Menu

Synthetic cannabinoid JWH-073 alters both acute behavior and in vivo/vitro electrophysiological responses in mice

Abstract

JWH-073 is a synthetic cannabinoid (SCB) that is illegally marketed within an “herbal blend”, causing psychoactive effects more intense than those produced by Cannabis. Users report that JWH-073 causes less harmful effects than other SCBs, misrepresenting it as a “safe JWH-018 alternative”, which in turn prompts its recreational use. The present study is aimed to investigate the in vivo pharmacological activity on physiological and neurobehavioral parameters in male CD-1 mice after acute 1 mg/kg JWH-073 administration. To this aim we investigate its effect on sensorimotor (visual, acoustic, and tactile), motor (spontaneous motor activity and catalepsy), and memory functions (novel object recognition; NOR) in mice coupling behavioral and EEG data. Moreover, to clarify how memory function is affected by JWH-073, we performed in vitro electrophysiological studies in hippocampal preparations using a Long-Term Potentiation (LTP) stimulation paradigm. We demonstrated that acute administration of JWH-073 transiently decreased motor activity for up to 25 min and visual sensorimotor responses for up to 105 min, with the highest effects at 25 min (~48 and ~38%, respectively), while the memory function was altered up to 24 h (~33%) in treated-mice as compared to the vehicle. EEG in the somatosensory cortex showed a maximal decrease of α (~23%) and γ (~26%) bands at 15 min, β (~26%) band at 25 min, a maximal increase of θ (~14%) band at 25 min and δ (~35%) band at 2 h, and a significant decrease of θ (~18%), α (~26%), and β (~10%) bands during 24 h. On the other hand, EEG in the hippocampus showed a significant decrease of all bands from 10 min to 2 h, with the maximal effect at 30 min for θ (~34%) and γ (~26%) bands and 2 h for α (~36%), β (~29%), and δ (~15%) bands. Notably, the δ band significant increase both at 5 min (~12%) and 24 h (~19%). Moreover, in vitro results support cognitive function impairment (~60% of decrease) by interfering with hippocampal synaptic transmission and LTP generation. Our results suggest that JWH-073 deeply alters brain electrical responsiveness with minor behavioral symptoms. Thus, it poses a subtle threat to consumers who mistakenly consider it safer than other SCBs.

Article type: Research Article

Keywords: JWH-073, JWH-018, synthetic cannabinoids, NOR, hippocampus, cortex, electrophysiology, NPS

Authors: Mario Barbieri, Micaela Tirri, Sabrine Bilel, Raffaella Arfè, Giorgia Corli, Beatrice Marchetti, Lorenzo Caruso, Marie Soukupova, Virginia Cristofori, Giovanni Serpelloni, Matteo Marti

Affiliations: Department of Neuroscience and Rehabilitation, University of Ferrara, Ferrara, Italy; Department of Translational Medicine, Section of Legal Medicine and Laboratory for Technologies of Advanced Therapies (LTTA) Centre, University of Ferrara, Ferrara, Italy; Department of Environment and Prevention Sciences, University of Ferrara, Ferrara, Italy; Department of Chemistry and Pharmaceutical Sciences, University of Ferrara, Ferrara, Italy; Neuroscience Clinical Center and Transcranial Magnetic Stimulation (TMS) Unit, Verona, Italy; Department for Anti-Drug Policies, Collaborative Center of the National Early Warning System, Presidency of the Council of Ministers, Rome, Italy

License: Copyright © 2022 Barbieri, Tirri, Bilel, Arfè, Corli, Marchetti, Caruso, Soukupova, Cristofori, Serpelloni and Marti. CC BY 4.0 This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Article links: DOI: 10.3389/fpsyt.2022.953909  |  PubMed: 36339851  |  PMC: PMC9634257

Relevance: Moderate: mentioned 3+ times in text

Full text: PDF (4.7 MB)

References

  1. MA Eissenstat, MR Bell, TE D’Ambra, EJ Alexander, SJ Daum, JH Ackerman. Aminoalkylindoles: structure-activity relationships of novel cannabinoid mimetics.. J Med Chem. (, 1995. [DOI | PubMed]
  2. JL Wiley, DR Compton, D Dai, JA Lainton, M Phillips, JW Huffman. Structure-activity relationships of indole- and pyrrole-derived cannabinoids.. J Pharmacol Exp Ther. (, 1998. [PubMed]
  3. MM Aung, G Griffin, JW Huffman, M Wu, C Keel, B Yang. Influence of the N-1 alkyl chain length of cannabimimetic indoles upon CB(1) and CB(2) receptor binding.. Drug Alcohol Depend. (, 2000. [DOI | PubMed]
  4. LK Brents, A Gallus-Zawada, A Radominska-Pandya, T Vasiljevik, TE Prisinzano, WE Fantegrossi. Monohydroxylated metabolites of the K2 synthetic cannabinoid JWH-073 retain intermediate to high cannabinoid 1 receptor (CB1R) affinity and exhibit neutral antagonist to partial agonist activity.. Biochem Pharmacol. (, 2012. [DOI | PubMed]
  5. A Ossato, I Canazza, C Trapella, F Vincenzi, MA De Luca, C Rimondo. Effect of JWH-250, JWH-073 and their interaction on “tetrad”, sensorimotor, neurological and neurochemical responses in mice.. Prog Neuropsychopharmacol Biol Psychiatry. (, 2016. [DOI | PubMed]
  6. F Grotenhermen. Pharmacokinetics and pharmacodynamics of cannabinoids.. Clin Pharmacokinet. (, 2003. [DOI | PubMed]
  7. S Tai, WE Fantegrossi. Pharmacological and toxicological effects of synthetic, cannabinoids and their metabolites.. Curr Top Behav Neurosci. (, 2017. [DOI | PubMed]
  8. CJ Lucas, P Galettis, J Schneider. The pharmacokinetics and the pharmacodynamics of cannabinoids.. Br J Clin Pharmacol. (, 2018. [DOI | PubMed]
  9. R Lindigkeit, A Boehme, I Eiserloh, M Luebbecke, M Wiggermann, L Ernst. For Sci Int., 2009. [DOI | PubMed]
  10. LK Brents, SM Zimmerman, AR Saffell, PL Prather, WE Fantegrossi. Differential drug-drug interactions of the synthetic Cannabinoids JWH-018 and JWH- 073: implications for drug abuse liability and pain therapy.. J Pharmacol Exp Ther. (, 2013. [DOI | PubMed]
  11. BK Atwood, D Lee, A Straiker, TS Widlanski, K Mackie. CP47,497-C8 and JWH-073, commonly found in ‘Spice’ herbal blends, are potent and efficacious CB(1) cannabinoid receptor agonists.. Eur J Pharmacol. (, 2011. [DOI | PubMed]
  12. N Uchiyama, R Kikura-Hanajiri, J Ogata, Y Goda. Chemical analysis of synthetic cannabinoids as designer drugs in herbal products.. Forensic Sci Int. (, 2010. [DOI | PubMed]
  13. V Auwärter, S Dresen, W Weinmann, M Müller, M Pütz, N Ferreirós. ‘Spice’ and other herbal blends: harmless incense or cannabinoid designer drugs?.. J Mass Spectromet. (, 2009. [DOI | PubMed]
  14. D Papanti, F Schifano, G Botteon, F Bertossi, J Mannix, D Vidoni. “Spiceophrenia”: a systematic overview of “spice”-related psychopathological issues and a case report.. Hum Psychopharmacol. (, 2013. [DOI | PubMed]
  15. M Hermanns-Clausen, S Kneisel, B Szabo, V Auwärter. Acute toxicity due to the confirmed consumption of synthetic cannabinoids: clinical and laboratory findings.. Addiction. (, 2013. [DOI | PubMed]
  16. JB Zawilska, J Wojcieszak. Spice/K2 drugs–more than innocent substitutes for marijuana.. Int J Neuropsychopharmacol. (, 2014. [DOI | PubMed]
  17. EY Chung, HJ Cha, HK Min, J Yun. Pharmacology and adverse effects of new psychoactive substances: synthetic cannabinoid receptor agonists.. Arch Pharm Res. (, 2021. [DOI | PubMed]
  18. L Martínez, N La Maida, E Papaseit, C Pérez-Mañá, L Poyatos, M Pellegrini. Acute pharmacological effects and oral fluid concentrations of the synthetic cannabinoids JWH-122 and JWH-210 in humans after self-administration: an observational study.. Front Pharmacol. 12:705643., 2021. [DOI | PubMed]
  19. F Schifano, F Napoletano, S Chiappini, A Guirguis, JM Corkery, S Bonaccorso. New/emerging psychoactive substances and associated psychopathological consequences.. Psychol Med. (, 2021. [DOI | PubMed]
  20. H Müller, W Sperling, M Köhrmann, H Huttner, J Kornhuber, J Maler. The synthetic cannabinoid Spice as a trigger for an acute exacerbation of cannabis induced recurrent psychotic episodes.. Schizophr Res. (, 2010. [DOI | PubMed]
  21. SM Gurney, KS Scott, SL Kacinko, BC Presley, BK Logan. Pharmacology, toxicology, and adverse effects of synthetic cannabinoid drugs.. For Sci Rev. (, 2014. [PubMed]
  22. CS Breivogel, JR Wells, A Jonas, AH Mistry, ML Gravley, RM Patel. Comparison of the neurotoxic and seizure-inducing effects of synthetic and endogenous cannabinoids with Δ9-tetrahydrocannabinol.. Cannabis Cannabinoid Res. (, 2020. [DOI | PubMed]
  23. R Marshell, T Kearney-Ramos, LK Brents, WS Hyatt, S Tai, PL Prather. In vivo effects of synthetic cannabinoids JWH-018 and JWH- 073 and phytocannabinoid Delta-THC in mice: inhalation versus intraperitoneal injection.. Pharmacol Biochem Behav. (, 2014. [DOI | PubMed]
  24. L Uttl, E Szczurowska, K Hájková, RR Horsley, K Štefková, T HloŽek. Behavioral and pharmacokinetic profile of indole-derived synthetic cannabinoids JWH-073 and JWH-210 as compared to the phytocannabinoid Δ9-THC in rats.. Front Neurosci. (, 2018. [DOI | PubMed]
  25. HJ Cha, KW Lee, MJ Song, YJ Hyeon, JY Hwang, CG Jang. Dependence potential of the synthetic cannabinoids JWH-073, JWH-081, and JWH-210: in vivo and in vitro approaches.. Biomol Ther. (, 2014. [DOI | PubMed]
  26. BC Ginsburg, DR Schulze, L Hruba, LR McMahon. JWH-018 and JWH-073: δ?-tetrahydrocannabinol-like discriminative stimulus effects in monkeys.. J Pharmacol Exp Ther. (, 2012. [DOI | PubMed]
  27. K Gounder, J Dunuwille, J Dunne, J Lee, P Silbert, N Lawn. The other side of the leaf: Seizures associated with synthetic cannabinoid use.. Epilepsy Behav. (, 2020. [DOI | PubMed]
  28. RJ Croft, AJ Mackay, AT Mills, JG Gruzelier. The relative contributions of ecstasy and cannabis to cognitive impairment.. Psychopharmacology. (, 2001. [DOI | PubMed]
  29. M Barbieri, A Ossato, I Canazza, C Trapella, AC Borelli, S Beggiato. Synthetic cannabinoid JWH-018 and its halogenated derivatives JWH-018-Cl and JWH-018-Br impair novel object recognition in mice: behavioral, electrophysiological and neurochemical evidence.. Neuropharmacology. (, 2016. [DOI | PubMed]
  30. S Malaca, FP Busardò, G Nittari, A Sirignano, G Ricci. Fourth generation of synthetic cannabinoid receptor agonists: A review on the latest insights.. Curr Pharm Des. (, 2021. [DOI | PubMed]
  31. A Giorgetti, FP Busardò, R Tittarelli, V Auwärter, R Giorgetti. Post-mortem toxicology: a systematic review of death cases involving synthetic cannabinoid receptor agonists.. Front Psychiatry. (, 2020. [DOI | PubMed]
  32. S Kumar, TR Baggi. Analytical methods for herbal products containing synthetic cannabinoids: a review.. For Chem. (, 2021. [DOI]
  33. S Akgönüllü, D Battal, MS Yalcin, H Yavuz, A Denizli. Rapid and sensitive detection of synthetic cannabinoids JWH-018, JWH-073 and their metabolites using molecularly imprinted polymer-coated QCM nanosensor in artificial saliva.. Microchem J. (, 2019. [DOI]
  34. DR Collins, RG Pertwee, SN Davies. The action of synthetic cannabinoids on the induction of long-term potentiation in the rat hippocampal slice.. Eur J Pharmacol. (, 1994. [DOI | PubMed]
  35. AF Hoffman, MD Lycas, JR Kaczmarzyk, CE Spivak, MH Baumann, CR Lupica. Disruption of hippocampal synaptic transmission and long-term potentiation by psychoactive synthetic cannabinoid ‘Spice’ compounds: comparison with δ9 – tetrahydrocannabinol.. Addict Biol. (, 2017. [DOI | PubMed]
  36. A Ossato, A Vigolo, C Trapella, C Seri, C Rimondo, G Serpelloni. JWH-018 impairs sensorimotor functions in mice.. Neuroscience. (, 2015. [DOI | PubMed]
  37. M Marti, M Neri, S Bilel, MD Paolo, RL Russa, A Ossato. MDMA alone affects sensorimotor and prepulse inhibition responses in mice and rats: tips in the debate on potential MDMA unsafety in human activity.. Forensic Toxicol. (, 2019. [DOI]
  38. S Bilel, M Tirri, R Arfè, A Ossato, C Trapella, G Serpelloni. Novel halogenated synthetic cannabinoids impair sensorimotor functions in mice.. Neurotoxicology. (, 2020. [DOI | PubMed]
  39. R Arfè, S Bilel, M Tirri, P Frisoni, G Serpelloni, M Neri. Comparison of N-methyl-2-pyrrolidone (NMP) and the “date rape” drug GHB: behavioral toxicology in the mouse model.. Psychopharmacology. (, 2021. [DOI | PubMed]
  40. R Morini, B Mlinar, G Baccini, R Corradetti. Enhanced hippocampal long- term potentiation following repeated MDMA treatment in Dark-Agouti rats.. Eur Neuropsychopharmacol. (, 2011. [DOI | PubMed]
  41. SS Spencer, J Kim, DD Spencer. Ictal spikes: a marker of specific hippocampal cell loss.. Electroencephalogr Clin Neurophysiol. (, 1992. [DOI | PubMed]
  42. RJ Racine. Modification of seizure activity by electrical stimulation. II. Motor seizure.. Electroencephalogr Clin Neurophysiol. (, 1972. [DOI | PubMed]
  43. O Benoit, A Daurat, J Prado. Slow (0.7–2 Hz) and fast (2–4 Hz) delta components are differently correlated to theta, alpha and beta frequency bands during NREM sleep.. Clin Neurophysiol. (, 2000. [DOI | PubMed]
  44. A White, PA Williams, JL Hellier, S Clark, FE Dudek, KJ Staley. EEG spike activity precedes epilepsy after kainate-induced status epilepticus.. Epilepsia. (, 2010. [DOI | PubMed]
  45. K Misulis. Atlas of EEG, Seizure Semiology, and Management., 2013
  46. O Grinenko, J Li, JC Mosher, IZ Wang, JC Bulacio, J Gonzalez-Martinez. A fingerprint of the epileptogenic zone in human epilepsies.. Brain. (, 2018. [DOI | PubMed]
  47. F Musshoff, B Madea, G Kernbach-Wighton, W Bicker, S Kneisel, M Hutter. Driving under the influence of synthetic cannabinoids (“Spice”): a case series.. Int J Legal Med. (, 2014. [DOI | PubMed]
  48. EL Theunissen, JT Reckweg, NRPW Hutten, KPC Kuypers, SW Toennes, MA Neukamm. Intoxication by a synthetic cannabinoid (JWH-018) causes cognitive and psychomotor impairment in recreational cannabis users.. Pharmacol Biochem Behav. (, 2021. [DOI | PubMed]
  49. S Ito, S Deyama, M Domoto, T Zhang, H Sasase, A Fukao. Effects of the synthetic cannabinoid 5F-AMB on anxiety and recognition memory in mice.. Psychopharmacology. (, 2019. [DOI | PubMed]
  50. S Tai, WS Hyatt, C Gu, LN Franks, T Vasiljevik, LK Brents. Repeated administration of phytocannabinoid δ(9)-THC or synthetic cannabinoids JWH-018 and JWH-073 induces tolerance to hypothermia but not locomotor suppression in mice, and reduces CB1 receptor expression and function in a brain region-specific manner.. Pharmacol Res. (, 2015. [DOI | PubMed]
  51. SB Baltaci, R Mogulkoc, AK Baltaci. Molecular mechanisms of early and late LTP.. Neurochem Res. (, 2019. [DOI | PubMed]
  52. D Robbe, SM Montgomery, A Thome, PE Rueda-Orozco, BL McNaughton, G Buzsaki. Cannabinoids reveal importance of spike timing coordination in hippocampal function.. Nat Neurosci. (, 2006. [DOI | PubMed]
  53. E Schlicker, M Kathmann. Modulation of transmitter release via presynaptic cannabinoid receptors.. Trends Pharmacol Sci. (, 2001. [DOI | PubMed]
  54. AB Ilan, A Gevins, M Coleman, MA ElSohly, H de Wit. Neurophysiological and subjective profile of marijuana with varying concentrations of cannabinoids.. Behav Pharmacol. (, 2005. [DOI | PubMed]
  55. M Matsuzaki, GA Casella, M Ratner. delta 9-Tetrahydrocannabinol: EEG changes, bradycardia and hypothermia in the rhesus monkey.. Brain Res Bull. (, 1987. [DOI | PubMed]
  56. M Buonamici, GA Young, N Khazan. Effects of acute δ9-THC administration of EEG and EEG power spectra in the rat.. Neuropharmacology. (, 1982. [DOI | PubMed]
  57. N Uchiyama, R Kikura-Hanajiri, N Matsumoto, ZL Huang, Y Goda, Y Urade. Effects of synthetic cannabinoids on electroencephalogram power spectra in rats, For Sci Int. (. 2012. [DOI | PubMed]
  58. MT Kucewicz, MD Tricklebank, R Bogacz, MW Jones. Dysfunctional prefrontal cortical network activity and interactions following cannabinoid receptor activation.. J Neurosci. (, 2011. [DOI | PubMed]
  59. SM Raver, SP Haughwout, A Keller. Adolescent cannabinoid exposure permanently suppresses cortical oscillations in adult mice.. Neuropsychopharmacology. (, 2013. [DOI | PubMed]
  60. M Hajós, WE Hoffmann, B Kocsis. Activation of cannabinoid-1 receptors disrupts sensory gating and neuronal oscillation: relevance to schizophrenia.. Biol Psychiatry. (, 2008. [DOI | PubMed]
  61. PD Skosnik, JA Cortes-Briones, M Hajós. It’s all in the rhythm: the role of cannabinoids in neural oscillations and psychosis.. Biol Psychiatry. (, 2016. [DOI | PubMed]
  62. PD Skosnik, M Hajós, JA Cortes-Briones, CR Edwards, BP Pittman, WE Hoffmann. Cannabinoid receptor- mediated disruption of sensory gating and neural oscillations: a translational study in rats and humans.. Neuropharmacology. (, 2018. [DOI | PubMed]
  63. JA Hobson, EF Pace-Schott. The cognitive neuroscience of sleep: neuronal systems, consciousness and learning.. Nat Rev Neurosci. (, 2002. [DOI | PubMed]
  64. Y Zhang, RR Llinas, JE Lisman. Inhibition of NMDARs in the nucleus reticularis of the thalamus produces delta frequency bursting.. Front Neural Circuits. (, 2009. [DOI | PubMed]
  65. R Sutter, PW Kaplan. Electroencephalographic patterns in coma: when things slow down.. Epileptologie. (, 2012
  66. WE Fantegrossi, CD Wilson, MD Berquist. Pro-psychotic effects of synthetic cannabinoids: interactions with central dopamine, serotonin, and glutamate systems.. Drug Metab Rev. (, 2018. [DOI | PubMed]
  67. MA Sherif, JA Cortes-Briones, M Ranganathan, PD Skosnik. Cannabinoid- glutamate interactions and neural oscillations: implications for psychosis.. Eur J Neurosci. (, 2018. [DOI | PubMed]
  68. MP Kirkpatrick, CD Clarke, HH Sonmezturk, B Abou-Khalil. Rhythmic delta activity represents a form of nonconvulsive status epilepticus in anti-NMDA receptor antibody encephalitis.. Epilepsy Behav. (, 2011. [DOI | PubMed]
  69. SE Schmitt, K Pargeon, ES Frechette, LJ Hirsch, J Dalmau, D Friedman. Extreme delta brush: a unique EEG pattern in adults with anti-NMDA receptor encephalitis.. Neurology. (, 2012. [DOI | PubMed]
  70. A Vigolo, A Ossato, C Trapella, F Vincenzi, C Rimondo, C Seri. Novel halogenated derivates of JWH-018: Behavioral and binding studies in mice.. Neuropharmacology. (, 2015. [DOI | PubMed]
  71. I Canazza, A Ossato, C Trapella, A Fantinati, MA De Luca, G Margiani. Effect of the novel synthetic cannabinoids AKB48 and 5F-AKB48 on “tetrad”, sensorimotor, neurological and neurochemical responses in mice. In vitro and in vivo pharmacological studies.. Psychopharmacology. (, 2016. [DOI | PubMed]
  72. GG Supp, M Siegel, JF Hipp, AK Engel. Cortical hypersynchrony predicts breakdown of sensory processing during loss of consciousness.. Curr Biol. (, 2011. [DOI | PubMed]
  73. A Nuñez, W Buño. The theta rhythm of the hippocampus: from neuronal and circuit mechanisms to behavior.. Front Cell Neurosci. (, 2021. [DOI | PubMed]
  74. J Cortes-Briones, PD Skosnik, D Mathalon, J Cahill, B Pittman, A Williams. δ9-THC disrupts gamma (γ)-band neural oscillations in humans.. Neuropsychopharmacology. (, 2015. [DOI | PubMed]
  75. A Robledo-Menendez, M Vella, P Grandes, E Soria-Gomez. Cannabinoid control of hippocampal functions: the where matters.. FEBS J. (, 2022. [DOI | PubMed]
  76. LCS Tavares, ABL Tort. Hippocampal-prefrontal interactions during spatial decision- making.. Hippocampus. (, 2022. [DOI | PubMed]
  77. CM Hernandez, CA Orsini, SL Blaes, JL Bizon, M Febo, AW Bruijnzeel. Effects of repeated adolescent exposure to cannabis smoke on cognitive outcomes in adulthood.. J Psychopharmacol. (, 2021. [DOI | PubMed]
  78. 78.World Health Organization. Expert Committee on Drug Dependence Thirty-eight Meeting. JWH-073 Critical Review Report Agenda item 4.11 Geneva, 14−18 November 2016. Geneva (2016).
  79. M De Curtis, G Avanzini. Interictal spikes in focal epileptogenesis.. Prog Neurobiol. (, 2001. [DOI | PubMed]
  80. N Maida, E Papaseit, L Martínez, C Pérez-Mañá, L Poyatos, M Pellegrini. Acute pharmacological effects and oral fluid biomarkers of the synthetic cannabinoid UR-144 and THC in recreational users.. Biology. (, 2021. [DOI | PubMed]

Related Posts

The content on this platform is provided for informational and educational purposes only and does not constitute medical advice, diagnosis, or treatment. Always consult a qualified healthcare professional before making any health-related decisions.