Cannabinoid CB1 Receptor Involvement in the Actions of CBD on Anxiety and Coping Behaviors in Mice

Abstract

The anxiolytic and antidepressant properties of cannabidiol (CBD) have been evaluated in several studies. However, the molecular mechanisms involved in these actions remain unclear. A total of 130 male mice were used. CBD’s ability to modulate emotional disturbances (anxiety and depressive-like behaviors) was evaluated at different doses in wild-type (CD1; 10, 20 and 30 mg/kg; i.p.) and knockout (CB1KO, CB2KO; GPR55KO; 20 mg/kg) mice. Moreover, CBD effects (20 mg/kg; i.p.) were evaluated in mice previously treated with the CB1r-antagonist SR141716A (2mg/kg; i.p.). Relative gene expression analyses of Cnr1 and Cnr2, Gpr55 and GABA(A)α2 and γ2 receptor subunits were performed in the amygdala (AMY) and hippocampus (HIPP) of CD1 mice. CBD (10 and 20 mg/kg) showed anxiolytic and antidepressant actions in CD1 mice, being more effective at 20 mg/kg. Its administration did not induce anxiolytic actions in CB1KO mice, contrary to CB2KO and GPR55KO. In all of them, the lack of cannabinoid receptors did not modify the antidepressant activity of CBD. Interestingly, the administration of the CB1r antagonist SR141716A blocked the anxiolytic-like activity of CBD. Real-time PCR studies revealed a significant reduction in Cnr1 and GABA(A)α2 and γ2 gene expression in the HIPP and AMY of CD1 mice treated with CBD. Opposite changes were observed in the Cnr2. Indeed, Gpr55 was increased in the AMY and reduced in the HIPP. CB1r appears to play a relevant role in modulating the anxiolytic actions of CBD. Moreover, this study revealed that CBD also modified the gene expression of GABA(A) subunits α2 and γ2 and CB1r, CB2r and GPR55, in a dose- and brain-region-dependent manner, supporting a multimodal mechanism of action for CBD.

Acute cannabidiol treatment enhances social interaction in adult male mice

“…The third major limitation of this preliminary study is that the mechanism of action of CBD to enhance the social behavior of BTBR mice was not elucidated. CBD has more than 65 potential therapeutic targets, and comprehensive studies to discover CBDs role in shaping behaviors through them are just beginning to unfold ( 1 , 39 ). Strengths of this study include the use of multiple mouse models of ASD, a variety of behavioral tests, and measurement by mass spectrometry of serum and brain homogenate CBD and our attempt to also measure the metabolite levels.…”

“…CBD has many different pharmacological effects, and potential physiological mediators ( 1 , 39 ). Based on previously established affinities, CBD administered to mice at 10 mg/kg is unlikely to bind to and compete with CB 1 or CB 2 receptors directly ( 10 ).…”

The Polypharmacological Effects of Cannabidiol

“…Another proposed mechanism is by the indirect potentiation of AEA transmission since CBD can inhibit the FAAH enzyme [ 155 ] ( Figure 5 ). This could be related to a recent study that demonstrated that CB 1 R (but not CB 2 R or GPR55-KO mice models) is relevant in modulating the anxiolytic actions of CBD using knockout mice for these receptors [ 158 ]. It is possible that these mechanisms and other ones can be acting in conjunction, since CBD can interact with other receptors involved in the regulation of anxiety such as GABA A R.…”

Cannabidiol markedly alleviates skin and liver fibrosis

“…Measures to improve welfare assistance and clinical status as well as endpoint criteria were established to minimize suffering and ensure animal welfare. CBD dosing was chosen based on previous experience using CBD derivatives for treating fibrosis ( Del Rio et al, 2018 ) and literature reporting pharmacological effects of CBD in vivo ( Rajesh et al, 2010 ; Cheng et al, 2014 ; Austrich-Olivares et al, 2022 ).…”