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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

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Abstract

Rationale

AKB48 and its fluorinate derivate 5F-AKB48 are two novel synthetic cannabinoids belonging to a structural class with an indazole core structure. They are marketed as incense, herbal preparations or chemical supply for their psychoactive Cannabis-like effects.

Objectives

The present study was aimed at investigating the in vitro and in vivo pharmacological activity of AKB48 and 5F-AKB48 in male CD-1 mice and comparing their in vivo effects with those caused by the administration of Δ9-THC and JWH-018.

Results

In vitro competition binding experiments performed on mouse and human CB1 and CB2 receptors revealed a nanomolar affinity and potency of the AKB48 and 5F-AKB48. In vivo studies showed that AKB48 and 5F-AKB48, induced hypothermia, increased pain threshold to both noxious mechanical and thermal stimuli, caused catalepsy, reduced motor activity, impaired sensorimotor responses (visual, acoustic and tactile), caused seizures, myoclonia, hyperreflexia and promoted aggressiveness in mice. Moreover, microdialysis study in freely moving mice showed that systemic administration of AKB48 and 5F-AKB48 stimulated dopamine release in the nucleus accumbens. Behavioural, neurological and neurochemical effects were fully prevented by the selective CB1 receptor antagonist/inverse agonist AM 251.

Conclusions

For the first time, the present study demonstrates the overall pharmacological effects induced by the administration of AKB48 and 5F-AKB48 in mice and suggests that the fluorination can increase the power and/or effectiveness of SCBs. Furthermore, this study outlines the potential detrimental effects of SCBs on human health.

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Abbreviations

AM 251:

1-(2,4-Dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide

AKB48:

N-(1-Adamantyl)-1-pentyl-1H-indazole-3-carboxamide

DA:

Dopamine

NAc shell:

Nucleus accumbens shell

Δ9-THC:

(−)-Δ9-THC or Dronabinol®

JWH-018:

Naphthalen-1-yl-(1-pentylindol-3-yl)methanone

5F-AKB48:

N-(1-Adamantyl)-1-(5-fluoropentyl)-1H-indazole-3- carboxamide

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Acknowledgments

This research has been funded by the Drug Policies Department, Presidency of the Council of Ministers, Italy (project NS-Drugs to M. Marti) and by local funds from the University of Ferrara to M. Marti. All applicable international, national and/or institutional guidelines for the care and use of animals were followed. All procedures performed in the studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

Author information

Authors and Affiliations

  1. Department of Life Sciences and Biotechnology (SVeB), University of Ferrara, via Fossato di Mortara 17-19, 44121, Ferrara, Italy

    Isabella Canazza, Andrea Ossato & Matteo Marti

  2. Department of Chemistry and Pharmaceutical Sciences, University of Ferrara, Ferrara, Italy

    Claudio Trapella & Anna Fantinati

  3. Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy

    Maria Antonietta De Luca & Giulia Margiani

  4. Department of Medical Sciences, University of Ferrara, Ferrara, Italy

    Fabrizio Vincenzi, Katia Varani & Pier Andrea Borea

  5. Department of Diagnostic and Public Health, University of Verona, Verona, Italy

    Claudia Rimondo

  6. Department of Scientific Investigation (RIS), Carabinieri, 00191, Rome, Italy

    Fabiana Di Rosa & Adolfo Gregori

  7. U.R.I.To.N., Forensic Toxicology Unit, Department of Health Science, University of Florence, Florence, Italy

    Giovanni Serpelloni

  8. Center for Neuroscience and Istituto Nazionale di Neuroscienze, ᅟ, Italy

    Matteo Marti

Authors
  1. Isabella Canazza
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  2. Andrea Ossato
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  3. Claudio Trapella
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  4. Anna Fantinati
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  5. Maria Antonietta De Luca
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  6. Giulia Margiani
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  7. Fabrizio Vincenzi
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  8. Claudia Rimondo
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  9. Fabiana Di Rosa
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  10. Adolfo Gregori
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  11. Katia Varani
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  12. Pier Andrea Borea
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  13. Giovanni Serpelloni
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  14. Matteo Marti
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Corresponding author

Correspondence to Matteo Marti.

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Conflict of interest

The authors have no conflict of interest to declare.

Additional information

Isabella Canazza and Andrea Ossato are equally contributed to this work.

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Canazza, I., Ossato, A., Trapella, C. et al. 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 233, 3685–3709 (2016). https://doi.org/10.1007/s00213-016-4402-y

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  • DOI: https://doi.org/10.1007/s00213-016-4402-y

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