Sex-specific behavioural, metabolic, and immunohistochemical changes after repeated administration of the synthetic cannabinoid AKB48 in mice.

Autor: Corli G; Department of Translational Medicine, Section of Legal Medicine and LTTA Centre, University of Ferrara, Ferrara, Italy., Roda E; Laboratory of Clinical & Experimental Toxicology, Pavia Poison Centre, National Toxicology Information Centre, Toxicology Unit, Istituti Clinici Scientifici Maugeri, IRCCS, Pavia, Italy., Tirri M; Department of Translational Medicine, Section of Legal Medicine and LTTA Centre, University of Ferrara, Ferrara, Italy., Bilel S; Department of Translational Medicine, Section of Legal Medicine and LTTA Centre, University of Ferrara, Ferrara, Italy., De Luca F; Department of Veterinary Medicine and Animal Sciences (DIVAS), University of Milan, Lodi, Italy., Strano-Rossi S; Institute of Public Health, Section of Legal Medicine, Catholic University of Rome, Rome, Italy., Gaudio RM; Department of Translational Medicine, Section of Legal Medicine and LTTA Centre, University of Ferrara, Ferrara, Italy.; University Center of Gender Medicine, University of Ferrara, Ferrara, Italy., De-Giorgio F; Department of Health Care Surveillance and Bioethics, Section of Legal Medicine, Università Cattolica del Sacro Cuore, Rome, Italy.; Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy., Fattore L; National Research Council, CNR Institute of Neuroscience-Cagliari, Cagliari, Italy., Locatelli CA; Laboratory of Clinical & Experimental Toxicology, Pavia Poison Centre, National Toxicology Information Centre, Toxicology Unit, Istituti Clinici Scientifici Maugeri, IRCCS, Pavia, Italy., Marti M; Department of Translational Medicine, Section of Legal Medicine and LTTA Centre, University of Ferrara, Ferrara, Italy.; Department of Anti-Drug Policies, Presidency of the Council of Ministers, Collaborative Center for the Italian National Early Warning System, Rome, Italy.
Jazyk: angličtina
Zdroj: British journal of pharmacology [Br J Pharmacol] 2024 May; Vol. 181 (9), pp. 1361-1382. Date of Electronic Publication: 2024 Jan 19.
DOI: 10.1111/bph.16311
Abstrakt: Background and Purpose: AKB48 is a synthetic cannabinoid illegally sold for its psychoactive cannabis-like effects that have been associated with acute intoxication and whose effects are poorly known.
Experimental Approach: Using a behavioural, neurochemical, and immunohistochemical approach, we investigated the pharmaco-toxicological effects, pharmacokinetics, and neuroplasticity at cannabinoid CB 1 receptors in the cerebellum and cortex induced by repeated AKB48 administration in male and female mice.
Key Results: The effects of AKB48 varied significantly depending on sex and treatment duration. The first injection impaired sensorimotor responses and reduced body temperature, analgesia, and breath rate to a greater extent in females than in males; the second injection induced stronger effects in males while the third injection of AKB48 induced weaker responses in both sexes, suggesting emergence of tolerance. The CB 1 receptor antagonist NESS-0327 prevented the effects induced by repeated AKB48, confirming a CB 1 receptor-mediated action. Blood AKB48 levels were higher in females than in males and repeated administration caused a progressive rise of AKB48 levels in both sexes, suggesting an inhibitory effect on cytochrome activity. Finally, immunohistochemical analysis revealed higher expression of CB 1 receptors in the cerebellum and cortex of females, and a rapid CB 1 receptor down-regulation in cerebellar and cortical areas following repeated AKB48 injections, with neuroadaptation occurring generally more rapidly in females than in males.
Conclusion and Implications: We have shown for the first time that AKB48 effects significantly vary with prolonged use and that sex affects the pharmacodynamic/pharmacokinetic responses to repeated administration, suggesting a sex-tailored approach in managing AKB48-induced intoxication.
(© 2023 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)
Databáze: MEDLINE
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