Advertisement

Psychopharmacology

, Volume 219, Issue 3, pp 859–873 | Cite as

Plasma and brain pharmacokinetic profile of cannabidiol (CBD), cannabidivarine (CBDV), Δ9-tetrahydrocannabivarin (THCV) and cannabigerol (CBG) in rats and mice following oral and intraperitoneal administration and CBD action on obsessive–compulsive behaviour

  • Serena Deiana
  • Akihito Watanabe
  • Yuki Yamasaki
  • Naoki Amada
  • Marlene Arthur
  • Shona Fleming
  • Hilary Woodcock
  • Patricia Dorward
  • Barbara Pigliacampo
  • Steve Close
  • Bettina Platt
  • Gernot RiedelEmail author
Original Investigation
First Online:

Abstract

Rationale

Phytocannabinoids are useful therapeutics for multiple applications including treatments of constipation, malaria, rheumatism, alleviation of intraocular pressure, emesis, anxiety and some neurological and neurodegenerative disorders. Consistent with these medicinal properties, extracted cannabinoids have recently gained much interest in research, and some are currently in advanced stages of clinical testing. Other constituents of Cannabis sativa, the hemp plant, however, remain relatively unexplored in vivo. These include cannabidiol (CBD), cannabidivarine (CBDV), Δ9-tetrahydrocannabivarin (Δ9-THCV) and cannabigerol (CBG).

Objectives and methods

We here determined pharmacokinetic profiles of the above phytocannabinoids after acute single-dose intraperitoneal and oral administration in mice and rats. The pharmacodynamic–pharmacokinetic relationship of CBD (120 mg/kg, ip and oral) was further assessed using a marble burying test in mice.

Results

All phytocannabinoids readily penetrated the blood–brain barrier and solutol, despite producing moderate behavioural anomalies, led to higher brain penetration than cremophor after oral, but not intraperitoneal exposure. In mice, cremophor-based intraperitoneal administration always attained higher plasma and brain concentrations, independent of substance given. In rats, oral administration offered higher brain concentrations for CBD (120 mg/kg) and CBDV (60 mg/kg), but not for Δ9-THCV (30 mg/kg) and CBG (120 mg/kg), for which the intraperitoneal route was more effective. CBD inhibited obsessive–compulsive behaviour in a time-dependent manner matching its pharmacokinetic profile.

Conclusions

These data provide important information on the brain and plasma exposure of new phytocannabinoids and guidance for the most efficacious administration route and time points for determination of drug effects under in vivo conditions.

Keywords

Phytocannabinoids Systemic administration Bioavailability Area under curve Elimination half-life Pharmacokinetic Pharmacodynamic Rats Mice 
This is a preview of subscription content, log in to check access.

Notes

Acknowledgements

This work was partly supported by a collaboration between GW Pharmaceuticals and Otsuka Pharma. Furthermore, and we are indebted to Drs. T Kikuchi for comments on an earlier draft of this manuscript.

Supplementary material

213_2011_2415_Fig7_ESM.jpg (47 kb)
Supplementary Fig. 1

HPLC spectra of compounds used in this study. Purity was above 95%. a CBD; b CBDV; c Δ9-THCV; d CBG (JPEG 47 kb)

213_2011_2415_Fig8_ESM.jpg (73 kb)
Supplementary Fig. 2

Pharmacokinetic comparison of CBD dissolved in solutol or chremophor and injected into rat. Administration routes included intraperitoneal (a, b) and oral (c, d) routes. CBD (120 mg/kg) was administered at time point 0 and tissue harvested at six time points within 24 h post-dosing. Drug levels are shown in top row (a and c) as log 10 of plasma concentration (C P) and in b and d as log 10 of brain concentration (C B). Mean ± SEM. (JPEG 73 kb)

References

  1. Abel EL, McMillan DE, Harris LS (1974) D9-Tetrahydro-cannabinol: effects of routes of administration on onset and duration of activity and tolerance development. Psychopharmacologia 35:29CrossRefGoogle Scholar
  2. Aghazadeh-Habashi A, Ibrahim A, Carran J, Anastassiades T, Jamali F (2006) Single dose pharmacokinetics and bioavailability of butyryl glucosamine in the rat. J Pharm Pharm Sci 9:359–364PubMedGoogle Scholar
  3. Agurell S, Halldin M, Lindgren JE, Ohlsson A, Widman M, Gillespie H, Hollister L (1986) Pharmacokinetics and metabolism of delta 1-tetrahydrocannabinol and other cannabinoids with emphasis on man. Pharmacol Rev 38:21–43PubMedGoogle Scholar
  4. Alozie SO, Martin BR, Harris LS, Dewey WL (1980) 3H-delta 9-Tetrahydrocannabinol, 3H-cannabinol and 3H-cannabidiol: penetration and regional distribution in rat brain. Pharmacol Biochem Behav 12:217–221PubMedCrossRefGoogle Scholar
  5. Appendino G, Gibbons S, Giana A, Pagani A, Grassi G, Stavri M, Smith E, Rahman MM (2008) Antibacterial cannabinoids from Cannabis sativa: a structure–activity study. J Nat Prod 71:1427–1430. doi: 10.1021/np8002673 PubMedCrossRefGoogle Scholar
  6. Baek SH, Kim YO, Kwag JS, Choi KE, Jung WY, Han DS (1998) Boron trifluoride etherate on silica-A modified Lewis acid reagent (VII). Antitumor activity of cannabigerol against human oral epitheloid carcinoma cells. Arch Pharm Res 21:353–356PubMedCrossRefGoogle Scholar
  7. 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 15:1623–1646PubMedCrossRefGoogle Scholar
  8. Barna I, Till I, Haller J (2009) Blood, adipose tissue and brain levels of the cannabinoid ligands WIN-55,212 and SR-141716A after their intraperitoneal injection in mice: compound-specific and area-specific distribution within the brain. Eur Neuropsychopharmacol 19:533–541. doi: 10.1016/j.euroneuro.2009.02.001 PubMedCrossRefGoogle Scholar
  9. Bifulco M, Grimaldi C, Gazzerro P, Pisanti S, Santoro A (2007) Rimonabant: just an antiobesity drug? Current evidence on its pleiotropic effects. Mol Pharmacol 71:1445–1456. doi: 10.1124/mol.106.033118 PubMedCrossRefGoogle Scholar
  10. 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. doi: 10.1038/sj.bjp.0704327 PubMedCrossRefGoogle Scholar
  11. Bittner B, Gonzalez RC, Walter I, Kapps M, Huwyler J (2003) Impact of Solutol HS 15 on the pharmacokinetic behaviour of colchicine upon intravenous administration to male Wistar rats. Biopharm Drug Dispos 24:173–181. doi: 10.1002/bdd.353 PubMedCrossRefGoogle Scholar
  12. Bolognini D, Costa B, Maione S, Comelli F, Marini P, Di Marzo V, Parolaro D, Ross RA, Gauson LA, Cascio MG, Pertwee RG (2010) The plant cannabinoid delta9-tetrahydrocannabivarin can decrease signs of inflammation and inflammatory pain in mice. Br J Pharmacol 160:677–687. doi: 10.1111/j.1476-5381.2010.00756.x PubMedCrossRefGoogle Scholar
  13. Borsini F, Podhorna J, Marazziti D (2002) Do animal models of anxiety predict anxiolytic-like effects of antidepressants? Psychopharmacology (Berl) 163:121–141. doi: 10.1007/s0 0213-002-1155-6 CrossRefGoogle Scholar
  14. Broekkamp CL, Rijk HW, Joly-Gelouin D, Lloyd KL (1986) Major tranquillizers can be distinguished from minor tranquillizers on the basis of effects on marble burying and swim-induced grooming in mice. Eur J Pharmacol 126:223–229PubMedCrossRefGoogle Scholar
  15. Carey M, Burish TG, Brenner DE (1983) delta-9-Tetrahydrocannabinol in cancer chemotherapy: research problems and issues. Ann Intern Med 99:106PubMedGoogle Scholar
  16. Carlini EA (2004) The good and the bad effects of (−) trans-delta-9-tetrahydrocannabinol (delta 9-THC) on humans. Toxicon 44:461–467. doi: 10.1016/j.toxicon.2004.05.009 PubMedCrossRefGoogle Scholar
  17. Casarotto PC, Gomes FV, Resstel LB, Guimaraes FS (2010) Cannabidiol inhibitory effect on marble-burying behaviour: involvement of CB1 receptors. Behav Pharmacol 21:353–358PubMedCrossRefGoogle Scholar
  18. Cascio MG, Gauson LA, Stevenson LA, Ross RA, Pertwee RG (2010) Evidence that the plant cannabinoid cannabigerol is a highly potent alpha2-adrenoceptor agonist and moderately potent 5HT1A receptor antagonist. Br J Pharmacol 159:129–141. doi: 10.1111/j.1476-5381.2009.00515.x PubMedCrossRefGoogle Scholar
  19. Claassen V (1994) Neglected factors in pharmacology and neuroscience research. Elsevier, AmsterdamGoogle Scholar
  20. Colasanti BK (1990) A comparison of the ocular and central effects of delta 9-tetrahydrocannabinol and cannabigerol. J Ocul Pharmacol 6:259–269PubMedCrossRefGoogle Scholar
  21. Colasanti BK, Craig CR, Allara RD (1984) Intraocular pressure, ocular toxicity and neurotoxicity after administration of cannabinol or cannabigerol. Exp Eye Res 39:251–259PubMedCrossRefGoogle Scholar
  22. Cornaire G, Woodley J, Hermann P, Cloarec A, Arellano C, Houin G (2004) Impact of excipients on the absorption of P-glycoprotein substrates in vitro and in vivo. Int J Pharm 278:119–131. doi: 10.1016/j.ijpharm.2004.03.001 PubMedCrossRefGoogle Scholar
  23. De Leo L, Di Toro N, Decorti G, Malusa N, Ventura A, Not T (2010) Fasting increases tobramycin oral absorption in mice. Antimicrob Agents Chemother 54:1644–1646. doi: 10.1128/AAC.01172-09 PubMedCrossRefGoogle Scholar
  24. de Mattos Viana B, Prais HA, Daker MV (2009) Melancholic features related to rimonabant. Gen Hosp Psychiatry 31:583–585. doi: 10.1016/j.genhosppsych.2008.12.009 PubMedCrossRefGoogle Scholar
  25. Despres JP (2009) Pleiotropic effects of rimonabant: clinical implications. Curr Pharm Des 15:553–570PubMedCrossRefGoogle Scholar
  26. Elsohly MA, Slade D (2005) Chemical constituents of marijuana: the complex mixture of natural cannabinoids. Life Sci 78:539–548. doi: 10.1016/j.lfs.2005.09.011 PubMedCrossRefGoogle Scholar
  27. Fang JY, Hsu SH, Leu YL, Hu JW (2009) Delivery of cisplatin from pluronic co-polymer systems: liposome inclusion and alginate coupling. J Biomater Sci Polym Ed 20:1031–1047. doi: 10.1163/156856209X444493 PubMedCrossRefGoogle Scholar
  28. Gaoni Y, Mechoulam R (1964) Isolation, structure and partial synthesis of an active constituent of hashish. J Am Chem Soc 86:1646–1647Google Scholar
  29. Gill EW, Paton WD, Pertwee RG (1970) Preliminary experiments on the chemistry and pharmacology of cannabis. Nature 228:134–136PubMedCrossRefGoogle Scholar
  30. Gomes FV, Casarotto PC, Resstel LB, Guimaraes FS (2011) Facilitation of CB1 receptor-mediated neurotransmission decreases marble burying behavior in mice. Prog Neuropsychopharmacol Biol Psychiatry 35:434–438. doi: 10.1016/j.pnpbp.2010.11.027 PubMedCrossRefGoogle Scholar
  31. Goulle JP, Saussereau E, Lacroix C (2008) delta-9-Tetrahydrocannabinol pharmacokinetics. Ann Pharm Fr 66:232–244. doi: 10.1016/j.pharma.2008.07.006 PubMedCrossRefGoogle Scholar
  32. Guzman M, Sanchez C, Galve-Roperh I (2002) Cannabinoids and cell fate. Pharmacol Ther 95:175–184PubMedCrossRefGoogle Scholar
  33. Hill AJ, Weston SE, Jones NA, Smith I, Bevan SA, Williamson EM, Stephens GJ, Williams CM, Whalley BJ (2010) delta-Tetrahydrocannabivarin suppresses in vitro epileptiform and in vivo seizure activity in adult rats. Epilepsia 51:1522–1532. doi: 10.1111/j.1528-1167.2010.02523.x PubMedCrossRefGoogle Scholar
  34. Hillig KW, Mahlberg PG (2004) A chemotaxonomic analysis of cannabinoids variation in Cannabis (Cannabaceae). Am J Bot 91:966PubMedCrossRefGoogle Scholar
  35. Ho BT, Fritchie GE, Englert LF, McIsaac WM, Idanpaan-Heikkila JE (1971) Marihuana: importance of the route of administration. J Pharm Pharmacol 23:309–310PubMedCrossRefGoogle Scholar
  36. Hollister LE (1974) Structure-activity relationships in man of cannabis constituents, and homologs and metabolites of delta9-tetrahydrocannabinol. Pharmacology 11:3–11PubMedCrossRefGoogle Scholar
  37. Iuvone T, Esposito G, De Filippis D, Scuderi C, Steardo L (2009) Cannabidiol: a promising drug for neurodegenerative disorders? CNS Neurosci Ther 15:65–75. doi: 10.1111/j.1755-5949.2008.00065.x PubMedCrossRefGoogle Scholar
  38. Iversen L (2007) The science of marijuana. Oxford University Press, OxfordCrossRefGoogle Scholar
  39. Jones AB, Elsohly MA, Bedford JA, Turner CE (1981) Determination of cannabidiol in plasma by electron-capture gas chromatography. J Chromatogr 226:99–105PubMedCrossRefGoogle Scholar
  40. Kast A, Nishikawa J (1981) The effect of fasting on oral acute toxicity of drugs in rats and mice. Lab Anim 15:359–364PubMedCrossRefGoogle Scholar
  41. Leweke FM, Koethe D, Pahlisch F, Schreiber D, Gerth CW, Nolden BM, Klosterkötter J, Hellmich M, Piomelli D (2009) Antipsychotic effects of cannabidiol. 17th EPA Congress. Eur Psychiatry 24:S207CrossRefGoogle Scholar
  42. Li X, Morrow D, Witkin JM (2006) Decreases in nestlet shredding of mice by serotonin uptake inhibitors: comparison with marble burying. Life Sci 78:1933–1939. doi: 10.1016/j.lfs.2005.08.002 PubMedCrossRefGoogle Scholar
  43. Ligresti A, Moriello AS, Starowicz K, Matias I, Pisanti S, De Petrocellis L, Laezza C, Portella G, Bifulco M, Di Marzo V (2006) Antitumor activity of plant cannabinoids with emphasis on the effect of cannabidiol on human breast carcinoma. J Pharmacol Exp Ther 318:1375–1387. doi: 10.1124/jpet.106.105247 PubMedCrossRefGoogle Scholar
  44. Mantilla-Plata B, Harbison RD (1975) Distribution studies of (14C)delta-9-tetrahydrocannabinol in mice: effect of vehicle, route of administration, and duration of treatment. Toxicol Appl Pharmacol 34:292–300PubMedCrossRefGoogle Scholar
  45. Nicolas LB, Kolb Y, Prinssen EP (2006) A combined marble burying-locomotor activity test in mice: a practical screening test with sensitivity to different classes of anxiolytics and antidepressants. Eur J Pharmacol 547:106–115. doi: 10.1016/j.ejphar.2006.07.015 PubMedCrossRefGoogle Scholar
  46. Njung'e K, Handley SL (1991) Evaluation of marble-burying behavior as a model of anxiety. Pharmacol Biochem Behav 38:63–67PubMedCrossRefGoogle Scholar
  47. Perrier T, Saulnier P, Fouchet F, Lautram N, Benoit JP (2010) Post-insertion into lipid nanocapsules (LNCs): from experimental aspects to mechanisms. Int J Pharm 396:204–209. doi: 10.1016/j.ijpharm.2010.06.019 PubMedCrossRefGoogle Scholar
  48. 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 (2010) International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB1 and CB2. Pharmacol Rev 62:588–631. doi: 10.1124/pr.110.003004 PubMedCrossRefGoogle Scholar
  49. Pertwee RG (2008) The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br J Pharmacol 153:199–215. doi: 10.1038/sj.bjp.0707442 PubMedCrossRefGoogle Scholar
  50. Pertwee RG (2007) GPR55: a new member of the cannabinoid receptor clan? Br J Pharmacol 152:984–986. doi: 10.1038/sj.bjp.0707464 PubMedCrossRefGoogle Scholar
  51. Pertwee RG (2004) The pharmacology and therapeutic potential of cannabidiol. In: Di Marzo V (ed) Cannabinoids. Kluwer Academic/Plenum, New York, p 32Google Scholar
  52. Pertwee RG (1997) Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacol Ther 74:129–180PubMedCrossRefGoogle Scholar
  53. Plotkin SR, Banks WA, Maness LM, Kastin AJ (2000) Differential transport of rat and human interleukin-1alpha across the blood–brain barrier and blood-testis barrier in rats. Brain Res 881:57–61PubMedCrossRefGoogle Scholar
  54. Riedel G, Fadda P, McKillop-Smith S, Pertwee RG, Platt B, Robinson L (2009) Synthetic and plant-derived cannabinoid receptor antagonists show hypophagic properties in fasted and non-fasted mice. Br J Pharmacol 156:1154–1166PubMedCrossRefGoogle Scholar
  55. Rog DJ (2010) Cannabis-based medicines in multiple sclerosis—a review of clinical studies. Immunobiology 215:658–672. doi: 10.1016/j.imbio.2010.03.009 PubMedCrossRefGoogle Scholar
  56. Russo EB, Burnett A, Hall B, Parker KK (2005) Agonistic properties of cannabidiol at 5-HT1a receptors. Neurochem Res 30:1037–1043. doi: 10.1007/s11064-005-6978-1 PubMedCrossRefGoogle Scholar
  57. 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. doi: 10.1038/sj.bjp.0707460 PubMedCrossRefGoogle Scholar
  58. Samara E, Bialer M, Mechoulam R (1988) Pharmacokinetics of cannabidiol in dogs. Drug Metab Dispos 16:469–472PubMedGoogle Scholar
  59. Scutt A, Williamson EM (2007) Cannabinoids stimulate fibroblastic colony formation by bone marrow cells indirectly via CB2 receptors. Calcif Tissue Int 80:50–59. doi: 10.1007/s00223-006-0171-7 PubMedCrossRefGoogle Scholar
  60. Sethi BB, Trivedi JK, Kumar P, Gulati A, Agarwal AK, Sethi N (1986) Antianxiety effect of cannabis: involvement of central benzodiazepine receptors. Biol Psychiatry 21:3–10PubMedCrossRefGoogle Scholar
  61. Siemens AJ, Walczak D, Buckley FE (1980) Characterization of blood disappearance and tissue distribution of [3H]cannabidiol. Biochem Pharmacol 29:462–464PubMedCrossRefGoogle Scholar
  62. Smith DA, Di L, Kerns EH (2010) The effect of plasma protein binding on in vivo efficacy: misconceptions in drug discovery. Nat Rev Drug Discov 9:929–939. doi: 10.1038/nrd3287 PubMedCrossRefGoogle Scholar
  63. Soderpalm AH, Schuster A, de Wit H (2001) Antiemetic efficacy of smoked marijuana: subjective and behavioral effects on nausea induced by syrup of ipecac. Pharmacol Biochem Behav 69:343–350PubMedCrossRefGoogle Scholar
  64. Syvanen S, Lindhe O, Palner M, Kornum BR, Rahman O, Langstrom B, Knudsen GM, Hammarlund-Udenaes M (2009) Species differences in blood–brain barrier transport of three positron emission tomography radioligands with emphasis on P-glycoprotein transport. Drug Metab Dispos 37:635–643. doi: 10.1124/dmd.108.024745 PubMedCrossRefGoogle Scholar
  65. Takeuchi H, Yatsugi S, Yamaguchi T (2002) Effect of YM992, a novel antidepressant with selective serotonin re-uptake inhibitory and 5-HT 2A receptor antagonistic activity, on a marble-burying behavior test as an obsessive-compulsive disorder model. Jpn J Pharmacol 90:197–200PubMedCrossRefGoogle Scholar
  66. Thomas A, Burant A, Bui N, Graham D, Yuva-Paylor LA, Paylor R (2009) Marble burying reflects a repetitive and perseverative behavior more than novelty-induced anxiety. Psychopharmacology (Berl) 204:361–373. doi: 10.1007/s00213-009-1466-y CrossRefGoogle Scholar
  67. 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 150:613–623. doi: 10.1038/sj.bjp.0707133 PubMedCrossRefGoogle Scholar
  68. Thomas A, Stevenson LA, Wease KN, Price MR, Baillie G, Ross RA, Pertwee RG (2005) Evidence that the plant cannabinoid delta9-tetrahydrocannabivarin is a cannabinoid CB1 and CB2 receptor antagonist. Br J Pharmacol 146:917–926. doi: 10.1038/sj.bjp.0706414 PubMedCrossRefGoogle Scholar
  69. Tubaro A, Giangaspero A, Sosa S, Negri R, Grassi G, Casano S, Della Loggia R, Appendino G (2010) Comparative topical anti-inflammatory activity of cannabinoids and cannabivarins. Fitoterapia 81:816–819. doi: 10.1016/j.fitote.2010.04.009 PubMedCrossRefGoogle Scholar
  70. Turcotte D, Le Dorze JA, Esfahani F, Frost E, Gomori A, Namaka M (2010) Examining the roles of cannabinoids in pain and other therapeutic indications: a review. Expert Opin Pharmacother 11:17–31. doi: 10.1517/14656560903413534 PubMedCrossRefGoogle Scholar
  71. Valiveti S, Hammell DC, Earles DC, Stinchcomb AL (2004) Transdermal delivery of the synthetic cannabinoid WIN 55,212-2: in vitro/in vivo correlation. Pharm Res 21:1137–1145PubMedCrossRefGoogle Scholar
  72. Voth EA, Schwartz RH (1997) Medicinal applications of delta-9-tetrahydrocannabinol and marijuana. Ann Intern Med 126:791–798PubMedGoogle Scholar
  73. Whyte LS, Ryberg E, Sims NA, Ridge SA, Mackie K, Greasley PJ, Ross RA, Rogers MJ (2009) The putative cannabinoid receptor GPR55 affects osteoclast function in vitro and bone mass in vivo. Proc Natl Acad Sci USA 106:16511–16516. doi: 10.1073/pnas.0902743106 PubMedCrossRefGoogle Scholar
  74. Woodburn K, Sykes E, Kessel D (1995) Interactions of Solutol HS 15 and cremophor EL with plasma lipoproteins. Int J Biochem Cell Biol 27:693–699PubMedCrossRefGoogle Scholar
  75. Zuardi AW (2008) Cannabidiol: from an inactive cannabinoid to a drug with wide spectrum of action. Rev Bras Psiquiatr 30:271–280PubMedCrossRefGoogle Scholar
  76. Zuardi AW, Crippa JA, Hallak JE, Moreira FA, Guimaraes FS (2006) Cannabidiol, a Cannabis sativa constituent, as an antipsychotic drug. Braz J Med Biol Res 39:421–429PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Serena Deiana
    • 1
  • Akihito Watanabe
    • 1
    • 2
  • Yuki Yamasaki
    • 1
    • 2
  • Naoki Amada
    • 1
    • 2
  • Marlene Arthur
    • 1
  • Shona Fleming
    • 1
  • Hilary Woodcock
    • 1
  • Patricia Dorward
    • 1
  • Barbara Pigliacampo
    • 1
  • Steve Close
    • 1
  • Bettina Platt
    • 1
  • Gernot Riedel
    • 1
    Email author
  1. 1.School of Medical Sciences, Institute of Medical SciencesUniversity of AberdeenAberdeenUK
  2. 2.Qs’ Research InstituteOtsuka Pharmaceutical Co. LtdTokushimaJapan

Personalised recommendations

Cite article

Buy options