Cannabidiol inhibits sucrose self‐administration by CB1 and CB2 receptor mechanisms in rodents

Abstract

A growing number of studies suggest therapeutic applications of cannabidiol (CBD), a recently U.S. Food and Drug Administration (FDA)–approved medication for epilepsy, in treatment of many other neuropsychological disorders. However, pharmacological action and the mechanisms by which CBD exerts its effects are not fully understood. Here, we examined the effects of CBD on oral sucrose self‐administration in rodents and explored the receptor mechanisms underlying CBD‐induced behavioral effects using pharmacological and transgenic approaches. Systemic administration of CBD (10, 20, and 40 mg/kg, ip) produced a dose‐dependent reduction in sucrose self‐administration in rats and in wild‐type (WT) and CB1−/− mice but not in CB2−/− mice. CBD appeared to be more efficacious in CB1−/− mice than in WT mice. Similarly, pretreatment with AM251, a CB1R antagonist, potentiated, while AM630, a selective CB2R antagonist, blocked CBD‐induced reduction in sucrose self‐administration, suggesting the involvement of CB1 and CB2 receptors. Furthermore, systemic administration of JWH133, a selective CB2R agonist, also produced a dose‐dependent reduction in sucrose self‐administration in WT and CB1−/− mice, but not in CB2−/− mice. Pretreatment with AM251 enhanced, while AM630 blocked JWH133‐induced reduction in sucrose self‐administration in WT mice, suggesting that CBD inhibits sucrose self‐administration likely by CB1 receptor antagonism and CB2 receptor agonism. Taken together, the present findings suggest that CBD may have therapeutic potential in reducing binge eating and the development of obesity.

Neuroprotective and Neuromodulatory Effects Induced by Cannabidiol and Cannabigerol in Rat Hypo-E22 cells and Isolated Hypothalamus

“…Actually, the inhibition of the POMC gene expression following CBD and CBG treatment is consistent with their putative role as negative allosteric modulators of CB1 receptor [30]. In contrast, the inhibition of the expression of the NPY gene registered after the treatment, although being consistent with the anorexigenic effects ascribed to CBD [6], appears to be discrepant with the orexigenic role of CBG [16,17]. This result is, however, in agreement with the expression of the CB1 receptor on synaptic endings innervating both NPY and POMC first order neurons in the hypothalamus [29,31].…”

“…The endocannabinoid-mediated activation of CB1 and CB2 has long been implicated in the onset of neuroprotective effects, whereas the neuroprotection occurring after phyto-cannabinoid administration could be better explained by a multitarget mechanism involving different receptor systems, including peroxisome proliferator-activated receptors (PPARs) and transient receptor potential (TRP) channels [3][4][5]. CB1 and CB2 receptors were considered as promising targets for the development of anti-obesity drugs [6] as well, to the point that the rimonabant, the prototype of the of CB1 blockers, was clinically employed for a short period (more than ten years ago) for its anorexigenic effects. Nevertheless, the rimonabant was soon after retired from the market for an increased frequency in psychiatric disorders following the treatment [7].…”

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

“…We found that systemic administration of CBD (10, 20, and 40 mg/kg, i.p.) produced a dose-dependent reduction in sucrose self-administration in rats and in wild-type (WT) mice [ 52 ]. Unexpectedly, CBD was more efficacious in transgenic CB1 receptor-knockout (CB1-KO) mice than in WT mice.…”

Antioxidant and Neuroprotective Effects Induced by Cannabidiol and Cannabigerol in Rat CTX-TNA2 Astrocytes and Isolated Cortexes

“…The ∆9-tetrahydrocannabinol (THC) has long been considered the sole psychotropic molecule, but a novel phytocannabinoid, the ∆9-tetrahydrocannabiphorol, which is even more potent than THC itself, was recently identified in C. sativa phytocomplex [2]. Cannabidiol (CBD) is another terpenophenol that has long been studied from a pharma-toxicological point of view [3][4][5][6]. Despite having a chemical structure very close to that of the THC, CBD was reported to act with a different multitarget mechanism, including the binding to more than 60 receptor proteins.…”