In contrast, contingent operant self-administration models allow to directly evaluate a drug’s reinforcing property with a high predictive value to model voluntary drug consumption in humans. Non-contingent drug administration animal models were firstly developed to evaluate short and long-lasting changes after exposure to a drug ( Panlilio et al., 1998). At the present moment, animal models of cannabinoid addiction have not been yet developed, and there is an urgent need of an accurate animal model to disentangle the neurobiological correlates of addiction to cannabinoids.Īnimal models of drug exposure allow to investigate brain long-lasting changes produced by drugs of abuse. Although multiple neuroadaptations induced by cannabinoids administration have been described, the precise neurobiological mechanisms underlying cannabinoid addiction in vulnerable individuals remain largely unknown. Not all individuals repeatedly exposed to the drug make this transition to addiction ( Piazza and Deroche-Gamonet, 2013), raising the question of why some vulnerable individuals become addicted while others are resilient. In this edition, the term addiction is synonymous with severe substance-use disorder and requires the accomplishment of six out of eleven diagnostic criteria ( Koob and Volkow, 2016).Ĭannabis addiction results from the interaction between gene networks, epigenetics, and socio-environmental factors ( Piazza and Deroche-Gamonet, 2013 Hamilton and Nestler, 2019 Lüscher et al., 2020 Maldonado et al., 2021). Ĭannabis use disorder is defined as a chronically relapsing neuropsychiatric disorder diagnosed by applying the criteria defined in the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). This lack of risk perception has led to an increase in the prevalence of cannabis use disorder, previously defined as cannabis dependence ( Zehra et al., 2018). However, attitudes toward cannabis use have softened since there is a growing social perception that cannabis is relatively harmless ( Weiss and Volkow, 2022). In Europe, cannabis use has enhanced from 5.7% in 2015 to 7.7% in 2022 in adults aged from 15 to 64 ( European Monitoring Centre for Drugs and Drug Addiction, 2015 European Monitoring Centre for Drugs and Drug Addiction, 2022). This model will shed light on the neurobiological substrate underlying cannabinoid addiction.Ĭannabis sativa derivatives are the most used illicit drugs worldwide, with an increased consumption over the recent years. This model included the chemogenetic inhibition of neuronal activity in the medial prefrontal cortex to the nucleus accumbens pathway to assess the neurobiological substrate of cannabinoid addiction. Therefore, we have established a novel and reliable model to study the neurobiological correlates underlying the resilience or vulnerability to develop cannabinoid addiction. We found that 35.6% of mice developed the criteria of cannabinoid addiction, allowing to differentiate between resilient and vulnerable mice. This model also allows to measure two parameters that have been related with the DSM-5 diagnostic criteria of craving, resistance to extinction and reinstatement, and two phenotypic traits suggested as predisposing factors, impulsivity and sensitivity to reward. This model allows to evaluate the addiction criteria by grouping them into 1) persistence of response during a period of non-availability of the drug, 2) motivation for WIN 55,212–2 with a progressive ratio, and 3) compulsivity when the reward is associated with a punishment such as an electric foot-shock, in agreement with the Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-5). We have established for the first time a mouse model of cannabinoid addiction using WIN 55,212–2 intravenous self-administration (0.0125 mg/kg/infusion) in C57Bl/6J mice. 3Departament de Psicobiologia i Metodologia de les Ciències de la Salut, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.2Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain.1Laboratory of Neuropharmacology-Neurophar, Department of Medicine and Life Sciences, Universitat Pompeu Fabra (UPF), Barcelona, Spain.María del Mar Cajiao-Manrique 1 Rafael Maldonado 1,2* † Elena Martín-García 1,2,3* †
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