The effects of cannabidiol on cue- and stress-induced reinstatement of cocaine seeking behavior in mice are reverted by the CB1 receptor antagonist AM4113

Abstract

Cocaine addiction is a brain disorder characterized by the consumption of the drug despite harmful consequences, the loss of control over drug intake and increased risk of relapse. Albeit prolonged research efforts, there is no available medication approved for the treatment of cocaine addiction. In the last decade, cannabinoid-based compounds have drawn increased interest for its potential therapeutic applications in various psychiatric conditions. Cannabidiol, a non-psychotomimetic constituent of the C. sativa plant, shows promising results in rodent models of anxiety, schizophrenia, depression and drug addiction. However, the specific effects and mechanisms of action of cannabidiol in a rodent model of extinction-based abstinence and drug seeking relapse remain unclear. Here, we administered cannabidiol (20 mg/kg) to male CD-1 mice trained to self-administer cocaine (0.75 mg/kg/inf) during extinction training (8-12 days). Then, we evaluated the reinstatement of cocaine seeking induced by cues, stress and drug priming. To ascertain the participation of CB1 receptors in these behavioral responses, we systemically administered the neutral cannabinoid antagonist AM4113 (5 mg/kg) before each reinstatement session. The results document that cannabidiol (20 mg/kg) does not modulate extinction training but attenuates 'extinction burst' responding after one cannabidiol injection. Furthermore, cannabidiol specifically blocked the reinstatement of cocaine seeking triggered by a cue presentation, an effect prevented by AM4113 (5 mg/kg). Unexpectedly, cannabidiol facilitated stress-induced reinstatement of cocaine seeking behavior, also by a CB1-dependent mechanism.Finally, cannabidiol did not affect cocaine-primed (10 mg/kg) precipitation of cocaine seeking. Our results reveal a series of complex changes induced by cannabidiol treatment with opposite implications for the reinstatement of cocaine seeking behavior that may limit therapeutic opportunities. The activity of CB1 receptors seems to play a 3 crucial role in the expression of cannabidiol-induced neuroplasticity underlying both the desirable and undesirable reinstatement effects here detailed.

Cannabidiol Modulates the Motivational and Anxiety-Like Effects of 3,4-Methylenedioxypyrovalerone (MDPV) in Mice

“…Self-administration experiments were conducted as described previously [ 40 , 41 ]. Mice were trained for 2 h/day to nose poke in order to receive a 0.05 or 0.075 mg/kg/infusion of MDPV on 10 consecutive days, under a fixed ratio 1 (FR1) reinforcement schedule.…”

Cannabidiol Modulates the Motivational and Anxiety-Like Effects of 3,4-Methylenedioxypyrovalerone (MDPV) in Mice

“…Self-administration experiments were conducted as described previously (Lujan et al, 2020;Soria et al, 2008). Mice were trained for 2h/day to nose poke to receive a 0.05 or 0.075 mg/kg/infusion of MDPV on 10 consecutive days, under a fixed ratio 1 (FR1) reinforcement schedule.…”

Cannabidiol effects on cocaine-seeking behaviour and incubation of craving in mice

“…The surgical procedure was conducted as previously described (Soria et al, 2005;Lujan et al, 2020) with minor changes. Surgical implantation of the catheter into the jugular vein was performed following anaesthetization with a mixture of ketamine hydrochloride (75 mg•kg -1 ; Imalgène1000, Lyon, France) and medetomidine hydrochloride (1 mg•kg -1 ; Medeson®, Barcelona, Spain).…”

“…However, it is maybe also the reason why the molecular mechanisms underlying its effects are so complex and, frequently, poorly understood. Although different preclinical studies have evaluated the effects of CBD on acquisition of cocaine self-administration (Mahmud et al, 2016;Luján et al, 2018), extinction (Lujan et al, 2020), reinstatement (Mahmud et al, 2016;Gonzalez-Cuevas et al, 2018;Luján et al, 2018;Lujan et al, 2020), and spontaneous cocaine withdrawal (Gasparyan et al, 2020), its effects on abstinence and cocaine-craving incubation have not yet been confirmed. Of note, CBD or CBDcontaining drugs have been clinically tested for the treatment of tobacco (Hindocha et al, 2018) and cannabis (Crippa et al, 2013;Allsop et al, 2014;Trigo et al, 2018) withdrawal, but not for cocaine.…”