Cannabidiol Modulates Behavioural and Gene Expression Alterations Induced by Spontaneous Cocaine Withdrawal
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ORIGINAL ARTICLE
Cannabidiol Modulates Behavioural and Gene Expression Alterations Induced by Spontaneous Cocaine Withdrawal Ani Gasparyan 1,2 & Francisco Navarrete 1,2 & Marta Rodríguez-Arias 2,3 & José Miñarro 2,3 & Jorge Manzanares 1,2 Accepted: 16 November 2020 # The American Society for Experimental NeuroTherapeutics, Inc. 2020
Abstract The aim of this study was to evaluate the effects of cannabidiol (CBD) on the behavioural and gene expression changes in a new animal model of spontaneous cocaine withdrawal. For this purpose, male CD-1 mice were exposed to progressive increasing doses of cocaine for 12 days (15 to 60 mg/kg/day, i.p.), evaluating spontaneous cocaine withdrawal 6 h after the last cocaine administration. The effects of CBD (10, 20, and 40 mg/kg, i.p.) were evaluated on cocaine withdrawal–induced alterations in motor activity, somatic signs, and anxiety-like behaviour. Furthermore, gene expression changes in dopamine transporter (DAT) and tyrosine hydroxylase (TH) in the ventral tegmental area, and in cannabinoid receptors 1 (CNR1) and 2 (CNR2) in the nucleus accumbens, were analysed by real-time PCR. The results obtained in the study showed that mice exposed to the spontaneous cocaine withdrawal model presented increased motor activity, somatic withdrawal signs, and high anxiety-like behaviour. Interestingly, the administration of CBD normalized motor and somatic signs disturbances and induced an anxiolytic effect. Moreover, the administration of CBD blocked the increase of DAT and TH gene expression in mice exposed to the cocaine withdrawal, regulated the decrease of CNR1 and induced an additional upregulation of CNR2 gene expression. Thus, this model of spontaneous cocaine withdrawal induces clear behavioural and gene expression changes in mice. Interestingly, CBD alleviates these behavioural and gene expression alterations suggesting its potential for the management of cocaine withdrawal. Key Words Cocaine . withdrawal . cannabidiol . mice . mRNA
Abbreviations CBD Cannabidiol CBr Cannabinoid receptor CNR Cannabinoid receptor gene CUD Cocaine use disorder DAT Dopamine transporter NAcc Nucleus accumbens SMART Spontaneous Motor Activity Recording and Tracking * Jorge Manzanares [email protected] 1
Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, Avda. de Ramón y Cajal s/n, San Juan de Alicante, 03550 Alicante, Spain
2
Red Temática de Investigación Cooperativa en Salud (RETICS), Red de Trastornos Adictivos, Instituto de Salud Carlos III, MICINN and FEDER, Madrid, Spain
3
Unidad de Investigación Psicobiología de las Drogodependencias, Departamento de Psicobiología, Facultad de Psicología, Universidad de Valencia, Valencia, Spain
TH VTA
Tyrosine hydroxylase Ventral tegmental area
Introduction Cocaine use disorder (CUD) is a chronic and relapsing disorder characterized by compulsive drug seeking and drug use despite the negative consequences. The most recent data suggest that CUD remains a major public health problem with an estimated 20 million users, making this drug of ab
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