Skip to main content

Advertisement

SpringerLink
Log in

Cannabidiol effects in the prepulse inhibition disruption induced by amphetamine

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

The information processing appears to be deficient in schizophrenia. Prepulse inhibition (PPI), which measures the inhibition of a motor response by a weak sensory event, is considered particularly useful to understand the biology of information processing in schizophrenia patients. Drugs that facilitate dopaminergic neurotransmission such as amphetamine induce PPI disruption in human and rodents. Clinical and neurobiological findings suggest that the endocannabinoid system and cannabinoids may be implicated in the pathophysiology and treatment of schizophrenia. Cannabidiol (CBD), a non-psychotomimetic constituent of the Cannabis sativa plant, has also been reported to have potential as an antipsychotic.

Objective

Our aim was to investigate if CBD pretreatment was able to prevent PPI disruption induced by amphetamine. Since one possible mechanism of CBD action is the facilitation of endocannabinoid-mediated neurotransmission through anandamide, we tested the effects of an anandamide hydrolysis inhibitor (URB597) in the amphetamine-induced PPI disruption.

Methods

Male Swiss mice were treated with CBD systemic or intra-accumbens, or URB597 (systemic) prior to amphetamine and were exposed to PPI test.

Results

Amphetamine (10 mg/kg) disrupted PPI while CBD (15–60 mg/kg) or URB597 (0.1–1 mg/kg) administered alone had no effect. Pretreatment with CBD attenuated the amphetamine-disruptive effects on PPI test after systemic or intra-accumbens administration. Similar effects were also found with the inhibitor of anandamide hydrolysis.

Conclusion

These results corroborate findings indicating that CBD induces antipsychotic-like effects. In addition, they pointed to the nucleus accumbens as a possible site of these effects. The increase of anandamide availability may be enrolled in the CBD effects.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

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

Similar content being viewed by others

References

  • Beltramo M, de Fonseca FR, Navarro M, Calignano A, Gorriti MA, Grammatikopoulos G, Sadile AG, Giuffrida A, Piomelli D (2000) Reversal of dopamine (D2) receptor responses by an anandamida transport inhibitor. J Neurosci 9:3401–3407

    Google Scholar 

  • Bird DC, Bujas-Bobanovic M, Robertson HA, Dursun SM (2001) Lack of phencyclidine-induced effects in mice with reduced neuronal nitric oxide synthase. Psychopharmacology (Berl) 155:299–309

    Article  CAS  Google Scholar 

  • 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 receptors, on the cellular uptake and enzymatic hydrolysis of anandamide. Br J Pharmacol 134:845–852

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Braff DL, Geyer MA (1990) Sensorimotor gating and schizophrenia. Human and animal model studies. Arch Gen Psychiatry 47:181–188

  • Braff D, Stone C, Callaway E, Geyer M, Glick I, Bali L (1978) Prestimulus effects on human startle reflex in normals and schizophrenics. Psychophysiology 15(4):339–343

    Article  CAS  PubMed  Google Scholar 

  • Braff DL, Grillon C, Geyer MA (1992) Gating and habituation of the startle reflex in schizophrenic patients. Arch Gen Psychiatry 49:206–215

    Article  CAS  PubMed  Google Scholar 

  • Braff DL, Swerdlow NR, Geyer MA (1999) Symptom correlates of prepulse inhibition deficits in male schizophrenic patients. Am J Psychiatry 156(4):596–602

    CAS  PubMed  Google Scholar 

  • Campos AC, Guimarães FS (2008) Involvement of 5HT1A receptors in the anxiolytic-like effects of cannabidiol injected into the dorsolateral periaqueductal gray of rats. Psychopharmacology (Berl) 199:223–230

    Article  CAS  Google Scholar 

  • Campos AC, Moreira FA, Gomes FV, Del Bel EA, Guimarães FS (2012) Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders. Philos Trans R Soc Lond B Biol Sci 367:3364–3378

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Campos AC, Ortega Z, Palazuelos J, Fogaça MV, Aguiar DC, Díaz-Alonso J, Ortega-Gutiérrez S, Vázquez-Villa H, Moreira FA, Guzmán M, Galve-Roperh I, Guimarães FS (2013) The anxiolytic effect of cannabidiol on chronically stressed mice depends on hippocampal neurogenesis: involvement of the endocannabinoid system. 16:1407–1419

  • Carlson S, Willott JF (1998) Caudal pontine reticular formation of C57BL/6 J mice: responses to startle stimuli, inhibition by tones, and plasticity. J Neurophysiol 79:2603–2614

    CAS  PubMed  Google Scholar 

  • Csernansky JG, Murphy GM, Faustman WO (1993) Limbic/mesolimbic connections and the pathogenesis of schizophrenia. Biol Psychiatry 30:383–400

    Article  Google Scholar 

  • Englund A, Morrison PD, Nottage J, Hague D, Kane F, Bonaccorso S, Stone JM, Reichenberg A, Brenneisen R, Holt D, Feilding A, Walker L, Murray RM, Kapur S (2013) Cannabidiol inhibits THC-elicited paranoid symptoms and hippocampal-dependent memory impairment. J Psychopharmacol 27:19–27

    Article  CAS  PubMed  Google Scholar 

  • Flood DG, Zuvich E, Marino MJ, Gasior M (2010) The effects of d-amphetamine, methylphenidate, sydnocarb, and caffeine on prepulse inhibition of the startle reflex in DBA/2 mice. Psychopharmacology (Berl) 3:325–336

    Article  Google Scholar 

  • Franklin KBJ, Paxinos G (2008) The mouse brain in stereotaxic coordinates, 3th edn. New York, Academic Press

  • Geyer MA, Krebs-Thomson K, Braff DL, Swerdlow NR (2001) Pharmacological studies of prepulse inhibition models of sensorimotor gating deficits in schizophrenia: a decade in review. Psychopharmacology (Berl) 156:117–154

    Article  CAS  Google Scholar 

  • Giuffrida A et al (2004) Cerebrospinal anandamide levels are elevated in acute schizophrenia and are inversely correlated with psychotic symptoms. Neuropsychopharmacology 29:2108–2114

    Article  CAS  PubMed  Google Scholar 

  • Gomes FV, Casarotto PC, Resstel LB, Guimarães FS (2011) Facilitation of CB1 receptor-mediated neurotransmission decreases marble burying behavior in mice. Prog Neuropsychopharmacol Biol Psychiatry 35:434–438

  • Guimarães VM, Zuardi AW, Del Bel EA, Guimarães FS (2004) Cannabidiol increases Fos expression in the nucleus accumbens but not in the dorsal striatum. Life Sci 75:633–638

    Article  PubMed  Google Scholar 

  • Gururajan A, Taylor DA, Malone DT (2011) Effect of cannabidiol in a MK-801-rodent model of aspects of schizophrenia. Behav Brain Res 222:299–308

    Article  CAS  PubMed  Google Scholar 

  • Howes OD, Kapur S (2009) The dopamine hypothesis of schizophrenia: version III—the final common pathway. Schizophr Bull 35:549–562

    Article  PubMed Central  PubMed  Google Scholar 

  • Issy AC, Del Bel EA (2014) 7-Nitroindazole blocks the prepulse inhibition disruption and c-Fos increase induced by methylphenidate. Behav Brain Res 262:74–83

    Article  CAS  PubMed  Google Scholar 

  • Issy AC, Salum C, Del Bel EA (2009) Nitric oxide modulation of methylphenidate-induced disruption of prepulse inhibition in Swiss mice. Behav Brain Res 205:475–481

  • 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 30:515–527

    Article  CAS  PubMed  Google Scholar 

  • Kane JM (2001) Extrapyramidal side effects are unacceptable. Eur Neuropsychopharmacol Rev 4:397–403

    Article  Google Scholar 

  • Koch M (1999) The neurobiology of startle. Prog Neurobiol 59:107–128

    Article  CAS  PubMed  Google Scholar 

  • Lau YS, Petroske E, Meredith GE, Wang JQ (2003) Elevated neuronal NOS expression in chronic haloperidol-treated rats. Neuropharmacology 45:986–994

    Article  CAS  PubMed  Google Scholar 

  • Levin R, Calzavara MB, Santos CM, Medrano WA, Niigaki ST, Abílio VC (2011) Spontaneously Hypertensive Rats (SHR) present deficits in prepulse inhibition of startle specifically reverted by clozapine. Prog Neuropsychopharmacol Biol Psychiatric 35:1748–1752

    Article  CAS  Google Scholar 

  • Levin R, Peres FF, Almeida V, Calzavara MB, Zuardi AW, Hallak JE, Crippa JA, Abílio VC (2014) Effects of cannabinoid drugs on the deficit of prepulse inhibition of startle in an animal model of schizophrenia: the SHR strain. Front Pharmacol 5:10

    Article  PubMed Central  PubMed  Google Scholar 

  • Leweke FM, Piomelli D, Pahlisch F, Muhl D, Gerth CW, Hoyer C, Klosterkötter J, Hellmich M, Koethe D (2012) Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia.Transl. Psychiatry 2:e94

    CAS  Google Scholar 

  • Lipska BK, Weinberg DR (2005) To Model a Psychiatric Disorder in Animals: Schizophrenia As a Reality Test. Neuropharmacology 23:223–239

    Google Scholar 

  • Long LE, Malone DT, Taylor DA (2006) Cannabidiol reverses MK-801-induced disruption of prepulse inhibition in mice. Neuropsychopharmacology 31:795–803

    Article  CAS  PubMed  Google Scholar 

  • Luque-Rojas MJ, Galeano P, Suárez J, Araos P, Santín LJ, de Fonseca FR, Calvo EB (2013) Hyperactivity induced by the dopamine D2/D3 receptor agonist quinpirole is attenuated by inhibitors of endocannabinoid degradation in mice. Int J Neuropsychopharmacol 16:661–676

    Article  CAS  PubMed  Google Scholar 

  • Mansbach RS, Geyer MA, Braff DL (1988) Dopaminergic stimulation disrupts sensorimotor gating in the rat. Psychopharmacology (Berl) 94:507–514

    Article  CAS  Google Scholar 

  • Martín AB, Fernandez-Espejo E, Ferrer B, Gorriti MA, Bilbao A, Navarro M, Rodriguez de Fonseca F, Moratalla R (2008) Expression and function of CB1 receptor in the rat striatum: localization and effects on D1 and D2 dopamine receptor-mediated motor behaviours. Neuropsychopharmacology 33:1667–1679

    Article  PubMed  Google Scholar 

  • Mechoulam R, Shvo Y, Hashish I (1963) The structure of cannabidiol. Tetrahedron 19:2073–2078

    Article  CAS  Google Scholar 

  • Meltzer HY (1999) The role of serotonin in antipsychotic drug action. Neuropsychopharmacology 21:106–115

    Article  Google Scholar 

  • 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 36:1077–1082

    Article  PubMed  Google Scholar 

  • Moore H, West AR, Grace AA (1999) The regulation of forebrain dopamine transmission: relevance to the pathophysiology and psychopathology of schizophrenia. Biol Psychiatry 46:40–55

    Article  CAS  PubMed  Google Scholar 

  • Moreira FA, Guimarães FS (2005) Cannabidiol inhibits the hyperlocomotion induced by psychotomimetic drugs. Eur J Pharmacol 512:199–205

    Article  CAS  PubMed  Google Scholar 

  • Peng RY, Mansbach RS, Braff DL, Geyer MA (1990) A D2 dopamine receptor agonist disrupts sensorimotor gating in rats. Implications for dopaminergic abnormalities in schizophrenia. Neuropsychopharmacology 3:211–218

    CAS  PubMed  Google Scholar 

  • Pertwee RG (2008) The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, canabidiol and delta9 tetrahydrocannabivarin. Br J Pharmacol 153:199–215

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Petitet F, Jeantaud B, Reibaud M, Imperato A, Dubroeucq MC (1998) Complex pharmacology of natural cannabinoids: evidence for partial agonist activity of delta9-tetrahydrocannabinol and antagonist activity of cannabidiol on rat brain cannabinoid receptors. Life Sci 63:1–6

    Article  Google Scholar 

  • Piomelli D, Tarzia G, Duranti A, Tontini A, Mor M, Compton TR, Dasse O, Monaghan EP, Parrott JA, Putman D (2006) Pharmacological Profile of the Selective FAAH Inhibitor KDS-4103 (URB597). CNS Drug Rev 12:21–38

    Article  CAS  PubMed  Google Scholar 

  • Russo EB, Burnett A, Hall B, Parker KK (2005) Agonistic properties of cannabidiol at 5-HT1a receptors. Neurochem Res 30:1037–1043

    Article  CAS  PubMed  Google Scholar 

  • Schubart CD, Sommer IE, Fusar-Poli P, de Witte L, Kahn RS, Boks MP (2013) Cannabidiol as a potential treatment for psychosis. Eur Neuropsychopharmacol 24:51–64

    Article  PubMed  Google Scholar 

  • Seeman P (2002) Atypical antipsychotics: mechanism of action. Can J Psychiatry 47:27–38

    PubMed  Google Scholar 

  • Swerdlow NR, Braff DL, Geyer MA, Koob GF (1986) Central dopamine hyperactivity in rats mimics abnormal acoustic startle response in schizophrenics. Biol Psychiatry 21(1):23–33

    Article  CAS  PubMed  Google Scholar 

  • Swerdlow NR, Braff DL, Geyer MA (1990) GABAergic projection from nucleus accumbens to ventral pallidum mediates dopamine-induced sensorimotor gating deficits of acoustic startle in rats. Brain Res 5:146–150

    Article  Google Scholar 

  • Swerdlow NR, Caine SB, Geyer MA (1992) Regionally selective effects of intracerebral dopamine infusion on sensorimotor gating of the startle reflex in rats. Psychopharmacology 108:189–195

    Article  CAS  PubMed  Google Scholar 

  • Swerdlow NR, Braff DL, Taaid N, Geyer MA (1994) Assessing the validity of an animal model of deficient sensorimotor gating in schizophrenic patients. Arch Gen Psychiatry 51:139–154

    Article  CAS  PubMed  Google Scholar 

  • Swerdlow NR, Braff DL, Geyer MA (2000) Animal models of deficient sensorimotor gating: what we know, what we think we know, and what we hope to know soon. Behav Pharmacol 11:185–204

    Article  CAS  PubMed  Google Scholar 

  • Swerdlow NR, Geyer MA, Braff DL (2001) Neural circuit regulation of prepulse inhibition of startle in the rat: current knowledge and future challenges. Psychopharmacology (Berl) 156:194–215

    Article  CAS  Google Scholar 

  • Thomas BF, Gilliam AF, Burch DF, Roche MJ, Seltzman HH (1998) Comparative receptor binding analyses of cannabinoid agonists and antagonists. J Pharmacol Exp Ther 285:285–292

    CAS  PubMed  Google Scholar 

  • Wan FJ, Geyer M, Swerdlow NR (1994) Accumbens D2 modulation of sensorimotor gating in rats: assessing anatomical localization. Pharmacol Biochem Behav 49:155–163

    Article  CAS  PubMed  Google Scholar 

  • Weike AI, Bauer U, Hamm AO (2000) Effective neuroleptic medication removes prepulse inhibition deficits in schizophrenia patients. Biol Psychiatry 47:61–70

    Article  CAS  PubMed  Google Scholar 

  • Weiss SM, Feldon J (2001) Environmental animal models for sensorimotor gating deficiencies in schizophrenia. Psychopharmacology (Berl) 156:305–326

    Article  CAS  Google Scholar 

  • Zhang J, Forkstam C, Engel JA, Svensson L (2000) Role of dopamine in prepulse inhibition of acoustic startle. Psychopharmacology 149:181–188

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Zuardi AW, Rodrigues JA, Cunha JM (1991) Effects of cannabidiol in animal models predictive of antipsychotic activity. Psychopharmacology 104:260–264

    Article  CAS  PubMed  Google Scholar 

  • Zuardi WA, Guimarães FS, Hallak JEC, Crippa JA (2011) Is the highest density of CB1 receptors in paranoid schizophrenia a correlate of endocannabinoid system functioning? Exp Rev Neurother 11:1111–1114

    Article  CAS  Google Scholar 

  • Zuardi AW, Crippa JA, Hallak JE, Bhattacharyya S, Atakan Z, Martin-Santos R, McGuire PK, Guimarães FS (2012) A critical review of the antipsychotic effects of cannabidiol: 30 years of a translational investigation. Curr Pharm Des 18:5131–5140

    Article  CAS  PubMed  Google Scholar 

  • Zygmunt PM, Petersson J, Andersson DA, Chuang H, Sørgård M, Di Marzo V, Julius D, Högestätt ED (1999) Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature 400:452–457

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We would like to thank Célia Aparecida da Silva for the technical support. The equipment and drugs used in this work were acquired from FAPESP, CNPq, CAPES, Brazil. The experiments presented in this manuscript comply with the current Brazilian laws.

Conflicts of interest

There are no conflicts of interest.

Author information

Authors and Affiliations

  1. Departamento de Morfologia, Estomatologia e Patologia Básica, Faculdade de Odontologia, Universidade de São Paulo, Ribeirão Preto, SP, 14049-904, Brasil

    J. F. C. Pedrazzi, A. C. Issy & E. A. Del-Bel

  2. Departamento de Farmacologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil

    F. V. Gomes, F. S. Guimarães & E. A. Del-Bel

  3. Departamento de Neurociências e Ciências do Comportamento, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil

    J. F. C. Pedrazzi & E. A. Del-Bel

  4. NAPNA, Universidade de São Paulo, Ribeirão Preto, Brasil

    J. F. C. Pedrazzi, A. C. Issy, F. V. Gomes, F. S. Guimarães & E. A. Del-Bel

Authors
  1. J. F. C. Pedrazzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. C. Issy
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. F. V. Gomes
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. F. S. Guimarães
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. E. A. Del-Bel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to E. A. Del-Bel.

Additional information

This work was supported by FAPESP

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pedrazzi, J.F.C., Issy, A.C., Gomes, F.V. et al. Cannabidiol effects in the prepulse inhibition disruption induced by amphetamine. Psychopharmacology 232, 3057–3065 (2015). https://doi.org/10.1007/s00213-015-3945-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-015-3945-7

Keywords

Search

Navigation