Cannabidiol (CBD) is a major, biologically active, but psycho-inactive component of cannabis. In this cell culture-based report, CBD is shown to displace the agonist, [3H]8-OH-DPAT from the cloned human 5-HT1a receptor in a concentration-dependent manner. In contrast, the major psychoactive component of cannabis, tetrahydrocannabinol (THC) does not displace agonist from the receptor in the same micromolar concentration range. In signal transduction studies, CBD acts as an agonist at the human 5-HT1a receptor as demonstrated in two related approaches. First, CBD increases [35S]GTPγS binding in this G protein coupled receptor system, as does the known agonist serotonin. Second, in this GPCR system, that is negatively coupled to cAMP production, both CBD and 5-HT decrease cAMP concentration at similar apparent levels of receptor occupancy, based upon displacement data. Preliminary comparative data is also presented from the cloned rat 5-HT2a receptor suggesting that CBD is active, but less so, relative to the human 5-HT1a receptor, in binding analyses. Overall, these studies demonstrate that CBD is a modest affinity agonist at the human 5-HT1a receptor. Additional work is required to compare CBD’s potential at other serotonin receptors and in other species. Finally, the results indicate that cannabidiol may have interesting and useful potential beyond the realm of cannabinoid receptors.
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WAY (n = 5) did not affect baseline values of blood pressure (F4,25 = 1.2, P > 0.05) or HR (F4,25 = 0.9, P > 0.05) compared with CBD (10 mg kg −1 , n = 6) and vehicle (n = 6, Table 1 ).
Mean arterial pressure and HR values were continuously recorded for 10 min before the 60 min restraint stress period. Data were expressed as means ± SEM of MAP or HR changes (respectively Δ MAP and Δ HR) sampled at 5 min intervals. Points sampled during the 10 min before restraint were used as control baseline value. MAP and HR changes were analysed using two-way anova with treatment as independent factor and time as repeated measurement factor. When interaction between the factors was observed, groups were compared using one-way anova followed by Bonferroni’s post hoc test.
The results suggest that CBD can attenuate acute autonomic responses to stress and its delayed emotional consequences by facilitating 5-HT1A receptor-mediated neurotransmission.
Twenty-four hours before being submitted to restraint stress, animals had a polyethylene catheter implanted into the femoral artery under anaesthesia (tribromoethanol, 250 mg kg −1 i.p.), for the recording of arterial blood pressure and HR. The catheter was exposed on the dorsum of the animals and attached to the skin, allowing arterial pressure recordings from conscious animals.
Systemic injection of CBD (1, 10 and 20 mg kg −1 ) did not affect baseline blood pressure (F4,25 = 1.2, P > 0.05) or HR (F4,25 = 0.9, P > 0.05) values when compared with vehicle control (n = 6, Table 1 ). As represented in Figure 1 , acute restraint induced a marked and sustained increase of HR and MAP during the 60 min test. There were significant effects of treatment (MAP: F3,240 = 93.5, P < 0.001; HR: F3,240 = 123, P < 0.001), time (MAP: F14,240 = 83.6, P < 0.001; HR: F14,240 = 27.9, P < 0.001) and treatment versus time interaction (MAP: F42,240 = 5.1, P < 0.01; HR: F42,240 = 7.9, P < 0.01).
The EPM test was conducted as described before (Padovan and Guimaraes, 2000). Briefly, the apparatus consisted of two opposite open arms (50 × 10 cm) crossed at a right angle by two arms of the same dimensions enclosed by 40 cm high walls with no roof. The maze was located 50 cm above the floor. Rodents naturally avoid the open arms of the EPM and anxiolytic compounds typically increase the exploration of these arms without changing the number of enclosed-arm entries (Pellow et al., 1985; Carobrez and Bertoglio, 2005). The EPM was cleaned and dried before each session and the Ethovision software (Version 1.9, Noldus, Netherlands) was employed for behavioural analysis.
Cannabidiol did not induce any significant change in basal MAP and HR which agrees with the reported lack of significant cardiovascular effects of this drug (McQueen et al., 2004; Resstel et al., 2006). At low doses, it also does not interfere with memory and learning processes (Lichtman et al., 1995; Fadda et al., 2004; 2006). It is unlikely, therefore, that the attenuation of the cardiovascular and delayed behavioural responses to restraint depend on direct cardiovascular effects or memory impairment induced by the drug, but rather on an attenuation of the emotional response to stress. In agreement with this proposal, acute administration of CBD has been shown to induce anxiolytic-like effects in several animal models, including the EPM, Vogel conflict test and contextual fear conditioning (Guimaraes et al., 1990; Onaivi et al., 1990; Moreira et al., 2006; Resstel et al., 2006). The effective doses of CBD in these previous studies were, in general, similar to ours. In the study by Guimaraes et al. (1990), however, CBD produced an inverted U-shaped dose-response curve, with the highest dose (20 mg kg −1 ) being ineffective. The reasons for this difference are unknown, but may depend on the model used (Calabrese, 2008). As the EPM test is based on exploratory activity, it could be more prone to interference of non-specific drug effects that affects this parameter (Calabrese, 2008). In addition, at least for classical anxiolytics such as diazepam, the EPM is more sensitive than other models such as the Vogel conflict test (see Calabrese, 2008).
The exact mechanism through which 5-HT1A agonists induce their anxiolytic activity remains unclear. 5-HT1A receptors are located presynaptically (somatodendritic autoreceptors) in 5-hydroxytryptaminergic cell bodies in the raphé nuclei of the brain stem and postsynaptically, predominantly in limbic structures such as the hippocampus and the hypothalamus (Verge et al., 1985; 1986; Chalmers and Watson, 1991). It is still controversial whether the anxiolytic-like effects induced by acute systemic administration of 5-HT1A agonists are due to the activation of the pre- or the post-synaptic receptors (File et al., 1996; Lopez-Rubalcava, 1996). Moreover, depending on the structure where post-synaptic 5-HT1A receptors are located, their activation may lead to anxiolytic or anxiogenic-like effects (Graeff et al., 1996; Zangrossi et al., 2001). Therefore, the exact mechanism of action of 5-HT1A agonists as anxiolytic compounds is complex and still warrants further investigation.