A male mouse model of WIN 55,212-2 self-administration to study cannabinoid addiction

María Del Mar Cajiao-Manrique; Rafael Maldonado; Elena Martín-García

doi:10.3389/fphar.2023.1143365

A male mouse model of WIN 55,212-2 self-administration to study cannabinoid addiction

Front Pharmacol. 2023 Mar 27:14:1143365. doi: 10.3389/fphar.2023.1143365. eCollection 2023.

Authors

María Del Mar Cajiao-Manrique¹, Rafael Maldonado^{1

2}, Elena Martín-García^{1

2

3}

Affiliations

¹ Laboratory of Neuropharmacology-Neurophar, Department of Medicine and Life Sciences, Universitat Pompeu Fabra (UPF), Barcelona, Spain.
² Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain.
³ Departament de Psicobiologia i Metodologia de les Ciències de la Salut, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.

Abstract

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. 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). 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. We found that 35.6% of mice developed the criteria of cannabinoid addiction, allowing to differentiate between resilient and vulnerable mice. Therefore, we have established a novel and reliable model to study the neurobiological correlates underlying the resilience or vulnerability to develop cannabinoid addiction. 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. This model will shed light on the neurobiological substrate underlying cannabinoid addiction.

Keywords: WIN 55,212-2 self-administration; cannabinoid addiction; compulsive-like behavior; motivation; mouse model; persistence of response.

Grants and funding

This work was supported by the Spanish “Ministerio de Ciencia e Innovación (MICIN), Agencia Estatal de Investigación (AEI)” (PID2020- 120029GB-I00/MICIN/AEI/10.13039/501100011033, RD21/0009/0019, to MR; the “Generalitat de Catalunya, AGAUR” (2017 SGR-669, to MR; the “ICREA-Acadèmia” (2020) to MR; the “European Commission-DG Research” (PainFact, H2020-SC1-2019-2-RTD-848099, QSPain Relief, H2020-SC1-2019-2-RTD-848068) to MR; the Spanish ”la Caixa” Foundation under the project code LCF/PR/HR22/52420017 to MR, the Spanish “Instituto de Salud Carlos III, RETICS-RTA” (RD16/0017/0020) to MR; the Spanish “Ministerio de Sanidad, Servicios Sociales e Igualdad, Plan Nacional Sobre Drogas” (PNSD- 2021I076, to MR; PNSD- 2019I006, to ME) and Ministerio de Ciencia e Innovación (ERA-NET) PCI2021-122073-2A to ME.