Effect of prior foot shock stress and Δ9-tetrahydrocannabinol, cannabidiolic acid, and cannabidiol on anxiety-like responding in the light-dark emergence test in rats

Abstract

Rationale

Cannabis is commonly used by humans to relieve stress.

Objectives and methods

Here, we evaluate the potential of intraperitoneally (i.p.) administered Δ9-tetrahydrocannabiol (THC) and cannabidiolic acid (CBDA, the precursor of cannabidiol [CBD]) to produce dose-dependent effects on anxiety-like responding in the light-dark (LD) emergence test of anxiety-like responding in rats, when administered acutely or chronically (21 days). As well, we evaluate the potential of THC, CBDA, and CBD to reduce anxiogenic responding produced by foot shock (FS) stress 24 h prior to the LD test.

Results

In the absence of the explicit FS stressor, THC (1 and 10 mg/kg) produced anxiogenic-like responding when administered acutely or chronically, but CBDA produced neither anxiogenic- nor anxiolytic-like responding. Administration of FS stress 24 h prior to the LD test enhanced anxiogenic-like responding (reduced time spent and increased latency to enter the light compartment) in rats pretreated with either vehicle (VEH) or THC (1 mg/kg); however, administration of CBDA (0.1–100 μg/kg) or CBD (5 mg/kg) prevented the FS-induced anxiogenic-like responding (an anxiolytic-like effect). The 5-hydroxytryptamine 1A (5-HT1A) receptor antagonist, WAY100635, reversed CBDA’s anxiolytic effect (1 μg/kg). Combining an anxiolytic dose of CBDA (1 μg/kg) or CBD (5 mg/kg) with an anxiogenic dose of THC (1 mg/kg) did not modify THC’s anxiogenic effect.

Conclusion

These results suggest the anxiolytic effects of CBDA and CBD may require the presence of a specific stressor.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. Bergamaschi MM, Queiroz RH, Chagas MH, de Oliveira DC, De Martinis BS, Kapczinski F et al (2011) Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naïve social phobia patients. Neuropsychopharmacology 36:1219–1226. doi:10.1038/npp.2011.6

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. Berrendero F, Maldonado R (2002) Involvement of the opioid system in the anxiolytic-like effects induced by Δ9-tetrahydrocannabinol. Psychopharmacology 163:111–117. doi:10.1007/s00213-002-1144-9

    CAS  Article  PubMed  Google Scholar 

  3. 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. doi:10.1016/j.euroneuro.2008.07.001

    CAS  Article  PubMed  Google Scholar 

  4. Bluett RJ, Gamble-George JC, Hermanson DJ, Hartley ND, Marnett LJ, Patel S (2014) Central anandamide deficiency predicts stress-induced anxiety: behavioral reversal through endocannabinoid augmentation. Transl Psychiatry 4:e408. doi:10.1038/tp.2014.53

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. Bolognini D, Rock EM, Cluny NL, Cascio MG, Limebeer CL, Duncan M et al (2013) Cannabidiolic acid prevents vomiting in Suncus murinus and nausea-induced behaviour in rats by enhancing 5-HT1A receptor activation. Br J Pharmacol 168:1456–1470. doi:10.1111/bph.12043

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. Bourin M, Hascoët M (2003) The mouse light/dark box test. Eur J Pharmacol 463:55–65. doi:10.1016/S0014-2999(03)01274-3

    CAS  Article  PubMed  Google Scholar 

  7. Brierley DI, Samuels J, Duncan M, Whalley BJ, Williams CM (2016) Neuromotor tolerability and behavioural characterisation of cannabidiolic acid, a phytocannabinoid with therapeutic potential for anticipatory nausea. Psychopharmacology 233:243–254. doi:10.1007/s00213-015-4100-1

    CAS  Article  PubMed  Google Scholar 

  8. Campos AC, Ferreira FR, Guimarães FS (2012) Cannabidiol blocks long-lasting behavioral consequences of predator threat stress: possible involvement of 5HT1A receptors. J Psychiatr Res 46:1501–1510. doi:10.1016/j.jpsychires.2012.08.012

    Article  PubMed  Google Scholar 

  9. Espejo-Porras F, Fernández-Ruiz J, Pertwee RG, Mechoulam R, García C (2013) Motor effects of the non-psychotropic phytocannabinoid cannabidiol that are mediated by 5-HT1A receptors. Neuropharmacology 75:155–163. doi:10.1016/j.neuropharm.2013.07.024

    CAS  Article  PubMed  Google Scholar 

  10. Fogaça MV, Reis FM, Campos AC, Guimarães FS (2014) Effects of intra-prelimbic prefrontal cortex injection of cannabidiol on anxiety-like behavior: involvement of 5HT1A receptors and previous stressful experience. Eur Neuropsychopharmacol 24:410–419. doi:10.1016/j.euroneuro.2013.10.012

    Article  PubMed  Google Scholar 

  11. Fokos S, Panagis G (2010) Effects of delta9-tetrahydrocannabinol on reward and anxiety in rats exposed to chronic unpredictable stress. J Psychopharmacol 24:767–777. doi:10.1177/0269881109104904

    CAS  Article  PubMed  Google Scholar 

  12. Gomes FV, Reis DG, Alves FH, Corrêa FM, Guimarães FS, Resstel LB (2012) Cannabidiol injected into the bed nucleus of the stria terminalis reduces the expression of contextual fear conditioning via 5-HT1A receptors. J Psychopharmacol 26:104–113. doi:10.1177/0269881110389095

    CAS  Article  PubMed  Google Scholar 

  13. Guimarães FS, Chiaretti TM, Graeff FG, Zuardi AW (1990) Antianxiety effect of cannabidiol in the elevated plus-maze. Psychopharmacology 100:558–559

    Article  PubMed  Google Scholar 

  14. Guimarães FS, de Aguiar JC, Mechoulam R, Breuer A (1994) Anxiolytic effect of cannabidiol derivatives in the elevated plus-maze. Gen Pharmacol 25:161–164

    Article  PubMed  Google Scholar 

  15. Hill MN, Gorzalka BB (2004) Enhancement of anxiety-like responsiveness to the cannabinoid CB 1 receptor agonist HU-210 following chronic stress. Eur J Pharmacol 499:291–295. doi:10.1016/j.ejphar.2004.06.069

    CAS  Article  PubMed  Google Scholar 

  16. Hindocha C, Freeman TP, Schafer G, Gardener C, Das RK, Morgan CJ et al (2015) Acute effects of delta-9-tetrahydrocannabinol, cannabidiol and their combination on facial emotion recognition: a randomised, double-blind, placebo-controlled study in cannabis users. Eur Neuropsychopharmacol 25:325–334. doi:10.1016/j.euroneuro.2014.11.014

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. Holmes A (2001) Targeted gene mutation approaches to the study of anxiety-like behavior in mice. Neurosci Biobehav Rev 25:261–273

    CAS  Article  PubMed  Google Scholar 

  18. Järbe TU, Andrzejewski ME, DiPatrizio NV (2002) Interactions between the CB1 receptor agonist Delta 9-THC and the CB1 receptor antagonist SR-141716 in rats: open-field revisited. Pharmacol Biochem Behav 73:911–919

    Article  PubMed  Google Scholar 

  19. Karniol IG, Shirakawa I, Kasinski N, Pfeferman A, Carlini EA (1974) Cannabidiol interferes with the effects of delta 9-tetrahydrocannabinol in man. Eur J Pharmacol 28:172–177

    CAS  Article  PubMed  Google Scholar 

  20. Klein C, Karanges E, Spiro A, Wong A, Spencer J, Huynh T et al (2011) Cannabidiol potentiates Δ9-tetrahydrocannabinol (THC) behavioural effects and alters THC pharmacokinetics during acute and chronic treatment in adolescent rats. Psychopharmacology 218:443–457. doi:10.1007/s00213-011-2342-0

    CAS  Article  PubMed  Google Scholar 

  21. Le Foll B, Wiggins M, Goldberg SR (2006) Nicotine pre-exposure does not potentiate the locomotor or rewarding effects of Delta-9-tetrahydrocannabinol in rats. Behav Pharmacol 17:195–199. doi:10.1097/01.fbp.0000197460.16516.81

    CAS  Article  PubMed  Google Scholar 

  22. 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 13:861–876. doi:10.1017/S1461145709990605

    CAS  Article  PubMed  Google Scholar 

  23. Martin-Santos R, Crippa JA, Batalla A, Bhattacharyya S, Atakan Z, Borgwardt S et al (2012) Acute effects of a single, oral dose of d9-tetrahydrocannabinol (THC) and cannabidiol (CBD) administration in healthy volunteers. Curr Pharm Des 18:4966–4979. doi:10.2174/138161212802884780

    CAS  Article  PubMed  Google Scholar 

  24. Mechoulam R, Gaoni Y (1965) Hashish—IV: the isolation and structure of cannabinolic cannabidiolic and cannabigerolic acids. Tetrahedron 21:1223–1229

    CAS  Article  PubMed  Google Scholar 

  25. Moreira FA, Aguiar DC, Guimaraes FS (2006) Anxiolytic-like effect of cannabidiol in the rat Vogel conflict test. Prog Neuro-Psychopharmacol Biol Psychiatry 30:1466–1471. doi:10.1016/j.pnpbp.2006.06.004

    CAS  Article  Google Scholar 

  26. O'Brien LD, Wills KL, Segsworth B, Dashney B, Rock EM, Limebeer CL et al (2013) Effect of chronic exposure to rimonabant and phytocannabinoids on anxiety-like behavior and saccharin palatability. Pharmacol Biochem Behav 103:597–602. doi:10.1016/j.pbb.2012.10.008

    Article  PubMed  Google Scholar 

  27. Onaivi ES, Green MR, Martin BR (1990) Pharmacological characterization of cannabinoids in the elevated plus maze. J Pharmacol Exp Ther 253:1002–1009

    CAS  PubMed  Google Scholar 

  28. Patel S, Hillard CJ (2006) Pharmacological evaluation of cannabinoid receptor ligands in a mouse model of anxiety: further evidence for an anxiolytic role for endogenous cannabinoid signaling. J Pharmacol Exp Ther 318:304–311. doi:10.1124/jpet.106.101287

    CAS  Article  PubMed  Google Scholar 

  29. Patel S, Hill MN, Hillard CJ (2014) Effects of phytocannabinoids on anxiety, mood, and the endocrine system. In: Pertwee RG (ed) Handbook of cannabis. Oxford University Press, Oxford, pp 189–207

    Google Scholar 

  30. Polissidis A, Chouliara O, Galanopoulos A, Rentesi G, Dosi M, Hyphantis T et al (2010) Individual differences in the effects of cannabinoids on motor activity, dopaminergic activity and DARPP-32 phosphorylation in distinct regions of the brain. Int J Neuropsychopharmacol 13:1175–1191. doi:10.1017/S1461145709991003

    CAS  Article  PubMed  Google Scholar 

  31. Reilly D, Didcott P, Swift W, Hall W (1998) Long-term cannabis use: characteristics of users in an Australian rural area. Addiction 93:837–846. doi:10.1046/j.1360-0443.1998.9368375.x

    CAS  Article  PubMed  Google Scholar 

  32. Resstel LB, Tavares RF, Lisboa SF, Joca SR, Corrêa FM, Guimarães 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. doi:10.1111/j.1476-5381.2008.00046.x

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. Rock EM, Parker LA (2013) Effect of low doses of cannabidiolic acid and ondansetron on LiCl-induced conditioned gaping (a model of nausea-induced behaviour) in rats. Br J Pharmacol 169:685–692. doi:10.1111/bph.12162

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. Rock EM, Limebeer CL, Parker LA (2015) Effect of combined doses of Δ(9)-tetrahydrocannabinol (THC) and cannabidiolic acid (CBDA) on acute and anticipatory nausea using rat (Sprague-Dawley) models of conditioned gaping. Psychopharmacology 232:4445–4454. doi:10.1007/s00213-015-4080-1

    CAS  Article  PubMed  Google Scholar 

  35. Rodgers RJ, Haller J, Holmes A, Halasz J, Walton TJ, Brain PF (1999) Corticosterone response to the plus-maze: high correlation with risk assessment in rats and mice. Physiol Behav 68:47–53

    CAS  Article  PubMed  Google Scholar 

  36. Rubino T, Sala M, Viganò D, Braida D, Castiglioni C, Limonta V et al (2007) Cellular mechanisms underlying the anxiolytic effect of low doses of peripheral Delta9-tetrahydrocannabinol in rats. Neuropsychopharmacology 32:2036–2045. doi:10.1038/sj.npp.1301330

    CAS  Article  PubMed  Google Scholar 

  37. Russo EB, Burnett A, Hall B, Parker KK (2005) Agonistic Properties of Cannabidiol at 5-HT1a Receptors. Neurochem Res 30(8):1037–1043

  38. Schofield D, Tennant C, Nash L, Degenhardt L, Cornish A, Hobbs C et al (2006) Reasons for cannabis use in psychosis. Aust N Z J Psychiatry 40:570–574. doi:10.1111/j.1440-1614.2006.01840.x

    Article  PubMed  Google Scholar 

  39. Schramm-Sapyta NL, Cha YM, Chaudhry S, Wilson WA, Swartzwelder HS, Kuhn CM (2007) Differential anxiogenic, aversive, and locomotor effects of THC in adolescent and adult rats. Psychopharmacology 191:867–877. doi:10.1007/s00213-006-0676-9

    CAS  Article  PubMed  Google Scholar 

  40. Song C, Stevenson CW, Guimaraes FS, Lee JL (2016) Bidirectional effects of cannabidiol on contextual fear memory extinction. Front Pharmacol 7:493. doi:10.3389/fphar.2016.00493

    PubMed  PubMed Central  Google Scholar 

  41. Thomas H (1993) Psychiatric symptoms in cannabis users. Br J Psychiatry 163:141–149

    CAS  Article  PubMed  Google Scholar 

  42. Todd SM, Arnold JC (2016) Neural correlates of interactions between cannabidiol and Δ(9)-tetrahydrocannabinol in mice: implications for medical cannabis. Br J Pharmacol 173:53–65. doi:10.1111/bph.13333

    CAS  Article  PubMed  Google Scholar 

  43. Todd SM, Zhou C, Clarke DJ, Chohan TW, BAhceci D, Arnold JC (2017) Interactions between cannabidiol and ∆-9 THC following acute and repeated dosing: rebound hyperactivity, sensorimotor gaiting and epigenetic and neuroadaptive changes in the mesolimbic pathway. Eur Neuropsychopharmacol 27:132–145. doi:10.1016/j.euroneuro.2016.12.004

    CAS  Article  PubMed  Google Scholar 

  44. Valjent E, Mitchell JM, Besson MJ, Caboche J, Maldonado R (2002) Behavioural and biochemical evidence for interactions between delta 9-tetrahydrocannabinol and nicotine. Br J Pharmacol 135:564–578. doi:10.1038/sj.bjp.0704479

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  45. Wiley JL, Martin BR (2003) Cannabinoid pharmacological properties common to other centrally acting drugs. Eur J Pharmacol 471:185–193. doi:10.1016/S0014-2999(03)01856-9

    CAS  Article  PubMed  Google Scholar 

  46. Zuardi AW, Shirakawa I, Finkelfarb E, Karniol IG (1982) Action of cannabidiol on the anxiety and other effects produced by delta 9-THC in normal subjects. Psychopharmacology 76:245–250

    CAS  Article  PubMed  Google Scholar 

  47. Zuardi AW, Cosme RA, Graeff FG, Guimarães FS (1993) Effects of ipsapirone and cannabidiol on human experimental anxiety. J Psychopharamcol 7:82–88. doi:10.1177/026988119300700112

    CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by a Natural Sciences and Engineering Research Council of Canada (NSERC) Collaborative Research and Development Grant (CRDPJ 476416-14) to LAP in partnership with Prairie Plant Systems Inc., as well as a grant to LAP from the NSERC (92056) and from Canadian Institute of Health Research (137122).

Author information

Affiliations

Authors

Corresponding author

Correspondence to Linda A. Parker.

Ethics declarations

All animal procedures complied with the Canadian Council on Animal Care and were approved by the Institutional Animal Care Committee (accredited by the Canadian Council on Animal Care).

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Rock, E.M., Limebeer, C.L., Petrie, G.N. et al. Effect of prior foot shock stress and Δ9-tetrahydrocannabinol, cannabidiolic acid, and cannabidiol on anxiety-like responding in the light-dark emergence test in rats. Psychopharmacology 234, 2207–2217 (2017). https://doi.org/10.1007/s00213-017-4626-5

Download citation

Keywords

  • Anxiety
  • Anxiolytic
  • Δ9-tetrahydrocannabiol
  • Cannabidiolic acid
  • Cannabidiol
  • Foot shock
  • Stress
  • Light-dark emergence test
  • Rat