Isabella Canazza1, Andrea Ossato1, Claudio Trapella2, Anna Fantinati2, Maria Antonietta De Luca3, Giulia Margiani3, Fabrizio Vincenzi4, Claudia Rimondo5, Fabiana Di Rosa6, Adolfo Gregori6, Katia Varani4, Pier Andrea Borea4, Giovanni Serpelloni7, Matteo Marti8,9. 1. Department of Life Sciences and Biotechnology (SVeB), University of Ferrara, via Fossato di Mortara 17-19, 44121, Ferrara, Italy. 2. Department of Chemistry and Pharmaceutical Sciences, University of Ferrara, Ferrara, Italy. 3. Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy. 4. Department of Medical Sciences, University of Ferrara, Ferrara, Italy. 5. Department of Diagnostic and Public Health, University of Verona, Verona, Italy. 6. Department of Scientific Investigation (RIS), Carabinieri, 00191, Rome, Italy. 7. U.R.I.To.N., Forensic Toxicology Unit, Department of Health Science, University of Florence, Florence, Italy. 8. Department of Life Sciences and Biotechnology (SVeB), University of Ferrara, via Fossato di Mortara 17-19, 44121, Ferrara, Italy. m.marti@unife.it. 9. Center for Neuroscience and Istituto Nazionale di Neuroscienze, ᅟ, Italy. m.marti@unife.it.
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.
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 humanCB1 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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