Pharmacological and Behavioral Effects of the Synthetic Cannabinoid AKB48 in Rats

Sabrine Bilel; Micaela Tirri; Raffaella Arfè; Serena Stopponi; Laura Soverchia; Roberto Ciccocioppo; Paolo Frisoni; Sabina Strano-Rossi; Cristina Miliano; Fabio De-Giorgio; Giovanni Serpelloni; Anna Fantinati; Maria Antonietta De Luca; Margherita Neri; Matteo Marti

doi:10.3389/fnins.2019.01163

Pharmacological and Behavioral Effects of the Synthetic Cannabinoid AKB48 in Rats

Front Neurosci. 2019 Oct 30:13:1163. doi: 10.3389/fnins.2019.01163. eCollection 2019.

Authors

Sabrine Bilel¹, Micaela Tirri¹, Raffaella Arfè^{1

2}, Serena Stopponi³, Laura Soverchia³, Roberto Ciccocioppo³, Paolo Frisoni¹, Sabina Strano-Rossi², Cristina Miliano⁴, Fabio De-Giorgio², Giovanni Serpelloni⁵, Anna Fantinati⁶, Maria Antonietta De Luca⁴, Margherita Neri¹, Matteo Marti^{1

7}

Affiliations

¹ Department of Morphology, Experimental Medicine and Surgery, Section of Legal Medicine and Laboratory for Technologies of Advanced Therapies (LTTA) Centre, University of Ferrara, Ferrara, Italy.
² Section of Legal Medicine, Institute of Public Health, Università Cattolica del Sacro Cuore, Rome, Italy.
³ Pharmacology Unit, School of Pharmacy, University of Camerino, Camerino, Italy.
⁴ Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
⁵ Department of Psychiatry in the College of Medicine, Drug Policy Institute, University of Florida, Gainesville, FL, United States.
⁶ Department of Chemistry and Pharmaceutical Sciences, University of Ferrara, Ferrara, Italy.
⁷ Department of Anti-Drug Policies, Presidency of the Council of Ministers, Collaborative Center for the Italian National Early Warning System, Ferrara, Italy.

Abstract

AKB48 is a designer drug belonging to the indazole synthetic cannabinoids class, illegally sold as herbal blend, incense, or research chemicals for their psychoactive cannabis-like effects. In the present study, we investigated the in vivo pharmacological and behavioral effects of AKB48 in male rats and measured the pharmacodynamic effects of AKB48 and simultaneously determined its plasma pharmacokinetic. AKB48 at low doses preferentially stimulated dopamine release in the nucleus accumbens shell (0.25 mg/kg) and impaired visual sensorimotor responses (0.3 mg/kg) without affecting acoustic and tactile reflexes, which are reduced only to the highest dose tested (3 mg/kg). Increasing doses (0.5 mg/kg) of AKB48 impaired place preference and induced hypolocomotion in rats. At the highest dose (3 mg/kg), AKB48 induced hypothermia, analgesia, and catalepsy; inhibited the startle/pre-pulse inhibition test; and caused cardiorespiratory changes characterized by bradycardia and mild bradipnea and SpO2 reduction. All behavioral and neurochemical effects were fully prevented by the selective CB₁ receptor antagonist/inverse agonist AM251. AKB48 plasma concentrations rose linearly with increasing dose and were correlated with changes in the somatosensory, hypothermic, analgesic, and cataleptic responses in rats. For the first time, this study shows the pharmacological and behavioral effects of AKB48 in rats, correlating them to the plasma levels of the synthetic cannabinoid. Chemical Compound Studied in This Article: AKB48 (PubChem CID: 57404063); AM251 (PubChem CID: 2125).

Keywords: AKB48; AM251; cardiorespiratory changes; conditioned place preference (CPP); microdialysis; prepulse inhibition (PPI); sensorimotor responses; synthetic cannabinoids.