Possible Receptor Mechanisms Underlying Cannabidiol Effects on Addictive-like Behaviors in Experimental Animals.

Ewa Galaj,Zheng-Xiong Xi

doi:10.3390/ijms22010134

Ewa Galaj, Zheng-Xiong Xi

Open Access

https://doi.org/10.3390/ijms22010134

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Abstract

Substance use disorder (SUD) is a serious public health problem worldwide for which available treatments show limited effectiveness. Since the legalization of cannabis and the approval of cannabidiol (CBD) by the US Food and Drug Administration, therapeutic potential of CBD for the treatment of SUDs and other diseases has been widely explored. In this mini-review article, we first review the history and evidence supporting CBD as a potential pharmacotherapeutic. We then focus on recent progress in preclinical research regarding the pharmacological efficacy of CBD and the underlying receptor mechanisms on addictive-like behavior. Growing evidence indicates that CBD has therapeutic potential in reducing drug reward, as assessed in intravenous drug self-administration, conditioned place preference and intracranial brain-stimulation reward paradigms. In addition, CBD is effective in reducing relapse in experimental animals. Both in vivo and in vitro receptor mechanism studies indicate that CBD may act as a negative allosteric modulator of type 1 cannabinoid (CB1) receptor and an agonist of type 2 cannabinoid (CB2), transient receptor potential vanilloid 1 (TRPV1), and serotonin 5-HT1A receptors. Through these multiple-receptor mechanisms, CBD is believed to modulate brain dopamine in response to drugs of abuse, leading to attenuation of drug-taking and drug-seeking behavior. While these findings suggest that CBD is a promising therapeutic candidate, further investigation is required to verify its safety, pharmacological efficacy and the underlying receptor mechanisms in both experimental animals and humans.

Highlights

Substance use disorder (SUD) is a serious public health problem worldwide for which available treatments show limited effectiveness
Through these multiple-receptor mechanisms, CBD is believed to modulate brain dopamine in response to drugs of abuse, leading to attenuation of drug-taking and drug-seeking behavior. While these findings suggest that CBD is a promising therapeutic candidate, further investigation is required to verify its safety, pharmacological efficacy and the underlying receptor mechanisms in both experimental animals and humans
Negative allosteric modulator, CB2 receptor antagonist/inverse agonist or partial agonist, and transient receptor potential vanilloid 1 (TRPV1) and GPR55 agonist (Table 1). Based on these new findings, we have recently explored the roles of CB1, CB2, GPR55, TRPV1, 5-HT1A, and mu opioid receptor (MOR)

Summary

CB1R Mechanism

CBD has low affinity for the CB1R orthosteric binding site [46], it displays high nM affinity for the CB1R allosteric binding site and functionally act as a negative allosteric modulator (Table 1, Figure 1) [41,42,43,51]. Pretreatment with AM251 failed to enhance CBD’s action in cocaine selfadministration or electrical BSR in rats [37], suggesting that the CB1R antagonism produced by CBD on the allosteric binding sites is not sufficient in the attenuation of cocaine reward. This is consistent with literature reports that blockade of CB1Rs by AM251 was able to inhibit cocaine self-administration in some reports [37,53,54], but not in others [55–. Repeated treatment with CBD increases the expression of CB1Rs in the striatum [36], suggesting possible interactions between CBD and CB1Rs

CB2R Mechanism

Major Findings

TRPV1 Mechanism

CBD Inhibits Methamphetamine Reward and Relapse by DA-Related Mechanisms