Reducing Effect of Cannabidiol on Alcohol Self-Administration in Sardinian Alcohol-Preferring Rats
Paola Maccioni, Jessica Bratzu, Mauro A.M. Carai, Giancarlo Colombo, and Gian Luigi Gessa
Cannabis and Cannabinoid Research, 2021,
Doi : 10.1089/can.2020.0132
Introduction : Cannabidiol (CBD) is a major cannabinoid extracted from Cannabis sativa with no abuse potential. Data from recent rodent studies suggest that amelioration of alcohol-motivated behaviors may be one of the numerous pharmacological effects of CBD. This study was designed to contribute to this research, assessing the effect of CBD on operant oral alcohol self-administration in selectively bred Sardinian alcohol preferring (sP) rats, a validated animal model of excessive alcohol consumption. In addition, this study investigated the effect of CBD on operant self-administration of a highly palatable chocolate solution in Wistar rats.
Materials and Methods : Male sP rats were trained to lever respond for alcohol (15% v/v) under the fixed ratio 4 (FR4) schedule of reinforcement. Once lever responding had stabilized, rats were exposed to test sessions under the FR4 and progressive ratio (PR) schedules of reinforcement. Test sessions were preceded by acute treatment with CBD (0, 6.25, 12.5, and 25 mg/kg or 0, 25, 50, and 100 mg/kg, i.p.; each dose range was tested in an independent experiment). Male Wistar rats were trained to lever respond for a chocolate solution (5% w/v chocolate powder) under the FR10 schedule of reinforcement. Once lever responding had stabilized, rats were exposed to test sessions under the same schedule. Test sessions were preceded by acute treatment with CBD (0, 6.25, 12.5, and 25 mg/kg or 0, 25, 50, and 100 mg/kg, i.p., in two independent experiments).
Results : Under the FR schedule, treatment with doses of CBD ‡ 12.5mg/kg markedly reduced lever responding for alcohol and amount of self-administered alcohol. Under the PR schedule, treatment with CBD produced a slight tendency toward a decrease in lever responding and breakpoint for alcohol. Finally, no dose of CBD affected lever responding for the chocolate solution and amount of self-administered chocolate solution.
Discussion : These results extend previous data on CBD ability to affect alcohol motivated behaviors to an animal model of genetically-determined proclivity to high alcohol consumption. Because of the predictive validity of sP rats, these results may be of relevance in view of possible future studies testing CBD in patients affected by alcohol use disorder.
Keywords : alcohol self-administration; cannabidiol; chocolate self-administration; endocannabinoid system; Sardinian alcohol-preferring rats
The role of the endocannabinoid (eCB) neurotransmitter system in the regulation of several alcohol-related behaviors is well documented and summarizable with cannabinoid CB1 receptor antagonists/inverse agonists inhibiting and cannabinoid CB1 receptor agonists stimulating alcohol drinking, operant alcohol selfadministration, and reinstatement of alcohol seeking in rats and mice.1–4 The adverse neuropsychiatric effects of the prototypic cannabinoid CB1 receptor antagonist/ inverse agonist, rimonabant, have regrettably prevented a proper translation to patients affected by alcohol use disorder (AUD) of the large number of remarkably consistent rodent studies reporting its ‘‘antialcohol’’ properties.
A role for the cannabinoid CB2 receptor has also been proposed, with the cannabinoid CB2 receptor agonist, JWH015, increasing alcohol drinking in mice.5
Over recent years, research in the eCB pharmacology field has been enriched by an increasing interest in cannabidiol (CBD), a major cannabinoid extracted from Cannabis sativa with no abuse potential.6,7 CBD acts as inverse agonist8 and negative allosteric modulator9 at both CB1 and CB2 cannabinoid receptors. CBD also affects the eCB system by blocking uptake of the endogenous cannabinoid receptor ligand, anandamide, and inhibiting its enzymatic hydrolysis.10
In the alcohol research field, to date, CBD has been tested in a limited number of preclinical studies.11,12
Specifically, acute and/or repeated treatment with CBD attenuated (i) context- and stress-induced reinstatement of alcohol seeking in rats,13 (ii) alcohol drinking in mice exposed to the ‘‘alcohol versus water’’ choice regimen,14 (iii) binge-like drinking in mice exposed to the ‘‘drinking-in-the-dark’’ procedure,15 and (iv) operant oral alcohol self-administration in mice.14,16 It is therefore of interest to test CBD in additional animal and experimental models of AUD, with the intent of better characterizing its ‘‘antialcohol’’ potential before possibly moving to clinical studies.
To this end, this study was designed to investigate the effect of treatment with CBD on operant oral alcohol self-administration in selectively bred Sardinian alcohol-preferring (sP) rats.17 Rats of the sP line appear to constitute a proper animal model for this investigation, as—in this rat line—(i) genetically determined differences in the eCB system contribute to high alcohol preference and consumption18; (ii) treatment with
rimonabant reversed alcohol-induced dysfunctions of eCB18; and (iii) alcohol self-administration proved highly sensitive to pharmacological manipulation of the CB1 receptor, with rimonabant treatment effectively suppressing lever responding for alcohol.19
As an additional aim, this study investigated the effect of CBD on operant self-administration of a chocolate solution in Wistar rats. Previous studies reported contrasting results on the ability of CBD to affect sucrose intake and self-administration in rodents,20–22 leaving open the question as to whether CBD may modulate the appetitive and consummatory aspects of palatable food. The relevance of this study may reside in the experimental model: self-administration of a chocolate solution possessing addictive-like properties and inducing exaggerated lever responding in rats.23