Skip to main content

Advertisement

SpringerLink
Log in

Cannabidiol Prevents the Expression of the Locomotor Sensitization and the Metabolic Changes in the Nucleus Accumbens and Prefrontal Cortex Elicited by the Combined Administration of Cocaine and Caffeine in Rats

  • Original Article
  • Published:
Neurotoxicity Research Aims and scope Submit manuscript

Abstract

In the last years, clinical and preclinical researchers have increased their interest in non-psychotomimetic cannabinoids, like cannabidiol (CBD), as a strategy for treating psychostimulant use disorders. However, there are discrepancies in the pharmacological effects and brain targets of CBD. We evaluated if CBD was able to prevent the locomotor sensitization elicited by cocaine and caffeine co-administration. The effect of CBD on putative alterations in the metabolic activity of the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc), and its respective subregions (cingulated, prelimbic, and infralimbic cortices, and NAc core and shell) associated to the behavioral response, was also investigated. Rats were intraperitoneally and repeatedly treated with CBD (20 mg/kg) or its vehicle, followed by the combination of cocaine and caffeine (Coc+Caf; 5 mg/kg and 2.5 mg/kg, respectively) or saline for 3 days. After 5 days of withdrawal, all animals were challenged with Coc+Caf (day 9). Locomotor activity was automatically recorded and analyzed by a video-tracking software. The metabolic activity was determined by measuring cytochrome oxidase-I (CO-I) staining. Locomotion was significantly and similarly increased both in Veh-Coc+Caf- and CBD-Coc+Caf-treated animals during the pretreatment period (3 days); however, on day 9, the expression of the sensitization was blunted in CBD-treated animals. A hypoactive metabolic response and a hyperactive metabolic response in mPFC and NAc subregions respectively were observed after the behavioral sensitization. CBD prevented almost all these changes. Our findings substantially contribute to the understanding of the functional changes associated with cocaine- and caffeine-induced sensitization and the effect of CBD on this process.

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
Fig. 5

Similar content being viewed by others

References

  • Abin Carriquiry JA, Martínez Busi M, Galvalisi M, Minteguiaga M, Prieto JP, Scorza C (2018) Identification and quantification of cocaine and active adulterants in coca-paste seized samples: useful scientific support to health care. Neurotox Res 34:295–304

    CAS  PubMed  Google Scholar 

  • Allen CP, Park K, Li A, Volkow ND, Koob GF, Pan Y, Hu XT, Du C (2019) Enhanced neuronal and blunted hemodynamic reactivity to cocaine in the prefrontal cortex following extended cocaine access: optical imaging study in anesthetized rats. Addict Biol 24(3):485–497

    CAS  PubMed  Google Scholar 

  • Bachtell RK, Jones JD, Heinzerling KG, Beardsley PM, Comer SD (2017) Glial and neuroinflammatory targets for treating substance use disorders. Drug Alcohol Depend 180:156–170

    CAS  PubMed  PubMed Central  Google Scholar 

  • Broséus J, Gentile N, Esseiva P (2016) The cutting of cocaine and heroin: a critical review. Forensic Sci Int 262:73–83

    PubMed  Google Scholar 

  • Calpe-López C, García-Pardo MP, Aguilar MA (2019) Cannabidiol treatment might promote resilience to cocaine and methamphetamine use disorders: a review of possible mechanisms. Molecules 24(14):2583

    PubMed Central  Google Scholar 

  • Castaño GA (2000) Cocaínas fumables en Latinoamérica. Adicciones 12:541–550

    Google Scholar 

  • Carrier EJ, Auchampach JA, Hillard CJ (2006) Inhibition of an equilibrative nucleoside transporter by cannabidiol: a mechanism of cannabinoid immunosuppression. Proc Natl Acad Sci U S A 103:7895–7900

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chen BT, Yau HJ, Hatch C, Kusumoto-Yoshida I, Cho SL, Hopf FW, Bonci A (2013) Rescuing cocaine-induced prefrontal cortex hypoactivity prevents compulsive cocaine seeking. Nature 496(7445):359–362

    CAS  PubMed  Google Scholar 

  • Churchill L, Swanson CJ, Urbina M, Kalivas PW (1999) Repeated cocaine alters glutamate receptor subunit levels in the nucleus accumbens and ventral tegmental area of rats that develop behavioral sensitization. J Neurochem 72:2397–2403

    CAS  PubMed  Google Scholar 

  • Chye Y, Christensen E, Solowij N, Yücel M (2019) The endocannabinoid system and cannabidiol’s promise for the treatment of substance use disorder. Front Psychiatry 10:63

    PubMed  PubMed Central  Google Scholar 

  • Cornish J, Kalivas P (2001) Cocaine sensitization and craving: differing roles for dopamine and glutamate in the nucleus accumbens. J Addict Dis 20:43–54

    CAS  PubMed  Google Scholar 

  • Czoty PW, Stoops WW, Rush CR (2016) Evaluation of the “pipeline” for development of medications for cocaine use disorder: a review of translational preclinical, human laboratory, and clinical trial research. Pharmacol Rev 68(3):533–562

    CAS  PubMed  PubMed Central  Google Scholar 

  • Di Chiara G (1995) The role of dopamine in drug abuse viewed from the perspective of its role in motivation. Drug Alcohol Depend 38:95–137

    PubMed  Google Scholar 

  • Dos Santos M, Cahill E, Bo G, Vanhoutte P, Caboche J, Giros B, Heck N (2018) Cocaine increases dopaminergic connectivity in the nucleus accumbens. Brain Struct Funct 223:913–923

    PubMed  Google Scholar 

  • Evrard I, Legleye S, Cadet-Taïrou A (2010) Composition, purity and perceived quality of street cocaine in France. Int J Drug Policy 21(5):399–406

    PubMed  Google Scholar 

  • Ferré S (2016) Mechanisms of the psychostimulant effects of caffeine: implications for substance use disorders. Psychopharmacology (Berlin) 233:1963–1979

    Google Scholar 

  • Filip M, Frankowska M, Zaniewska M, Przegaliński E, Muller CE, Agnati L, Franco R, Roberts D, Fuxe K (2006) Involvement of adenosine A2A and dopamine receptors in the locomotor and sensitizing effects of cocaine. Brain Res 1077:67–80

    CAS  PubMed  Google Scholar 

  • Fischer B, Kuganesan S, Gallassi A, Malcher-Lopes R, van den Brink W, Wood E (2015) Addressing the stimulant treatment gap: a call to investigate the therapeutic benefits potential of cannabinoids for crack-cocaine use. Int J Drug Policy 26(12):1177–1182

    PubMed  Google Scholar 

  • Fukushima AR, Carvalho VM, Carvalho DG, Diaz E, Bustillos JO, Spinosa HD et al (2014) Purity and adulterant analysis of crack seizures in Brazil. Forensic Sci Int 243C:95–98

    Google Scholar 

  • Goldstein RZ, Volkow ND (2011) Dysfunction of the prefrontal cortex in addiction: neuroimaging findings and clinical implications. Nat Rev Neurosci 12:652–669

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gossop M, Griffiths P, Powis B, Strang J (1992) Severity of dependence and route of administration of heroin, cocaine, and amphetamines. Br J Addict 87:1527–1536

    CAS  PubMed  Google Scholar 

  • Hatsukami D, Fischman M (1996) Crack cocaine and cocaine hydrochloride. Are the differences myth or reality? JAMA 276:1580–1588

    CAS  PubMed  Google Scholar 

  • Jeri FR (1982) The coca paste epidemic in South America: epidemiological, clinical, experimental and therapeutic observations. Revista de la Sanidad de las Fuerzas Policiales 43:170–179

    Google Scholar 

  • Jordan CJ, Cao J, Newman AH, Xi ZX (2019) Progress in agonist therapy for substance use disorders: lessons learned from methadone and buprenorphine. Neuropharmacology 158:107609

    PubMed  Google Scholar 

  • Lammel S, Hetzel A, Häckel O, Jones I, Liss B, Roeper J (2008) Unique properties of mesoprefrontal neurons within a dual mesocorticolimbic dopamine system. Neuron 57(5):760–773

    CAS  PubMed  Google Scholar 

  • Laprairie RB, Bagher AM, Kelly ME, Denovan-Wright EM (2015) Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor. Br J Pharmacol 172(20):4790–4805

    CAS  PubMed  PubMed Central  Google Scholar 

  • López Hill X, Prieto J, Meikle M, Urbanavicius J, Prunell J, Abin Carriquiry A, Umpiérrez E, Scorza C (2011) Coca-paste seized samples characterization: chemical analysis, stimulating effect in rats and relevance of caffeine as a major adulterant. Behav Brain Res 221:134–141

    PubMed  Google Scholar 

  • Luján MÁ, Castro-Zavala A, Alegre-Zurano L, Valverde O (2018) Repeated Cannabidiol treatment reduces cocaine intake and modulates neural proliferation and CB1R expression in the mouse hippocampus. Neuropharmacology 143:163–175

    PubMed  Google Scholar 

  • Luján MÁ, Cantacorps L, Valverde O (2019) The pharmacological reduction of hippocampal neurogenesis attenuates the protective effects of cannabidiol on cocaine voluntary intake Addict Biol e12778

  • Mariani JJ, Levin FR (2012) Psychostimulant treatment of cocaine dependence. Psychiatr Clin North Am 35(2):425–439

    PubMed  PubMed Central  Google Scholar 

  • Marinho EA, Oliveira-Lima AJ, Santos R, Hollais AW, Baldaia MA, Wuo-Silva R et al (2015) Effects of rimonabant on the development of single dose-induced behavioral sensitization to ethanol, morphine and cocaine in mice. Prog Neuro-Psychopharmacol Biol Psychiatry 58:22–31

    CAS  Google Scholar 

  • Martínez-Pinilla E, Varani K, Reyes-Resina I, Angelats E, Vincenzi F, Ferreiro-Vera C, Oyarzabal J, Canela EI, Lanciego JL, Nadal X, Navarro G, Borea PA, Franco R (2017) Binding and signaling studies disclose a potential allosteric site for cannabidiol in cannabinoid CB2 receptors. Front Pharmacol 8:744

    PubMed  PubMed Central  Google Scholar 

  • Muñiz J, Prieto JP, González B, Sosa M, Cadet JL, Scorza C, Urbano F, Bisagno V (2017) Cocaine and caffeine effects on the conditioned place preference test: concomitant changes on early genes within the mouse prefrontal cortex and nucleus accumbens. Front Behav Neurosci 11:200

    PubMed  PubMed Central  Google Scholar 

  • Navarro G, Reyes-Resina I, Rivas-Santisteban R, Sánchez de Medina V, Morales P, Casano S, Ferreiro-Vera C, Lillo A, Aguinaga D, Jagerovic N, Nadal X, Franco R (2018) Cannabidiol skews biased agonism at cannabinoid CB1 and CB2 receptors with smaller effect in CB1-CB2 heteroreceptor complexes. Biochem Pharmacol 157:148–158

    CAS  PubMed  Google Scholar 

  • Noji T, Takayama M, Mizutani M, Okamura Y, Takai H, Karasawa A, Kusaka H (2002) KF24345, an adenosine uptake inhibitor, suppresses lipopolysaccharide-induced tumor necrosis factor-alpha production and leukopenia via endogenous adenosine in mice. J Pharmacol Exp Ther 300(1):200–205

    CAS  PubMed  Google Scholar 

  • Norris C, Loureiro M, Kramar C, Zunder J, Renard J, Rushlow W, Laviolette SR (2016) Cannabidiol modulates fear memory formation through interactions with serotonergic transmission in the mesolimbic system. Neuropsychopharmacology 41(12):2839–2850

    CAS  PubMed  PubMed Central  Google Scholar 

  • Parker L, Burton P, Sorge R, Yakiwchuk C, Mechoulam R (2004) Effect of low doses of delta9-tetrahydrocannabinol and cannabidiol on the extinction of cocaine-induced and amphetamine-induced conditioned place preference learning in rats. Psychopharmacology 175:360–366

    CAS  PubMed  Google Scholar 

  • Paxinos G, Watson C (2005) The rat brain in stereotaxic coordinates, 5th edn. Academic press, Sydney

    Google Scholar 

  • Perez J (2003) Clínica de la adicción a pasta base de cocaína. Revista Chilena de Neuropsiquatría 41:55–63

    Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • Pierce RC, Bell K, Duffy P, Kalivas PW (1996) Repeated cocaine augments excitatory amino acid transmission in the nucleus accumbens only in rats having developed behavioral sensitization. J Neurosci 16:1550–1560

    CAS  PubMed  PubMed Central  Google Scholar 

  • Pisanti S, Malfitano A, Ciaglia E, Lamberti A, Ranieri R, Cuomo G, Abate M et al (2017) Cannabidiol: state of the art and new challenges for therapeutic applications. Pharmacol Therapeut 175:133–150

    CAS  Google Scholar 

  • Prieto JP, Meikle M, López Hill X, Urbanavicius J, Abin Carriquiry A, Prunell G, Scorza MC (2012) Relevancia del adulterante activo cafeína en la acción estimulante de la pasta base de cocaína. Rev Psiquiatr Uru 76:35–48

    Google Scholar 

  • Prieto JP, Galvalisi M, López Hill X, Meikle MN, Abin Carriquiry JA, Scorza C (2015) Caffeine enhances and accelerates the expression of sensitization induced by coca paste indicating its relevance as a main adulterant. Am J Addict 24:475–481

    PubMed  Google Scholar 

  • Prieto JP, Scorza C, Serra GP, Perra V, Piras G, Galvalisi M, Abin Carriquiry JA, Valentini V (2016) Cocaine motivational value is enhanced when co-administered with caffeine: relevance of adulterants in reinforcement. Psychopharmacol 233:2879–2889

    CAS  Google Scholar 

  • Prieto JP, González B, Muñiz J, Bisagno V, Scorza C (2020) Molecular changes in the nucleus accumbens and prefrontal cortex associated with the locomotor sensitization induced by coca paste seized sample. Psychopharmacology doi. https://doi.org/10.1007/s00213-020-05474-3

  • Rachid F (2018) Neurostimulation techniques in the treatment of cocaine dependence: a review of the literature. Addict Behav 76:145–155

    PubMed  Google Scholar 

  • Renard J, Loureiro M, Rosen LG, Zunder J, de Oliveira C, Schmid S (2016) Cannabidiol counteracts amphetamine-induced neuronal and behavioral sensitization of the mesolimbic dopamine pathway through a novel mTOR/p70S6 kinase signaling pathway. J Neurosci 36:5160–5169

    CAS  PubMed  PubMed Central  Google Scholar 

  • Robinson TE, Berridge KC (1993) The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res Brain Res Rev 18(3):247–291

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Sabogal J, Urrego J (2012) Quantifying the chemical composition of crack-cocaine (bazuco) samples seized in Colombia during the first half of 2010. J Public Health 14(6):1014–1025

    Google Scholar 

  • Samaha A, Robinson T (2005) Why does the rapid delivery of drugs to the brain promote addiction? Trends Pharmacol Sci 26:82–87

    CAS  PubMed  Google Scholar 

  • Scofield M, Heinsbroek J, Gipson C, Kupchik Y, Spencer S, Smith A, Roberts-Wolfe D, Kalivas P (2016) The nucleus accumbens: mechanisms of addiction across drug classes reflect the importance of glutamate homeostasis. Pharmacol Rev 68:816–871

    CAS  PubMed  PubMed Central  Google Scholar 

  • Schwarzkopf N, Lagos P, Falconi A, Scorza C, Torterolo P (2018) Caffeine as an adulterant of coca paste seized samples: preclinical study on the rat sleep-wake cycle. Behav Pharmacol 29(6):519–529

    CAS  PubMed  Google Scholar 

  • Steketee J, Kalivas P (2011) Drug wanting: behavioral sensitization and relapse to drug-seeking behavior. J Pharmacol Exp Ther 63:348–365

    CAS  Google Scholar 

  • Tham M, Yilmaz O, Alaverdashvili M, Kelly MEM, Denovan-Wright EM, Laprairie RB (2019) Allosteric and orthosteric pharmacology of cannabidiol and cannabidiol-dimethylheptyl at the type 1 and type 2 cannabinoid receptors. Br J Pharmacol 176:1455–1469

    CAS  PubMed  Google Scholar 

  • Tseng KY, Amin F, Lewis BL, O’Donnell P (2006) Altered prefrontal cortical metabolic response to mesocortical activation in adult animals with a neonatal ventral hippocampal lesion. Biol Psychiatry 60(6):585–590

    CAS  PubMed  PubMed Central  Google Scholar 

  • Vélez-Hernández ME, Padilla E, Gonzalez-Lima F, Jiménez-Rivera CA (2014) Cocaine reduces cytochrome oxidase activity in the prefrontal cortex and modifies its functional connectivity with brainstem nuclei. Brain Res 1542:56–69

    PubMed  PubMed Central  Google Scholar 

  • Volkow ND, Fowler JS, Wang GJ, Hitzemann R, Logan J, Schlyer DJ, Dewey SL, Wolf AP (1993) Decreased dopamine D2 receptor availability is associated with reduced frontal metabolism in cocaine abusers. Synapse 14:169–177

    CAS  PubMed  Google Scholar 

  • Walker JR, Sevarino KA (1995) Regulation of cytochrome c oxidase subunit mRNA and enzyme activity in rat brain reward regions during withdrawal from chronic cocaine. J Neurochem 64(2):497–502

    CAS  PubMed  Google Scholar 

  • Ware MA (2018) Medical cannabis research: issues and priorities. Neuropsychopharmacology 43:214–215

    PubMed  Google Scholar 

  • Wenzel JM, Cheer JF (2018) Endocannabinoid regulation of reward and reinforcement through interaction with dopamine and endogenous opioid signaling. Neuropsychopharmacology 43:103–115

    CAS  PubMed  Google Scholar 

  • Wong-Riley MTT (1979) Cytochrome oxidase: an endogenous metabolic marker for neuronal activity. Trends Neurosci 12:94–101

    Google Scholar 

Download references

Acknowledgments

We are grateful to Prof. Kuei Y. Tseng for his remarkable help in the analysis of the results and to María Paula Latorre for her technical assistance.

Funding

This study was financially supported by ANII-FCE_3_2018_1_149210, Premio Concursable Junta Nacional de Drogas (Uruguay) and PEDECIBA (Uruguay). José Pedro Prieto has postgraduate fellowships from ANII (Uruguay) and CAP (Universidad de la República, Uruguay).

Author information

Authors and Affiliations

  1. Departamento de Neurofarmacología Experimental, Instituto de Investigaciones Biológicas Clemente Estable, Avenida Italia 3318, 11600, Montevideo, Uruguay

    José Pedro Prieto, Ximena López Hill, Jessika Urbanavicius & Cecilia Scorza

  2. Phytoplant Research S.L., Córdoba, Spain

    Verónica Sanchez & Xavier Nadal

  3. Barcelona, Spain

    Xavier Nadal

Authors
  1. José Pedro Prieto
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ximena López Hill
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jessika Urbanavicius
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Verónica Sanchez
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xavier Nadal
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Cecilia Scorza
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Cecilia Scorza.

Ethics declarations

All experimental procedures were conducted according to the National Animal Care Law (No. 18611) and the “Guide to the care and use of laboratory animals” (8th edition, National Academy Press, Washington DC, 2010). Furthermore, all experimental protocols had been approved by the IIBCE Animal Care Committee.

Conflict of Interest

Cannabidiol was donated by Phytoplant Research (Spain). Verónica Sanchez and Xavier Nadal both work for Phytoplant Research S.L.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Prieto, J.P., López Hill, X., Urbanavicius, J. et al. Cannabidiol Prevents the Expression of the Locomotor Sensitization and the Metabolic Changes in the Nucleus Accumbens and Prefrontal Cortex Elicited by the Combined Administration of Cocaine and Caffeine in Rats. Neurotox Res 38, 478–486 (2020). https://doi.org/10.1007/s12640-020-00218-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12640-020-00218-9

Keywords

Search

Navigation