Psychopharmacology

, 199:223 | Cite as

Involvement of 5HT1A receptors in the anxiolytic-like effects of cannabidiol injected into the dorsolateral periaqueductal gray of rats

  • Alline Cristina Campos
  • Francisco Silveira Guimarães
Original Investigation

Abstract

Rationale

Cannabidiol (CBD) is a non-psychotomimetic constituent of Cannabis sativa plant that induces anxiolytic effects. However, the brain sites and mechanisms of these effects remain poorly understood. The dorsolateral periaqueductal gray (dlPAG) is a midbrain structure related to anxiety that contains receptors proposed to interact with CBD such as 5HT1A. In addition, since CBD has been shown to inhibit anandamide metabolism, CB1 receptors could also be involved in the effects of this cannabinoid.

Objectives

To investigate if the dlPAG could be a possible site of the anxiolytic effects induced by CBD and if these effects depend on CB1 or 5HT1A receptors.

Materials and methods

Male Wistar rats with cannulae aimed at the dlPAG were tested in the elevated plus maze (EPM) and the Vogel conflict test (VCT).

Results

CBD injected into the dlPAG produced anxiolytic-like effects in the EPM with a bell-shaped dose–response curve. The anxiolytic effect of CBD was confirmed in the VCT. These effects were prevented by WAY100635, a 5HT1A receptor antagonist, but not by AM251, an antagonist of CB1 receptors.

Conclusion

These results suggest the CBD interacts with 5HT1A receptors to produce anxiolytic effects in the dlPAG.

Keywords

Cannabinoids Anxiety Serotonin Animal model 

Notes

Acknowledgments

We thank Dr. Eleni T. Gomes and José Carlos de Aguiar for technical support. This research was supported by grants from FAPESP and CNPq. ACC was a recipient of a FAPESP fellowship.

References

  1. Bandler R, Keay KA, Floyd N, Price J (2000) Central circuits mediating patterned autonomic activity during active vs. passive emotional coping. Brain Res Bull 53:95–104PubMedCrossRefGoogle Scholar
  2. Beijamini V, Guimarães FS (2006) c-Fos expression increase in NADPH-diaphorase positive neurons after exposure to a live cat. Behav Brain Res 170:52–61PubMedCrossRefGoogle Scholar
  3. 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 134:845–52PubMedCrossRefGoogle Scholar
  4. Carlini EA, Leite JR, Tannhauser M, Berardi AC (1973) Cannabidiol and Cannabis sativa extract protect mice and rats against convulsive agents. J Pharm Pharmacol 25:664–665PubMedGoogle Scholar
  5. Carobrez AP, Bertoglio LJ (2005) Ethological and temporal analyses of anxiety-like behavior: The elevated plus-maze model 20 years on. Neurosci Biobehav Rev 29:1193–205PubMedCrossRefGoogle Scholar
  6. Carrasco GA, Van de Kar LD (2003) Neuroendocrine pharmacology of stress. Eur J Pharmacol 463:235–72PubMedCrossRefGoogle Scholar
  7. 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 103:7895–900PubMedCrossRefGoogle Scholar
  8. Corradetti R, Mlinar B, Falsini C, Pugliese AM, Cilia A, Destefani C, Testa R (2005) Differential effects of the 5-hydroxytryptamine (5-HT)1A receptor inverse agonists Rec 27/0224 and Rec 27/0074 on electrophysiological responses to 5-HT1A receptor activation in rat dorsal raphe nucleus and hippocampus in vitro. J Pharmacol Exp Ther 315:109–117PubMedCrossRefGoogle Scholar
  9. Cristino L, de Petrocellis L, Pryce G, Baker D, Guglielmotti V, Di Marzo V (2006) Immunohistochemical localization of cannabinoid type 1 and vanilloid transient receptor potential vanilloid type 1 receptors in the mouse brain. Neuroscience 139:1405–1415PubMedCrossRefGoogle Scholar
  10. D’Amour FE, Smith DL (1941) A method for determining loss of pain sensation. J Pharmacol Exp Ther 72:74–79Google Scholar
  11. De Paula Soares V, Zangrossi H Jr (2004) Involvement of 5-HT1A and 5-HT2 receptors of the dorsal periaqueductal gray in the regulation of the defensive behaviors generated by the elevated T-maze. Brain Res Bull 64:181–188PubMedCrossRefGoogle Scholar
  12. Devane WA, Dysarz FA 3rd, Johnson MR, Melvin LS, Howlett AC (1988) Determination and characterization of a cannabinoid receptor in rat brain. Mol Pharmacol 34:605–613PubMedGoogle Scholar
  13. File SE (1992) Behavioural detection of anxiolytic action. In: Elliott JM, Heal DJ, Marsden CA (eds) Experimental approaches to anxiety and depression. Wiley, New York, pp 25–44Google Scholar
  14. Geller I, Kulak JT Jr, Seifter J (1962) The effects of chlordiazepoxide and chlorpromazine on a punishment discrimination. Psychopharmacologia 3:374–385PubMedCrossRefGoogle Scholar
  15. Guimarães FS, Chiaretti TM, Graeff FG, Zuardi AW (1990) Antianxiety effect of cannabidiol in the elevated plus-maze. Psychopharmacology (Berl) 100:558–559CrossRefGoogle Scholar
  16. Hamon M, Lanfumey L, el Mestikawy S, Boni C, Miquel MC, Bolaños F, Schechter L, Gozlan H (1990) The main features of central 5-HT1 receptors. Neuropsychopharmacology 3:349–360PubMedGoogle Scholar
  17. Herkenham M, Lynn AB, Johnson MR, Melvin LS, de Costa BR, Rice KC (1991) Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study. J Neurosci 11:563–583PubMedGoogle Scholar
  18. Hohmann AG, Suplita RL, Bolton NM, Neely MH, Fegley D, Mangieri R, Krey JF, Walker JM, Holmes PV, Crystal JD, Duranti A, Tontini A, Mor M, Tarzia G, Piomelli D (2005) An endocannabinoid mechanism for stress-induced analgesia. Nature 435:1108–1112PubMedCrossRefGoogle Scholar
  19. 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 97:9561–9566PubMedCrossRefGoogle Scholar
  20. Mechoulam R, Gaoni Y (1965) Hashish. IV. The isolation and structure of cannabinolic cannabidiolic and cannabigerolic acids. Tetrahedron 21:1223–1229PubMedCrossRefGoogle Scholar
  21. Millan MJ (2003) The neurobiology and control of anxious states. Prog Neurobiol 70:83–244PubMedCrossRefGoogle Scholar
  22. Mishima K, Hayakawa K, Abe K, Ikeda T, Egashira N, Iwasaki K, Fujiwara M (2005) Cannabidiol prevents cerebral infarction via a serotonergic 5-hydroxytryptamine1A receptor-dependent mechanism. Stroke 36:1077–1082PubMedCrossRefGoogle Scholar
  23. Molchanov ML, Guimarães FS (2002) Anxiolytic-like effects of AP7 injected into the dorsolateral or ventrolateral columns of the periaqueductal gray of rats. Psychopharmacology (Berl) 160:30–38CrossRefGoogle Scholar
  24. Moreira FA, Guimarães FS (2005) Cannabidiol inhibits the hyperlocomotion induced by psychotomimetic drugs in mice. Eur J Pharmacol 512:199–205PubMedCrossRefGoogle Scholar
  25. Moreira FA, Aguiar DC, Guimarães FS (2006) Anxiolytic-like effect of cannabidiol in the rat Vogel conflict test. Prog Neuropsychopharmacol Biol Psychiatry 30:1466–1471PubMedCrossRefGoogle Scholar
  26. Moreira FA, Aguiar DC, Guimarães FS (2007) Anxiolytic-like effect of cannabinoids injected into the rat dorsolateral periaqueductal gray. Neuropharmacology 52:958–965PubMedCrossRefGoogle Scholar
  27. Nogueira RL, Graeff FG (1995) Role of 5-HT receptor subtypes in the modulation of dorsal periaqueductal gray generated aversion. Pharmacol Biochem Behav 52:1–6PubMedCrossRefGoogle Scholar
  28. Palazzo E, de Novellis V, Marabese I, Cuomo D, Rossi F, Berrino L, Rossi F, Maione S (2002) Interaction between vanilloid and glutamate receptors in the central modulation of nociception. Eur J Pharmacol 439:69–75PubMedCrossRefGoogle Scholar
  29. Paxinos G, Watson C (1997) The rat brain in stereotaxic coordinates. Academic, New YorkGoogle Scholar
  30. Pedigo NW, Dewey WL, Harris LS (1975) Determination and characterization of the antinociceptive activity of intraventricularly administered acetylcholine in mice. J Pharmacol Exp Ther 193:849–852Google Scholar
  31. Pérez-Padilla A, Pellón R (2007) Behavioural and pharmacological specificity of the effects of drugs on punished schedule-induced polydipsia. Behav Pharmacol 18:681–689PubMedCrossRefGoogle Scholar
  32. Pertwee RG (2005) Inverse agonism and neutral antagonism at cannabinoid CB1 receptors. Life Sci 76:307–324CrossRefGoogle Scholar
  33. Raymond JR, Mukhin YV, Gettys TW, Garnovskaya MN (1999) The recombinant 5-HT1A receptor: G protein coupling and signalling pathways. Br J Pharmacol 127:1751–1764PubMedCrossRefGoogle Scholar
  34. Resstel LB, Joca SR, Moreira FA, Corrêa FM, Guimarães FS (2006) Effects of cannabidiol and diazepam on behavioral and cardiovascular responses induced by contextual conditioned fear in rats. Behav Brain Res 72:294–298CrossRefGoogle Scholar
  35. Rubino T, Realini N, Castiglioni C, Guidali C, Viganó D, Marras E, Petrosino S, Perletti G, Maccarrone M, Di Marzo V, Parolaro D (2007) Role in anxiety behavior of the endocannabinoid system in the prefrontal cortex. Cereb Cortex (in press)Google Scholar
  36. Russo E, Guy GW (2006) A tale of two cannabinoids: the therapeutic rationale for combining tetrahydrocannabinol and canabidiol. Med Hypotheses 66:234–246PubMedCrossRefGoogle Scholar
  37. Russo EB, Burnett A, Hall B, Parker KK (2005) Agonistic properties of cannabidiol at 5-HT1a receptors. Neurochem Res 30:1037–1043PubMedCrossRefGoogle Scholar
  38. Ryberg E, Larsson N, Sjögren 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 152:1092–1101PubMedCrossRefGoogle Scholar
  39. 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 150:613–623PubMedCrossRefGoogle Scholar
  40. Vogel JR, Beer B, Clody DE (1971) A simple and reliable conflict procedure for testing anti-anxiety agents. Psychopharmalogia, 21:1–7CrossRefGoogle Scholar
  41. Zanoveli JM, Nogueira RL, Zangrossi H Jr (2003) Serotonin in the dorsal periaqueductal gray modulates inhibitory avoidance and one-way escape behaviors in the elevated T-maze. Eur J Pharmacol 473:153–161PubMedCrossRefGoogle Scholar
  42. Zuardi AW, Finkelfarb E, Bueno OF, Musty RE, Karniol IG (1981) Characteristics of the stimulus produced by the mixture of cannabidiol with delta 9-tetrahydrocannabinol. Arch Int Pharmacodyn Ther 249:137–146PubMedGoogle Scholar
  43. Zuardi AW, Morais SL, Guimarães FS, Mechoulam R (1995) Antipsychotic effect of cannabidiol. J Clin Psychiatry 56:485–486PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Alline Cristina Campos
    • 1
  • Francisco Silveira Guimarães
    • 1
  1. 1.Department of PharmacologySchool of Medicine of Ribeirão Preto, Campus USPMonte Alegre, Ribeirão PretoBrazil

Personalised recommendations