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\begin{document}

\title{Sex-specific behavioural, metabolic and immunohistochemical changes
after repeated administration of the synthetic cannabinoid AKB48 in mice}



\author[1]{Giorgia Corli}%
\author[2]{Elisa Roda}%
\author[1]{Micaela Tirri}%
\author[1]{Sabrine Bilel}%
\author[3]{Fabrizio De Luca }%
\author[4]{Sabina Strano Rossi}%
\author[1]{Rosa Maria Gaudio}%
\author[4]{Fabio De Giorgio}%
\author[5]{Liana Fattore}%
\author[2]{Carlo Alessandro Locatelli }%
\author[1]{Matteo Marti}%
\affil[1]{University of Ferrara}%
\affil[2]{Istituti Clinici Scientifici Maugeri SpA IRCCS Pavia}%
\affil[3]{University of Milan}%
\affil[4]{Catholic University of the Sacred Heart - Rome Campus}%
\affil[5]{CNR Neuroscience Institute}%


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  \date{May 28, 2024}


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\begin{abstract}
AKB48 is a synthetic cannabinoid illegally sold for its psychoactive
cannabis-like effects that has been associated to several acute
intoxications and which effects are poorly known. Using a behavioural,
neurochemical and immunohistochemical approach we investigated the
pharmaco-toxicological effects, plasma pharmacokinetic and
neuroplasticity at cannabinoid CB1 receptor (CB1R) in the cerebellum and
cortex induced by repeated AKB48 administration in male and female mice.
The effects of AKB48 varied significantly depending on sex and length of
treatment. The 1st injection impaired sensorimotor responses and reduced
body temperature, analgesia, and breath rate at a greater extent in
females than in males, the 2nd injection induced stronger effects in
males while the 3rd injection of AKB48 induced weaker responses in both
sexes, suggesting the emergence of tolerance. The CB1R antagonist
NESS-0327 prevented the effects induced by repeated AKB48, confirming a
CB1R-mediated action of the drug. Blood AKB48 levels were higher in
females than in males and repeated administration caused a progressive
rise of AKB48 content in blood samples of both sexes, suggesting an
inhibitory effect on cytochrome activity. Finally, immunohistochemical
analysis revealed higher expression of CB1Rs in the cerebellum and
cortex of females, and a rapid CB1R downregulation in cerebellar and
cortical areas following repeated AKB48 injections, with neuroadaptation
occurring generally more rapidly in females than in males. We showed for
the first time that AKB48 effects significantly vary with prolonged use
and that sex affects the pharmacodynamic/pharmacokinetic responses to
its repeated administration, suggesting a sex-tailored approach in
managing AKB48-induced intoxication.%
\end{abstract}%



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