicle-treated APPxPS1 mice demonstrated impairments in social recognition and novel object recognition compared to wild type-like mice. Chronic CBD treatment reversed these cognitive deficits in APPxPS1 mice without affecting anxiety-related behaviours.

Conclusions

This is the first study to investigate the effect of chronic CBD treatment on cognition in an AD transgenic mouse model. Our findings suggest that CBD may have therapeutic potential for specific cognitive impairments associated with AD.

Keywords

Alzheimer’s disease Novel therapeutic Cannabidiol Transgenic APPswe/PS1∆E9 mice Cognition Behaviour Social recognition memory Object recognition memory 

References

  1. Barger SW, Basile AS (2001) Activation of microglia by secreted amyloid precursor protein evokes release of glutamate by cystine exchange and attenuates synaptic function. J Neurochem 76:846–54PubMedCrossRefGoogle Scholar
  2. Benito C, Nunez E, Pazos MR, Tolon RM, Romero J (2007) The endocannabinoid system and Alzheimer’s disease. Mol Neurobiol 36:75–81PubMedCrossRefGoogle Scholar
  3. Booz GW (2011) Cannabidiol as an emergent therapeutic strategy for lessening the impact of inflammation on oxidative stress. Free Radic Biol Med 51:1054–61PubMedCrossRefPubMedCentralGoogle Scholar
  4. Borchelt DR, Ratovitski T, van Lare J, Lee MK, Gonzales V, Jenkins NA, Copeland NG, Price DL, Sisodia SS (1997) Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins. Neuron 19:939–45PubMedCrossRefGoogle Scholar
  5. Campos AC, Guimaraes FS (2008) Involvement of 5HT1A receptors in the anxiolytic-like effects of cannabidiol injected into the dorsolateral periaqueductal gray of rats. Psychopharmacol (Berl) 199:223–30CrossRefGoogle Scholar
  6. Campos AC, Moreira FA, Gomes FV, Del Bel EA, Guimaraes FS (2012) Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders. Philos Trans R Soc Lond Ser B Biol Sci 367:3364–78CrossRefGoogle Scholar
  7. Campos AC, Ortega Z, Palazuelos J, Fogaca MV, Aguiar DC, Diaz-Alonso J, Ortega-Gutierrez S, Vazquez-Villa H, Moreira FA, Guzman M, Galve-Roperh I, Guimaraes FS (2013) The anxiolytic effect of cannabidiol on chronically stressed mice depends on hippocampal neurogenesis: involvement of the endocannabinoid system. Int J Neuropsychopharmacol 16:1407–19PubMedCrossRefGoogle Scholar
  8. Cheng D, Logge W, Low JK, Garner B, Karl T (2013) Novel behavioural characteristics of the APP(Swe)/PS1DeltaE9 transgenic mouse model of Alzheimer’s disease. Behav Brain Res 245:120–7PubMedCrossRefGoogle Scholar
  9. Chesworth R, Downey L, Logge W, Killcross S, Karl T (2012) Cognition in female transmembrane domain neuregulin 1 mutant mice. Behav Brain Res 226:218–23PubMedCrossRefGoogle Scholar
  10. Chung JA, Cummings JL (2000) Neurobehavioral and neuropsychiatric symptoms in Alzheimer’s disease: characteristics and treatment. Neurol Clin 18:829–46PubMedCrossRefGoogle Scholar
  11. Deiana S, Watanabe A, Yamasaki Y, Amada N, Arthur M, Fleming S, Woodcock H, Dorward P, Pigliacampo B, Close S, Platt B, Riedel G (2012) Plasma and brain pharmacokinetic profile of cannabidiol (CBD), cannabidivarine (CBDV), Delta(9)-tetrahydrocannabivarin (THCV) and cannabigerol (CBG) in rats and mice following oral and intraperitoneal administration and CBD action on obsessive-compulsive behaviour. Psychopharmacol (Berl) 219:859–73CrossRefGoogle Scholar
  12. Dere E, Huston JP, De Souza Silva MA (2007) The pharmacology, neuroanatomy and neurogenetics of one-trial object recognition in rodents. Neurosci Biobehav Rev 31:673–704PubMedCrossRefGoogle Scholar
  13. Donkin JJ, Stukas S, Hirsch-Reinshagen V, Namjoshi D, Wilkinson A, May S, Chan J, Fan J, Collins J, Wellington CL (2010) ATP-binding cassette transporter A1 mediates the beneficial effects of the liver X receptor agonist GW3965 on object recognition memory and amyloid burden in amyloid precursor protein/presenilin 1 mice. J Biol Chem 285:34144–54PubMedCrossRefPubMedCentralGoogle Scholar
  14. Duffy L, Cappas E, Lai D, Boucher AA, Karl T (2010) Cognition in transmembrane domain neuregulin 1 mutant mice. Neuroscience 170:800–7PubMedCrossRefGoogle Scholar
  15. Duszczyk M, Kuszczyk M, Guridi M, Lazarewicz JW, Sadowski MJ (2012) In vivo hippocampal microdialysis reveals impairment of NMDA receptor-cGMP signaling in APP(SW) and APP(SW)/PS1(L166P) Alzheimer’s transgenic mice. Neurochem Int 61:976–80PubMedCrossRefPubMedCentralGoogle Scholar
  16. ElBatsh MM, Assareh N, Marsden CA, Kendall DA (2012) Anxiogenic-like effects of chronic cannabidiol administration in rats. Psychopharmacol (Berl) 221:239–47CrossRefGoogle Scholar
  17. Esposito G, De Filippis D, Carnuccio R, Izzo AA, Iuvone T (2006) The marijuana component cannabidiol inhibits beta-amyloid-induced tau protein hyperphosphorylation through Wnt/beta-catenin pathway rescue in PC12 cells. J Mol Med 84:253–8PubMedCrossRefGoogle Scholar
  18. Esposito G, Scuderi C, Savani C, Steardo L Jr, De Filippis D, Cottone P, Iuvone T, Cuomo V, Steardo L (2007) Cannabidiol in vivo blunts beta-amyloid induced neuroinflammation by suppressing IL-1beta and iNOS expression. Br J Pharmacol 151:1272–9PubMedCrossRefPubMedCentralGoogle Scholar
  19. Esposito G, Scuderi C, Valenza M, Togna GI, Latina V, De Filippis D, Cipriano M, Carratu MR, Iuvone T, Steardo L (2011) Cannabidiol reduces Aβ-induced neuroinflammation and promotes hippocampal neurogenesis through PPARgamma involvement. PLoS One 6:e28668PubMedCrossRefPubMedCentralGoogle Scholar
  20. Faizi M, Bader PL, Saw N, Nguyen TV, Beraki S, Wyss-Coray T, Longo FM, Shamloo M (2012) Thy1-hAPP(Lond/Swe+) mouse model of Alzheimer’s disease displays broad behavioral deficits in sensorimotor, cognitive and social function. Brain Behav 2:142–54PubMedCrossRefPubMedCentralGoogle Scholar
  21. Farlow MR, Alva G, Meng X, Olin JT (2010) A 25-week, open-label trial investigating rivastigmine transdermal patches with concomitant memantine in mild-to-moderate Alzheimer’s disease: a post hoc analysis. Curr Med Res Opin 26:263–9PubMedCrossRefGoogle Scholar
  22. Fernandez F, Morishita W, Zuniga E, Nguyen J, Blank M, Malenka RC, Garner CC (2007) Pharmacotherapy for cognitive impairment in a mouse model of Down syndrome. Nat Neurosci 10:411–3PubMedGoogle Scholar
  23. Filali M, Lalonde R, Rivest S (2011) Anomalies in social behaviors and exploratory activities in an APPswe/PS1 mouse model of Alzheimer’s disease. Physiol Behav 104:880–5PubMedCrossRefGoogle Scholar
  24. Gotz J, Ittner LM (2008) Animal models of Alzheimer’s disease and frontotemporal dementia. Nat Rev Neurosci 9:532–44PubMedCrossRefGoogle Scholar
  25. Guimaraes FS, Chiaretti TM, Graeff FG, Zuardi AW (1990) Antianxiety effect of cannabidiol in the elevated plus-maze. Psychopharmacol (Berl) 100:558–9CrossRefGoogle Scholar
  26. Hallak JE, Dursun SM, Bosi DC, de Macedo LR, Machado-de-Sousa JP, Abrao J, Crippa JA, McGuire P, Krystal JH, Baker GB, Zuardi AW (2011) The interplay of cannabinoid and NMDA glutamate receptor systems in humans: preliminary evidence of interactive effects of cannabidiol and ketamine in healthy human subjects. Prog Neuropsychopharmacol Biol Psychiatry 35:198–202PubMedCrossRefGoogle Scholar
  27. Hamilton A, Holscher C (2012) The effect of ageing on neurogenesis and oxidative stress in the APP(swe)/PS1(deltaE9) mouse model of Alzheimer’s disease. Brain Res 1449:83–93PubMedCrossRefGoogle Scholar
  28. Hampson AJ, Grimaldi M, Axelrod J, Wink D (1998) Cannabidiol and (-)Delta9-tetrahydrocannabinol are neuroprotective antioxidants. Proc Natl Acad Sci U S A 95:8268–73PubMedCrossRefPubMedCentralGoogle Scholar
  29. Hill AJ, Williams CM, Whalley BJ, Stephens GJ (2012) Phytocannabinoids as novel therapeutic agents in CNS disorders. Pharmacol Ther 133:79–97PubMedCrossRefGoogle Scholar
  30. Iuvone T, Esposito G, Esposito R, Santamaria R, Di Rosa M, Izzo AA (2004) Neuroprotective effect of cannabidiol, a non-psychoactive component from Cannabis sativa, on beta-amyloid-induced toxicity in PC12 cells. J Neurochem 89:134–41PubMedCrossRefGoogle Scholar
  31. Iuvone T, Esposito G, De Filippis D, Scuderi C, Steardo L (2009) Cannabidiol: a promising drug for neurodegenerative disorders? CNS Neurosci Ther 15:65–75PubMedCrossRefGoogle Scholar
  32. Izzo AA, Borrelli F, Capasso R, Di Marzo V, Mechoulam R (2009) Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends Pharmacol Sci 30:515–27PubMedCrossRefGoogle Scholar
  33. Jankowsky JL, Slunt HH, Ratovitski T, Jenkins NA, Copeland NG, Borchelt DR (2001) Co-expression of multiple transgenes in mouse CNS: a comparison of strategies. Biomol Eng 17:157–65PubMedCrossRefGoogle Scholar
  34. Jankowsky JL, Fadale DJ, Anderson J, Xu GM, Gonzales V, Jenkins NA, Copeland NG, Lee MK, Younkin LH, Wagner SL, Younkin SG, Borchelt DR (2004a) Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: evidence for augmentation of a 42-specific gamma secretase. Hum Mol Genet 13:159–70PubMedCrossRefGoogle Scholar
  35. Jankowsky JL, Slunt HH, Gonzales V, Jenkins NA, Copeland NG, Borchelt DR (2004b) APP processing and amyloid deposition in mice haplo-insufficient for presenilin 1. Neurobiol Aging 25:885–92PubMedCrossRefGoogle Scholar
  36. Jardanhazi-Kurutz D, Kummer MP, Terwel D, Vogel K, Dyrks T, Thiele A, Heneka MT (2010) Induced LC degeneration in APP/PS1 transgenic mice accelerates early cerebral amyloidosis and cognitive deficits. Neurochem Int 57:375–82PubMedCrossRefGoogle Scholar
  37. Johnson VE, Stewart JE, Begbie FD, Trojanowski JQ, Smith DH, Stewart W (2013) Inflammation and white matter degeneration persist for years after a single traumatic brain injury. Brain 136:28–42PubMedCrossRefPubMedCentralGoogle Scholar
  38. Kalifa S, Polston EK, Allard JS, Manaye KF (2011) Distribution patterns of cannabinoid CB1 receptors in the hippocampus of APPswe/PS1DeltaE9 double transgenic mice. Brain Res 1376:94–100PubMedCrossRefGoogle Scholar
  39. Karl T, Duffy L, Herzog H (2008) Behavioural profile of a new mouse model for NPY deficiency. Eur J Neurosci 28:173–80PubMedCrossRefGoogle Scholar
  40. Karl T, Bhatia S, Cheng D, Kim WS, Garner B (2012a) Cognitive phenotyping of amyloid precursor protein transgenic J20 mice. Behav Brain Res 228:392–7PubMedCrossRefGoogle Scholar
  41. Karl T, Cheng D, Garner B, Arnold JC (2012b) The therapeutic potential of the endocannabinoid system for Alzheimer’s disease. Expert Opin Ther Targets 16:407–20PubMedCrossRefGoogle Scholar
  42. Koppel J, Davies P (2008) Targeting the endocannabinoid system in Alzheimer’s disease. J Alzheimer’s Dis JAD 15:495–504Google Scholar
  43. Krishnan S, Cairns R, Howard R (2009) Cannabinoids for the treatment of dementia. Cochrane Database Syst Rev: (2). doi:10.1002/14651858.CD007204.pub2
  44. Lalonde R, Kim HD, Fukuchi K (2004) Exploratory activity, anxiety, and motor coordination in bigenic APPswe + PS1/DeltaE9 mice. Neurosci lett 369:156–61PubMedCrossRefGoogle Scholar
  45. Logge W, Cheng D, Chesworth R, Bhatia S, Garner B, Kim WS, Karl T (2012) Role of Abca7 in mouse behaviours relevant to neurodegenerative diseases. PLoS One 7:e45959PubMedCrossRefPubMedCentralGoogle Scholar
  46. Long LE, Chesworth R, Huang XF, McGregor IS, Arnold JC, Karl T (2010) A behavioural comparison of acute and chronic Delta9-tetrahydrocannabinol and cannabidiol in C57BL/6JArc mice. Int J Neuropsychopharmacol 13:861–76PubMedCrossRefGoogle Scholar
  47. Long LE, Chesworth R, Huang XF, Wong A, Spiro A, McGregor IS, Arnold JC, Karl T (2012) Distinct neurobehavioural effects of cannabidiol in transmembrane domain neuregulin 1 mutant mice. PLoS One 7:e34129PubMedCrossRefPubMedCentralGoogle Scholar
  48. Machova E, Rudajev V, Smyckova H, Koivisto H, Tanila H, Dolezal V (2010) Functional cholinergic damage develops with amyloid accumulation in young adult APPswe/PS1dE9 transgenic mice. Neurobiol Dis 38:27–35PubMedCrossRefGoogle Scholar
  49. Marchalant Y, Brothers HM, Wenk GL (2008) Inflammation and aging: can endocannabinoids help? Biomed Pharmacother 62:212–7PubMedCrossRefPubMedCentralGoogle Scholar
  50. Martin-Moreno AM, Reigada D, Ramirez BG, Mechoulam R, Innamorato N, Cuadrado A, de Ceballos ML (2011) Cannabidiol and other cannabinoids reduce microglial activation in vitro and in vivo: relevance to Alzheimer’s disease. Mol Pharmacol 79:964–73PubMedCrossRefPubMedCentralGoogle Scholar
  51. Micale V, Mazzola C, Drago F (2007) Endocannabinoids and neurodegenerative diseases. Pharmacol Res 56:382–92PubMedCrossRefGoogle Scholar
  52. Montgomery KC (1955) The relation between fear induced by novel stimulation and exploratory behavior. J Comp Physiol Psychol 48:254–260PubMedCrossRefGoogle Scholar
  53. Montgomery KC, Monkman JA (1955) The relation between fear and exploratory behavior. J Comp Physiol Psychol 48:132–136PubMedCrossRefGoogle Scholar
  54. Moreira FA, Aguiar DC, Guimaraes FS (2006) Anxiolytic-like effect of cannabidiol in the rat Vogel conflict test. Prog Neuropsychopharmacol Biol Psychiatry 30:1466–71PubMedCrossRefGoogle Scholar
  55. Moy SS, Nadler JJ, Perez A, Barbaro RP, Johns JM, Magnuson TR, Piven J, Crawley JN (2004) Sociability and preference for social novelty in five inbred strains: an approach to assess autistic-like behavior in mice. Genes Brain Behav 3:287–302PubMedCrossRefGoogle Scholar
  56. Nilsson M, Hansson S, Carlsson A, Carlsson ML (2007) Differential effects of the N-methyl-d-aspartate receptor antagonist MK-801 on different stages of object recognition memory in mice. Neuroscience 149:123–30PubMedCrossRefGoogle Scholar
  57. Onaivi ES, Green MR, Martin BR (1990) Pharmacological characterization of cannabinoids in the elevated plus maze. J Pharmacol Exp Ther 253:1002–9PubMedGoogle Scholar
  58. Pomara N, Singh R, Deptula D, Chou JC, Schwartz MB, LeWitt PA (1992) Glutamate and other CSF amino acids in Alzheimer’s disease. Am J Psychiatry 149:251–4PubMedGoogle Scholar
  59. Pratico D, Sung S (2004) Lipid peroxidation and oxidative imbalance: early functional events in Alzheimer’s disease. J Alzheimer’s Dis JAD 6:171–5Google Scholar
  60. Rammsayer TH (2001) Effects of pharmacologically induced changes in NMDA-receptor activity on long-term memory in humans. Learn Mem (Cold Spring Harbor, NY) 8:20–5CrossRefGoogle Scholar
  61. Reisberg B, Ferris SH, de Leon MJ, Crook T (1982) The Global Deterioration Scale for assessment of primary degenerative dementia. Am J Psychiatry 139:1136–9PubMedGoogle Scholar
  62. Reiserer RS, Harrison FE, Syverud DC, McDonald MP (2007) Impaired spatial learning in the APPSwe + PSEN1DeltaE9 bigenic mouse model of Alzheimer’s disease. Genes Brain Behav 6:54–65PubMedCrossRefGoogle Scholar
  63. Scholtzova H, Wadghiri YZ, Douadi M, Sigurdsson EM, Li YS, Quartermain D, Banerjee P, Wisniewski T (2008) Memantine leads to behavioral improvement and amyloid reduction in Alzheimer’s-disease-model transgenic mice shown as by micromagnetic resonance imaging. J Neurosci Res 86:2784–91PubMedCrossRefPubMedCentralGoogle Scholar
  64. Scuderi C, Esposito G, Blasio A, Valenza M, Arietti P, Steardo L Jr, Carnuccio R, De Filippis D, Petrosino S, Iuvone T, Di Marzo V, Steardo L (2011) Palmitoylethanolamide counteracts reactive astrogliosis induced by beta-amyloid peptide. J Cell Mol Med 15:2664–74PubMedCrossRefGoogle Scholar
  65. Tariot PN, Farlow MR, Grossberg GT, Graham SM, McDonald S, Gergel I (2004) Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA 291:317–24PubMedCrossRefGoogle Scholar
  66. Thomas A, Baillie GL, Phillips AM, Razdan RK, Ross RA, Pertwee RG (2007) Cannabidiol displays unexpectedly high potency as an antagonist of CB1 and CB2 receptor agonists in vitro. Br J Pharmacol 150:613–23PubMedCrossRefPubMedCentralGoogle Scholar
  67. Webster SJ, Bachstetter AD, Van Eldik LJ (2013) Comprehensive behavioral characterization of an APP/PS-1 double knock-in mouse model of Alzheimer’s disease. Alzheimer’s Res Ther 5:28CrossRefGoogle Scholar
  68. Williams TI, Lynn BC, Markesbery WR, Lovell MA (2006) Increased levels of 4-hydroxynonenal and acrolein, neurotoxic markers of lipid peroxidation, in the brain in mild cognitive impairment and early Alzheimer’s disease. Neurobiol Aging 27:1094–9PubMedCrossRefGoogle Scholar
  69. Wolf SA, Bick-Sander A, Fabel K, Leal-Galicia P, Tauber S, Ramirez-Rodriguez G, Muller A, Melnik A, Waltinger TP, Ullrich O, Kempermann G (2010) Cannabinoid receptor CB1 mediates baseline and activity-induced survival of new neurons in adult hippocampal neurogenesis. Cell Commun signal CCS 8:12CrossRefGoogle Scholar
  70. Yoshiike Y, Kimura T, Yamashita S, Furudate H, Mizoroki T, Murayama M, Takashima A (2008) GABA(A) receptor-mediated acceleration of aging-associated memory decline in APP/PS1 mice and its pharmacological treatment by picrotoxin. PLoS One 3:e3029PubMedCrossRefPubMedCentralGoogle Scholar
  71. Zuardi AW (2008) Cannabidiol: from an inactive cannabinoid to a drug with wide spectrum of action. Rev Bras Psiquiatr 30:271–80PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • David Cheng
    • 1
    • 2
  • Jac Kee Low
    • 1
    • 3
  • Warren Logge
    • 1
    • 3
  • Brett Garner
    • 4
    • 5
  • Tim Karl
    • 1
    • 2
    • 3
  1. 1.Neuroscience Research AustraliaRandwickAustralia
  2. 2.School of Medical SciencesUniversity of New South WalesKensingtonAustralia
  3. 3.Schizophrenia Research InstituteDarlinghurstAustralia
  4. 4.Illawarra Health and Medical Research InstituteUniversity of WollongongWollongongAustralia
  5. 5.School of Biological SciencesUniversity of WollongongWollongongAustralia

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