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Cannabidiol Prevents the Expression of the Locomotor Sensitization and the Metabolic Changes in the Nucleus Accumbens and Prefrontal Cortex Elicited by the Combined Administration of Cocaine and Caffeine in Rats

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Abstract

In the last years, clinical and preclinical researchers have increased their interest in non-psychotomimetic cannabinoids, like cannabidiol (CBD), as a strategy for treating psychostimulant use disorders. However, there are discrepancies in the pharmacological effects and brain targets of CBD. We evaluated if CBD was able to prevent the locomotor sensitization elicited by cocaine and caffeine co-administration. The effect of CBD on putative alterations in the metabolic activity of the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc), and its respective subregions (cingulated, prelimbic, and infralimbic cortices, and NAc core and shell) associated to the behavioral response, was also investigated. Rats were intraperitoneally and repeatedly treated with CBD (20 mg/kg) or its vehicle, followed by the combination of cocaine and caffeine (Coc+Caf; 5 mg/kg and 2.5 mg/kg, respectively) or saline for 3 days. After 5 days of withdrawal, all animals were challenged with Coc+Caf (day 9). Locomotor activity was automatically recorded and analyzed by a video-tracking software. The metabolic activity was determined by measuring cytochrome oxidase-I (CO-I) staining. Locomotion was significantly and similarly increased both in Veh-Coc+Caf- and CBD-Coc+Caf-treated animals during the pretreatment period (3 days); however, on day 9, the expression of the sensitization was blunted in CBD-treated animals. A hypoactive metabolic response and a hyperactive metabolic response in mPFC and NAc subregions respectively were observed after the behavioral sensitization. CBD prevented almost all these changes. Our findings substantially contribute to the understanding of the functional changes associated with cocaine- and caffeine-induced sensitization and the effect of CBD on this process.

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Acknowledgments

We are grateful to Prof. Kuei Y. Tseng for his remarkable help in the analysis of the results and to María Paula Latorre for her technical assistance.

Funding

This study was financially supported by ANII-FCE_3_2018_1_149210, Premio Concursable Junta Nacional de Drogas (Uruguay) and PEDECIBA (Uruguay). José Pedro Prieto has postgraduate fellowships from ANII (Uruguay) and CAP (Universidad de la República, Uruguay).

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Correspondence to Cecilia Scorza.

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All experimental procedures were conducted according to the National Animal Care Law (No. 18611) and the “Guide to the care and use of laboratory animals” (8th edition, National Academy Press, Washington DC, 2010). Furthermore, all experimental protocols had been approved by the IIBCE Animal Care Committee.

Conflict of Interest

Cannabidiol was donated by Phytoplant Research (Spain). Verónica Sanchez and Xavier Nadal both work for Phytoplant Research S.L.

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Prieto, J.P., López Hill, X., Urbanavicius, J. et al. Cannabidiol Prevents the Expression of the Locomotor Sensitization and the Metabolic Changes in the Nucleus Accumbens and Prefrontal Cortex Elicited by the Combined Administration of Cocaine and Caffeine in Rats. Neurotox Res 38, 478–486 (2020). https://doi.org/10.1007/s12640-020-00218-9

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