Role of Cannabinoid CB2 Receptor in Alcohol Use Disorders: From Animal to Human Studies

Abstract

Cumulative evidence has pointed out cannabinoid CB2 receptors (CB2r) as a potential therapeutic key target for treating alcohol use disorder (AUD). This review provides the most relevant results obtained from rodent and human studies, including an integrative section focused on the involvement of CB2r in the neurobiology of alcohol addiction. A literature search was conducted using the electronic databases Medline and Scopus for articles. The search strategy was as follows: “Receptor, Cannabinoid, CB2” AND “Alcohol-Related Disorders” AND “human/or patients”; “Receptor, Cannabinoid, CB2” AND “Alcohol” OR “Ethanol” AND “rodents/or mice/or rats”. Pharmacological approaches demonstrated that the activation or blockade of CB2r modulated different alcohol-addictive behaviors. Rodent models of alcoholism revealed significant alterations of CB2r in brain areas of the reward system. In addition, mice lacking CB2r (CB2KO) show increased alcohol consumption, motivation, and relapse alterations. It has been stressed that the potential neurobiological mechanisms underlying their behavioral effects involve critical elements of the alcohol reward system. Interestingly, recent postmortem studies showed CB2r gene expression alterations in brain areas of alcoholic patients. Moreover, although the number of studies is limited, the results revealed an association between some genetic alterations of the CB2r gene and an increased risk for developing AUD. This review provides evidence that CB2r may play a role in alcohol addiction. Clinical studies are necessary to figure out whether CB2r ligands may prove useful for the treatment of AUD in humans.

Cannabidiol as a Modulator of the Development of Alcohol Tolerance in Rats

“…The difference between the OIL + CBD and EtOH + CBD groups was insignificant, indicating that the presence of ethanol may be responsible for the significant reduction in EtOH-treated groups. These observations are in line with the results of others [ 30 , 86 ].…”

“…However, in combination, a synergism occurred, leading to an increased CB2R gene transcription above those of these groups, aligning with CBD’s effects in chronic ethanol-treated rats during the two-bottle choice paradigm [ 68 , 81 ]. Those observations also agree with other results proving that CB2Rs can modulate alcohol-reward-related behaviors [ 29 , 30 ]. Similarly, the CB2R in PCOR was not modulated by EtOH or CBD alone, but in combination—a small, statistically significant synergism increased CB2R expression above the control value.…”

“…Differences in this aspect between these groups of animals indicate that CBD inhibited the development of tolerance to peripheral alcohol effects. This observation is in line with the results of experiments of others, clearly indicating that this compound may influence various aspects of the effects of alcohol, including the possibility of CBD-induced blockade of peripheral hypothermic EtOH activity [ 30 , 34 , 68 ].…”

“…An experiment on CB2R knockout (KO) mice proved that CB2Rs are indeed involved in the modulation of alcohol-reward-related behaviors [ 29 ]. So, based on the above findings, there is a growing opinion that the components of the endocannabinoid system mentioned above are critical elements of the alcohol reward system [ 30 ].…”

Neurotoxicology of alcohol: a bibliometric and science mapping analysis

“…However, the mechanisms involved are not fully elucidated. Therefore, several groups have focused on understanding the mechanisms involved, including receptors, neurochemical changes, genetic factors and tissue response ( Teixeira et al, 2014 ; Oliveira et al, 2015 ; Hamada and Lasek, 2020 ; Panula, 2020 ; García-Gutiérrez et al, 2022 ).…”