Beta-caryophyllene inhibits cocaine  addiction-related behavior by activation of PPARα and PPARγ: repurposing a FDA-approved food additive for cocaine use disorder

Abstract

Cocaine abuse continues to be a serious health problem worldwide. Despite intense research, there is still no FDA-approved medication to treat cocaine use disorder (CUD). In this report, we explored the potential utility of beta-caryophyllene (BCP), an FDA-approved food additive for the treatment of CUD. We found that BCP, when administered intraperitoneally or intragastrically, dose-dependently attenuated cocaine self-administration, cocaine-conditioned place preference, and cocaine-primed reinstatement of drug seeking in rats. In contrast, BCP failed to alter food self-administration or cocaine-induced hyperactivity. It also failed to maintain self-administration in a drug substitution test, suggesting that BCP has no abuse potential. BCP was previously reported to be a selective CB2 receptor agonist. Unexpectedly, pharmacological blockade or genetic deletion of CB1, CB2, or GPR55 receptors in gene-knockout mice failed to alter BCP’s action against cocaine self-administration, suggesting the involvement of non-CB1, non-CB2, and non-GPR55 receptor mechanisms. Furthermore, pharmacological blockade of μ opioid receptor or Toll-like receptors complex failed to alter, while blockade of peroxisome proliferator-activated receptors (PPARα, PPARγ) reversed BCP-induced reduction in cocaine self-administration, suggesting the involvement of PPARα and PPARγ in BCP’s action. Finally, we used electrical and optogenetic intracranial self-stimulation (eICSS, oICSS) paradigms to study the underlying neural substrate mechanisms. We found that BCP is more effective in attenuation of cocaine-enhanced oICSS than eICSS, the former driven by optical activation of midbrain dopamine neurons in DAT-cre mice. These findings indicate that BCP may be useful for the treatment of CUD, likely by stimulation of PPARα and PPARγ in the mesolimbic system.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: The effects of BCP on cocaine addiction-related behavior in rats.
Fig. 2: The effects of BCP on cocaine self-administration in mice under a FR2 schedule of reinforcement.
Fig. 3: The effects of BCP (100 mg/kg, i.p.) on self-administration of multiple cocaine doses in the presence or absence of different receptor antagonists or agonists (n = 8–10 rats in each group).
Fig. 4: The effects of cocaine and BCP on electrical brain-stimulation reward (BSR) (n = 12).
Fig. 5: The effects of cocaine and BCP on optical intracranial self-stimulation (oICSS) maintained by optical stimulation of VTA DA neurons in DAT-cre mice.

References

  1. 1.

    Koob GF, Volkow ND. Neurobiology of addiction: a neurocircuitry analysis. Lancet Psychiatry. 2016;3:760–73.

    PubMed  Google Scholar 

  2. 2.

    Galaj E, Xi Z-X. Potential of cannabinoid receptor ligands as treatment for substance use disorders. CNS Drugs. 2019;33:1001–30.

    PubMed  Google Scholar 

  3. 3.

    Manzanares J, Cabañero D, Puente N, García-Gutiérrez MS, Grandes P, Maldonado R. Role of the endocannabinoid system in drug addiction. Biochem Pharmacol. 2018;157:108–21.

    CAS  PubMed  Google Scholar 

  4. 4.

    Arnold JC. The role of endocannabinoid transmission in cocaine addiction. Pharm Biochem Behav. 2005;81:396–406.

    CAS  Google Scholar 

  5. 5.

    Galaj E, Bi G-H, Yang H-J, Xi Z-X. Cannabidiol attenuates the rewarding effects of cocaine in rats by CB2, 5-HT1A and TRPV1 receptor mechanisms. Neuropharmacology. 2020;167:107740.

    CAS  PubMed  Google Scholar 

  6. 6.

    Wiskerke J, Pattij T, Schoffelmeer ANM, De, Vries TJ. The role of CB1 receptors in psychostimulant addiction. Addict Biol. 2008;13:225–38.

    CAS  PubMed  Google Scholar 

  7. 7.

    Xi Z-X, Spiller K, Pak AC, Gilbert J, Dillon C, Li X, et al. Cannabinoid cb1 receptor antagonists attenuate cocaine’s rewarding effects: experiments with self-administration and brain-stimulation reward in rats. Neuropsychopharmacology. 2008;33:1735–45.

    CAS  PubMed  Google Scholar 

  8. 8.

    Xi Z-X, Peng X-Q, Li X, Song R, Zhang H-Y, Liu Q-R, et al. Brain cannabinoid CB2 receptors modulate cocaine’s actions in mice. Nat Neurosci. 2011;14:1160–6.

    CAS  PubMed  Google Scholar 

  9. 9.

    Delis F, Polissidis A, Poulia N, Justinova Z, Nomikos GG, Goldberg SR, et al. Attenuation of cocaine-induced conditioned place preference and motor activity via cannabinoid cb2 receptor agonism and cb1 receptor antagonism in rats. Int J Neuropsychopharmacol. 2017;20:269–78.

    CAS  PubMed  Google Scholar 

  10. 10.

    Lopes JB, Bastos JR, Costa RB, Aguiar DC, Moreira FA. The roles of cannabinoid CB1 and CB2 receptors in cocaine-induced behavioral sensitization and conditioned place preference in mice. Psychopharmacol. (Berl) 2020;237:385–94.

    CAS  Google Scholar 

  11. 11.

    Yu L-L, Zhou S-J, Wang X-Y, Liu J-F, Xue Y-X, Jiang W, et al. Effects of cannabinoid CB1 receptor antagonist rimonabant on acquisition and reinstatement of psychostimulant reward memory in mice. Behav Brain. Res 2011;217:111–6.

    CAS  PubMed  Google Scholar 

  12. 12.

    Zhang H-Y, Gao M, Liu Q-R, Bi G-H, Li X, Yang H-J, et al. Cannabinoid CB2 receptors modulate midbrain dopamine neuronal activity and dopamine-related behavior in mice. Proc Natl Acad Sci USA. 2014;111:E5007–5015.

    CAS  PubMed  Google Scholar 

  13. 13.

    De Vries TJ, Shaham Y, Homberg JR, Crombag H, Schuurman K, Dieben J, et al. A cannabinoid mechanism in relapse to cocaine seeking. Nat Med. 2001;7:1151–4.

    PubMed  Google Scholar 

  14. 14.

    Ward SJ, Rosenberg M, Dykstra LA, Walker EA. The CB1 antagonist rimonabant (SR141716) blocks cue-induced reinstatement of cocaine seeking and other context and extinction phenomena predictive of relapse. Drug Alcohol Depend. 2009;105:248–55.

    CAS  PubMed  Google Scholar 

  15. 15.

    Xi Z-X, Gilbert JG, Peng X-Q, Pak AC, Li X, Gardner EL. Cannabinoid CB1 receptor antagonist AM251 inhibits cocaine-primed relapse in rats: role of glutamate in the nucleus accumbens. J Neurosci. 2006;26:8531–6.

    CAS  PubMed  Google Scholar 

  16. 16.

    Lesscher HMB, Hoogveld E, Burbach JPH, van Ree JM, Gerrits MAFM. Endogenous cannabinoids are not involved in cocaine reinforcement and development of cocaine-induced behavioural sensitization. Eur Neuropsychopharmacol. 2005;15:31–37.

    CAS  PubMed  Google Scholar 

  17. 17.

    Cossu G, Ledent C, Fattore L, Imperato A, Böhme GA, Parmentier M, et al. Cannabinoid CB1 receptor knockout mice fail to self-administer morphine but not other drugs of abuse. Behav Brain Res. 2001;118:61–65.

    CAS  PubMed  Google Scholar 

  18. 18.

    Fattore L, Martellotta MC, Cossu G, Mascia MS, Fratta W. CB1 cannabinoid receptor agonist WIN 55,212-2 decreases intravenous cocaine self-administration in rats. Behav Brain Res. 1999;104:141–6.

    CAS  PubMed  Google Scholar 

  19. 19.

    Caillé S, Alvarez-Jaimes L, Polis I, Stouffer DG, Parsons LH. Specific alterations of extracellular endocannabinoid levels in the nucleus accumbens by ethanol, heroin, and cocaine self-administration. J Neurosci. 2007;27:3695–702.

    PubMed  Google Scholar 

  20. 20.

    Filip M, Gołda A, Zaniewska M, McCreary AC, Nowak E, Kolasiewicz W, et al. Involvement of cannabinoid CB1 receptors in drug addiction: effects of rimonabant on behavioral responses induced by cocaine. Pharm Rep. 2006;58:806–19.

    CAS  Google Scholar 

  21. 21.

    Tanda G, Munzar P, Goldberg SR. Self-administration behavior is maintained by the psychoactive ingredient of marijuana in squirrel monkeys. Nat Neurosci. 2000;3:1073–4.

    CAS  PubMed  Google Scholar 

  22. 22.

    Martin M, Ledent C, Parmentier M, Maldonado R, Valverde O. Cocaine, but not morphine, induces conditioned place preference and sensitization to locomotor responses in CB1 knockout mice. Eur J Neurosci. 2000;12:4038–46.

    CAS  PubMed  Google Scholar 

  23. 23.

    Miller LL, Ward SJ, Dykstra LA. Chronic unpredictable stress enhances cocaine-conditioned place preference in type 1 cannabinoid receptor knockout mice. Behav Pharmacol. 2008;19:575–81.

    CAS  PubMed  Google Scholar 

  24. 24.

    Li X, Hoffman AF, Peng X-Q, Lupica CR, Gardner EL, Xi Z-X. Attenuation of basal and cocaine-enhanced locomotion and nucleus accumbens dopamine in cannabinoid CB1-receptor-knockout mice. Psychopharmacol (Berl). 2009;204:1–11.

    CAS  Google Scholar 

  25. 25.

    Aracil-Fernández A, Trigo JM, García-Gutiérrez MS, Ortega-Álvaro A, Ternianov A, Navarro D, et al. Decreased cocaine motor sensitization and self-administration in mice overexpressing cannabinoid CB2 receptors. Neuropsychopharmacology. 2012;37:1749–63.

    PubMed  Google Scholar 

  26. 26.

    Le Foll B, Gorelick DA, Goldberg SR. The future of endocannabinoid-oriented clinical research after CB1 antagonists. Psychopharmacology. 2009;205:171–4.

    PubMed  Google Scholar 

  27. 27.

    Jordan CJ, Xi Z-X. Progress in brain cannabinoid CB2 receptor research: From genes to behavior. Neurosci Biobehav Rev. 2019;98:208–20.

    CAS  PubMed  Google Scholar 

  28. 28.

    Mediavilla V, Steinemann S. Essential oil of cannabis sativa L. strains. I Int Hemp Res. 1997;4:80–2.

    Google Scholar 

  29. 29.

    Sharma C, Al Kaabi JM, Nurulain SM, Goyal SN, Kamal MA, Ojha S. Polypharmacological properties and therapeutic potential of β-caryophyllene: a dietary phytocannabinoid of pharmaceutical promise. Curr Pharm Des. 2016;22:3237–64.

    CAS  PubMed  Google Scholar 

  30. 30.

    Gertsch J, Leonti M, Raduner S, Racz I, Chen J-Z, Xie X-Q, et al. Beta-caryophyllene is a dietary cannabinoid. Proc Natl Acad Sci USA. 2008;105:9099–104.

    CAS  PubMed  Google Scholar 

  31. 31.

    Cho JY, Chang H-J, Lee S-K, Kim H-J, Hwang J-K, Chun HS. Amelioration of dextran sulfate sodium-induced colitis in mice by oral administration of beta-caryophyllene, a sesquiterpene. Life Sci. 2007;80:932–9.

    CAS  PubMed  Google Scholar 

  32. 32.

    Klauke A-L, Racz I, Pradier B, Markert A, Zimmer AM, Gertsch J, et al. The cannabinoid CB2 receptor-selective phytocannabinoid beta-caryophyllene exerts analgesic effects in mouse models of inflammatory and neuropathic pain. Eur Neuropsychopharmacol. 2014;24:608–20.

    CAS  PubMed  Google Scholar 

  33. 33.

    Katsuyama S, Mizoguchi H, Kuwahata H, Komatsu T, Nagaoka K, Nakamura H, et al. Involvement of peripheral cannabinoid and opioid receptors in β-caryophyllene-induced antinociception. Eur J Pain. 2013;17:664–75.

    CAS  Google Scholar 

  34. 34.

    Bahi A, Al Mansouri S, Al Memari E, Al Ameri M, Nurulain SM, Ojha S. β-Caryophyllene, a CB2 receptor agonist produces multiple behavioral changes relevant to anxiety and depression in mice. Physiol Behav. 2014;135:119–24.

    CAS  PubMed  Google Scholar 

  35. 35.

    Cheng Y, Dong Z, Liu S. β-caryophyllene ameliorates the alzheimer-like phenotype in APP/PS1 mice through CB2 receptor activation and the PPARγ pathway. Pharmacology. 2014;94:1–12.

    CAS  PubMed  Google Scholar 

  36. 36.

    Guo K, Mou X, Huang J, Xiong N, Li H. Trans-caryophyllene suppresses hypoxia-induced neuroinflammatory responses by inhibiting NF-κB activation in microglia. J Mol Neurosci. 2014;54:41–8.

    CAS  PubMed  Google Scholar 

  37. 37.

    Fidyt K, Fiedorowicz A, Strządała L, Szumny A. β-caryophyllene and β-caryophyllene oxide-natural compounds of anticancer and analgesic properties. Cancer Med. 2016;5:3007–17.

    CAS  PubMed  Google Scholar 

  38. 38.

    He Y, Galaj E, Bi G-H, Wang X-F, Gardner E, Xi Z-X. β-caryophyllene, a dietary terpenoid, inhibits nicotine taking and nicotine seeking in rodents. Br J Pharmacol. 2020;177:2058–72.

    CAS  PubMed  Google Scholar 

  39. 39.

    Bento AF, Marcon R, Dutra RC, Claudino RF, Cola M, Pereira Leite DF, et al. β-Caryophyllene inhibits dextran sulfate sodium-induced colitis in mice through CB2 receptor activation and PPARγ pathway. Am J Pathol. 2011;178:1153–66.

    CAS  PubMed  Google Scholar 

  40. 40.

    Varga ZV, Matyas C, Erdelyi K, Cinar R, Nieri D, Chicca A, et al. β‐Caryophyllene protects against alcoholic steatohepatitis by attenuating inflammation and metabolic dysregulation in mice. Br J Pharmacol. 2018;175:320–34.

    CAS  PubMed  Google Scholar 

  41. 41.

    Finlay DB, Sircombe KJ, Nimick M, Jones C, Glass M. Terpenoids From cannabis do not mediate an entourage effect by acting at cannabinoid receptors. Front Pharmacol. 2020;11:359. https://doi.org/10.3389/fphar.2020.00359.

    CAS  Article  PubMed  Google Scholar 

  42. 42.

    Santiago M, Sachdev S, Arnold JC, McGregor IS, Connor M. Absence of entourage: terpenoids commonly found in cannabis sativa do not modulate the functional activity of Δ9-THC at human CB1 and CB2 receptors. Cannabis Cannabinoid Res. 2019;4:165–76.

    CAS  PubMed  Google Scholar 

  43. 43.

    Wang X-F, Galaj E, Bi G-H, Zhang C, He Y, Zhan J, et al. Different receptor mechanisms underlying phytocannabinoid- versus synthetic cannabinoid-induced tetrad effects: opposite roles of CB1 /CB2 versus GPR55 receptors. Br J Pharmacol. 2020;177:1865–80.

    CAS  PubMed  Google Scholar 

  44. 44.

    de Guglielmo G, Melis M, De Luca MA, Kallupi M, Li HW, Niswender K, et al. PPARγ activation attenuates opioid consumption and modulates mesolimbic dopamine transmission. Neuropsychopharmacology. 2015;40:927–37.

    PubMed  Google Scholar 

  45. 45.

    Scheggi S, Melis M, De Felice M, Aroni S, Muntoni AL, Pelliccia T, et al. PPARα modulation of mesolimbic dopamine transmission rescues depression-related behaviors. Neuropharmacology. 2016;110:251–9.

    CAS  PubMed  Google Scholar 

  46. 46.

    Paula-Freire LIG, Andersen ML, Gama VS, Molska GR, Carlini ELA. The oral administration of trans-caryophyllene attenuates acute and chronic pain in mice. Phytomedicine. 2014;21:356–62.

    CAS  PubMed  Google Scholar 

  47. 47.

    Basha RH, Sankaranarayanan C. β-Caryophyllene, a natural sesquiterpene lactone attenuates hyperglycemia mediated oxidative and inflammatory stress in experimental diabetic rats. Chem Biol Interact. 2016;245:50–8.

    CAS  PubMed  Google Scholar 

  48. 48.

    Suijun W, Zhen Y, Ying G, Yanfang W. A role for trans-caryophyllene in the moderation of insulin secretion. Biochem Biophys Res Commun. 2014;444:451–4.

    CAS  PubMed  Google Scholar 

  49. 49.

    Hwang E-S, Kim H-B, Lee S, Kim M-J, Kim K-J, Han G, et al. Antidepressant-like effects of β-caryophyllene on restraint plus stress-induced depression. Behav Brain Res. 2020;380:112439.

    CAS  PubMed  Google Scholar 

  50. 50.

    Alberti TB, Barbosa WLR, Vieira JLF, Raposo NRB, Dutra RC. (-)-β-caryophyllene, a cb2 receptor-selective phytocannabinoid, suppresses motor paralysis and neuroinflammation in a murine model of multiple sclerosis. Int J Mol Sci. 2017;18:691. https://doi.org/10.3390/ijms18040691.

    CAS  Article  Google Scholar 

  51. 51.

    Fontes LBA, Dias DDS, Aarestrup BJV, Aarestrup FM, Da Silva Filho AA, Corrêa JO, et al. β-Caryophyllene ameliorates the development of experimental autoimmune encephalomyelitis in C57BL/6 mice. Biomed Pharmacother. 2017;91:257–64.

    CAS  PubMed  Google Scholar 

  52. 52.

    Dahham SS, Tabana YM, Iqbal MA, Ahamed MBK, Ezzat MO, Majid ASA, et al. The anticancer, antioxidant and antimicrobial properties of the sesquiterpene β-caryophyllene from the essential oil of aquilaria crassna. Molecules. 2015;20:11808–29.

    CAS  PubMed  Google Scholar 

  53. 53.

    Legault J, Pichette A. Potentiating effect of beta-caryophyllene on anticancer activity of alpha-humulene, isocaryophyllene and paclitaxel. J Pharm Pharmacol. 2007;59:1643–7.

    CAS  PubMed  Google Scholar 

  54. 54.

    Canseco-Alba A, Schanz N, Sanabria B, Zhao J, Lin Z, Liu Q-R, et al. Behavioral effects of psychostimulants in mutant mice with cell-type specific deletion of CB2 cannabinoid receptors in dopamine neurons. Behav Brain Res. 2018;360:286–97.

    PubMed  Google Scholar 

  55. 55.

    Hu Y, Zeng Z, Wang B, Guo S. Trans-caryophyllene inhibits amyloid β (Aβ) oligomer-induced neuroinflammation in BV-2 microglial cells. Int Immunopharmacol. 2017;51:91–8.

    CAS  PubMed  Google Scholar 

  56. 56.

    Javed H, Azimullah S, Haque ME, Ojha SK. Cannabinoid Type 2 (CB2) Receptors activation protects against oxidative stress and neuroinflammation associated dopaminergic neurodegeneration in rotenone model of parkinson’s disease. Front Neurosci. 2016;10:321.

    PubMed  Google Scholar 

  57. 57.

    Ojha S, Javed H, Azimullah S, Haque ME. β-Caryophyllene, a phytocannabinoid attenuates oxidative stress, neuroinflammation, glial activation, and salvages dopaminergic neurons in a rat model of Parkinson disease. Mol Cell Biochem. 2016;418:59–70.

    CAS  PubMed  Google Scholar 

  58. 58.

    Viveros-Paredes JM, González-Castañeda RE, Gertsch J, Chaparro-Huerta V, López-Roa RI, Vázquez-Valls E, et al. Neuroprotective Effects of β-caryophyllene against dopaminergic neuron injury in a murine model of Parkinson’s disease induced by MPTP. Pharmaceutical. 2017;10:60. https://doi.org/10.3390/ph10030060.

    CAS  Article  Google Scholar 

  59. 59.

    Kim YS, Park SJ, Lee EJ, Cerbo RM, Lee SM, Ryu CH, et al. Antibacterial compounds from Rose Bengal-sensitized photooxidation of beta-caryophyllene. J Food Sci. 2008;73:C540–5.

    CAS  PubMed  Google Scholar 

  60. 60.

    Pieri FA, Souza MC de C, Vermelho LLR, Vermelho MLR, Perciano PG, et al. Use of β-caryophyllene to combat bacterial dental plaque formation in dogs. BMC Vet Res. 2016;12:216. https://doi.org/10.1186/s12917-016-0842-1.

    CAS  Article  PubMed  Google Scholar 

  61. 61.

    Bahr T, Allred K, Martinez D, Rodriguez D, Winterton P. Effects of a massage-like essential oil application procedure using copaiba and deep blue oils in individuals with hand arthritis. Complement Ther Clin Pract. 2018;33:170–6.

    PubMed  Google Scholar 

  62. 62.

    Shim HI, Song DJ, Shin CM, Yoon H, Park YS, Kim N. et al. [Inhibitory effects of β-caryophyllene on helicobacter pylori infection: a randomized double-blind, placebo-controlled study]. Korean J Gastroenterol.2019;74:199–204.

    PubMed  Google Scholar 

  63. 63.

    Ou M-C, Hsu T-F, Lai AC, Lin Y-T, Lin C-C. Pain relief assessment by aromatic essential oil massage on outpatients with primary dysmenorrhea: a randomized, double-blind clinical trial. J Obstet Gynaecol Res. 2012;38:817–22.

    PubMed  Google Scholar 

  64. 64.

    Al Mansouri S, Ojha S, Al Maamari E, Al Ameri M, Nurulain SM, Bahi A. The cannabinoid receptor 2 agonist, β-caryophyllene, reduced voluntary alcohol intake and attenuated ethanol-induced place preference and sensitivity in mice. Pharm Biochem Behav. 2014;124:260–8.

    CAS  Google Scholar 

  65. 65.

    Santos PS, Oliveira TC, R Júnior LM, Figueiras A, Nunes LCC. β-caryophyllene delivery systems: enhancing the oral pharmacokinetic and stability. Curr Pharm Des. 2018;24:3440–53.

    CAS  PubMed  Google Scholar 

  66. 66.

    Schmitt D, Levy R, Carroll B. Toxicological evaluation of β-caryophyllene oil: subchronic toxicity in rats. Int J Toxicol 2016;35:558–67.

    CAS  PubMed  Google Scholar 

  67. 67.

    Oliveira GL, da S, Machado KC, Machado KC, da Silva APDSCL, Feitosa CM, et al. Non-clinical toxicity of β-caryophyllene, a dietary cannabinoid: absence of adverse effects in female Swiss mice. Regul Toxicol Pharmacol 2018;92:338–46.

    CAS  PubMed  Google Scholar 

  68. 68.

    Aly E, Khajah MA, Masocha W. β-Caryophyllene, a CB2-receptor-selective phytocannabinoid, suppresses mechanical allodynia in a mouse model of antiretroviral-induced neuropathic pain. Molecules. 2019;25:106. https://doi.org/10.3390/molecules25010106.

    CAS  Article  Google Scholar 

  69. 69.

    Huffman JW. CB2 receptor ligands. Mini Rev Med Chem. 2005;5:641–9.

    CAS  PubMed  Google Scholar 

  70. 70.

    Zhang H-Y, Bi G-H, Li X, Li J, Qu H, Zhang S-J, et al. Species differences in cannabinoid receptor 2 and receptor responses to cocaine self-administration in mice and rats. Neuropsychopharmacology. 2015;40:1037–51.

    CAS  PubMed  Google Scholar 

  71. 71.

    Gobira PH, Oliveira AC, Gomes JS, da Silveira VT, Asth L, Bastos JR, et al. Opposing roles of CB1 and CB2 cannabinoid receptors in the stimulant and rewarding effects of cocaine. Br J Pharmacol. 2018. 12, 10.1111/bph.14473.

  72. 72.

    Zhang H-Y, Gao M, Shen H, Bi G-H, Yang H-J, Liu Q-R, et al. Expression of functional cannabinoid CB2 receptor in VTA dopamine neurons in rats. Addict Biol. 2017;22:752–65.

    CAS  PubMed  Google Scholar 

  73. 73.

    Foster DJ, Wilson JM, Remke DH, Mahmood MS, Uddin MJ, Wess J, et al. antipsychotic-like effects of m4 positive allosteric modulators are mediated by CB2 receptor-dependent inhibition of dopamine release. Neuron. 2016;91:1244–52.

    CAS  PubMed  Google Scholar 

  74. 74.

    Cho H-I, Hong J-M, Choi J-W, Choi H-S, Kwak JH, Lee D-U, et al. β-caryophyllene alleviates D-galactosamine and lipopolysaccharide-induced hepatic injury through suppression of the TLR4 and RAGE signaling pathways. Eur J Pharmacol. 2015;764:613–21.

    CAS  PubMed  Google Scholar 

  75. 75.

    Irrera N, D’Ascola A, Pallio G, Bitto A, Mazzon E, Mannino F, et al. β-caryophyllene mitigates collagen antibody induced arthritis (CAIA) in mice through a cross-talk between CB2 and PPAR-γ receptors. Life Sci. 2019;237:116915. https://doi.org/10.1016/j.lfs.2019.116915.

    CAS  Article  Google Scholar 

  76. 76.

    Tian X, Liu H, Xiang F, Xu L, Dong Z. β-Caryophyllene protects against ischemic stroke by promoting polarization of microglia toward M2 phenotype via the TLR4 pathway. Life Sci. 2019;237:116915.

    CAS  PubMed  Google Scholar 

  77. 77.

    Wu C, Jia Y, Lee JH, Jun H, Lee H-S, Hwang K-Y, et al. Trans-caryophyllene is a natural agonistic ligand for peroxisome proliferator-activated receptor-α. Bioorg Med Chem Lett. 2014;24:3168–74.

    CAS  Google Scholar 

  78. 78.

    Haile CN, Kosten TA. The peroxisome proliferator-activated receptor alpha agonist fenofibrate attenuates alcohol self-administration in rats. Neuropharmacology. 2017;116:364–70.

    CAS  PubMed  Google Scholar 

  79. 79.

    Jackson A, Bagdas D, Muldoon PP, Lichtman AH, Carroll FI, Greenwald M, et al. In vivo interactions between α7 nicotinic acetylcholine receptor and nuclear peroxisome proliferator-activated receptor-α: Implication for nicotine dependence. Neuropharmacology. 2017;118:38–45.

    CAS  PubMed  Google Scholar 

  80. 80.

    Le Foll B, Di Ciano P, Panlilio LV, Goldberg SR, Ciccocioppo R. Peroxisome proliferator-activated receptor (PPAR) agonists as promising new medications for drug addiction: preclinical evidence. Curr Drug Targets. 2013;14:768–76.

    PubMed  Google Scholar 

  81. 81.

    Mascia P, Pistis M, Justinova Z, Panlilio LV, Luchicchi A, Lecca S, et al. Blockade of nicotine reward and reinstatement by activation of alpha-type peroxisome proliferator-activated receptors. Biol Psychiatry. 2011;69:633–41.

    CAS  PubMed  Google Scholar 

  82. 82.

    de Guglielmo G, Kallupi M, Scuppa G, Demopulos G, Gaitanaris G, Ciccocioppo R. Pioglitazone attenuates the opioid withdrawal and vulnerability to relapse to heroin seeking in rodents. Psychopharmacol. 2017;234:223–34.

    Google Scholar 

  83. 83.

    Miller WR, Fox RG, Stutz SJ, Lane SD, Denner L, Cunningham KA, et al. PPARγ agonism attenuates cocaine cue reactivity. Addict Biol. 2018;23:55–68.

    CAS  PubMed  Google Scholar 

  84. 84.

    Schmitz JM, Green CE, Hasan KM, Vincent J, Suchting R, Weaver MF, et al. PPAR-gamma agonist pioglitazone modifies craving intensity and brain white matter integrity in patients with primary cocaine use disorder: a double-blind randomized controlled pilot trial. Addiction. 2017;112:1861–8.

    PubMed  Google Scholar 

  85. 85.

    Domi E, Caputi FF, Romualdi P, Domi A, Scuppa G, Candeletti S, et al. Activation of PPARγ attenuates the expression of physical and affective nicotine withdrawal symptoms through mechanisms involving amygdala and hippocampus neurotransmission. J Neurosci. 2019;39:9864–75.

    PubMed  Google Scholar 

  86. 86.

    Maeda T, Kiguchi N, Fukazawa Y, Yamamoto A, Ozaki M, Kishioka S. Peroxisome proliferator-activated receptor gamma activation relieves expression of behavioral sensitization to methamphetamine in mice. Neuropsychopharmacology. 2007;32:1133–40.

    CAS  PubMed  Google Scholar 

  87. 87.

    Gendy MNS, Di Ciano P, Kowalczyk WJ, Barrett SP, George TP, Heishman S, et al. Testing the PPAR hypothesis of tobacco use disorder in humans: a randomized trial of the impact of gemfibrozil (a partial PPARα agonist) in smokers. PLoS ONE. 2018;13:e0201512.

    PubMed  Google Scholar 

  88. 88.

    Fu J, Gaetani S, Oveisi F, Lo Verme J, Serrano A, Rodríguez De Fonseca F, et al. Oleylethanolamide regulates feeding and body weight through activation of the nuclear receptor PPAR-alpha. Nature. 2003;425:90–3.

    CAS  PubMed  Google Scholar 

  89. 89.

    Melis M, Carta G, Pistis M, Banni S. Physiological role of peroxisome proliferator-activated receptors type α on dopamine systems. CNS Neurol Disord Drug Targets. 2013;12:70–7.

    CAS  PubMed  Google Scholar 

  90. 90.

    Bouaboula M, Hilairet S, Marchand J, Fajas L, Le Fur G, Casellas P. Anandamide induced PPARgamma transcriptional activation and 3T3-L1 preadipocyte differentiation. Eur J Pharmacol. 2005;517:174–81.

    CAS  PubMed  Google Scholar 

  91. 91.

    Moreno S, Farioli-Vecchioli S, Cerù MP. Immunolocalization of peroxisome proliferator-activated receptors and retinoid X receptors in the adult rat CNS. Neuroscience. 2004;123:131–45.

    CAS  PubMed  Google Scholar 

  92. 92.

    Warden A, Truitt J, Merriman M, Ponomareva O, Jameson K, Ferguson LB, et al. Localization of PPAR isotypes in the adult mouse and human brain. Sci Rep. 2016;6:27618.

    CAS  PubMed  Google Scholar 

  93. 93.

    Sarruf DA, Yu F, Nguyen HT, Williams DL, Printz RL, Niswender KD, et al. Expression of peroxisome proliferator-activated receptor-gamma in key neuronal subsets regulating glucose metabolism and energy homeostasis. Endocrinology. 2009;150:707–12.

    CAS  PubMed  Google Scholar 

  94. 94.

    Melis M, Carta S, Fattore L, Tolu S, Yasar S, Goldberg SR, et al. Peroxisome proliferator-activated receptors-alpha modulate dopamine cell activity through nicotinic receptors. Biol Psychiatry. 2010;68:256–64.

    CAS  PubMed  Google Scholar 

  95. 95.

    Luchicchi A, Lecca S, Carta S, Pillolla G, Muntoni AL, Yasar S, et al. Effects of fatty acid amide hydrolase inhibition on neuronal responses to nicotine, cocaine and morphine in the nucleus accumbens shell and ventral tegmental area: involvement of PPAR-alpha nuclear receptors. Addict Biol. 2010;15:277–88.

    CAS  PubMed  Google Scholar 

  96. 96.

    Wenzel JM, Cheer JF. Endocannabinoid regulation of reward and reinforcement through interaction with dopamine and endogenous opioid signaling. Neuropsychopharmacology. 2018;43:103–15.

    CAS  PubMed  Google Scholar 

  97. 97.

    Gardner EL. Endocannabinoid signaling system and brain reward: emphasis on dopamine. Pharm Biochem Behav. 2005;81:263–84.

    CAS  Google Scholar 

Download references

Author information

Affiliations

Authors

Contributions

EG, ELG, and ZXX designed the experiments. EG, GHB, AM, KC, and YH conducted the experiments. EG, GHB, and ZXX performed data analyses. EG and ZXX wrote the manuscript. All authors have approved the final version of this article.

Corresponding author

Correspondence to Zheng-Xiong Xi.

Additional information

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

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Galaj, E., Bi, GH., Moore, A. et al. Beta-caryophyllene inhibits cocaine  addiction-related behavior by activation of PPARα and PPARγ: repurposing a FDA-approved food additive for cocaine use disorder. Neuropsychopharmacol. (2020). https://doi.org/10.1038/s41386-020-00885-4

Download citation

Search