Agonistic Properties of Cannabidiol at 5-HT1a Receptors

Abstract

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]GTPgammaS 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.

Molecular Targets of Cannabidiol in Neurological Disorders

“…In addition to 5-HT 1A agonism, the same study presented evidence for CBD binding to the 5-HT 2A receptor. In NIH/3T3 cells, CBD (8-32 μM) served as a partial agonist of the 5-HT 2A receptor with weaker efficacy than its action at the 5-HT 1A receptor [26]. 5-HT receptors are also implicated in autonomic control [47], and again here CBD has been shown to modulate 5-HT 1A -mediated responses in vivo [42].…”

“…CBD may also act via serotonin (5-HT) receptors [26,[42][43][44][45]. The 5-HT 1A receptor is coupled to G protein G i/o, where it is thought to mediate inhibitory neurotransmission [46].…”

“…The 5-HT 1A receptor is coupled to G protein G i/o, where it is thought to mediate inhibitory neurotransmission [46]. CBD binds to the 5-HT 1A receptor within a range of 8-32 μM (Table 1) [26]. In cultured Chinese hamster ovary cells, CBD displaced radiolabelled 8-OH-DPAT [7-(dipropylamino)-5,6,7, 8-tetrahydronaphthalen-1-ol] from 5-HT 1A receptors.…”

Cannabidiol as a Potential Treatment for Anxiety Disorders

“…Mechanisms underlying the anxiolytic effects of 5-HT 1A R activation are complex, varying between both brain region, and pre-versus postsynaptic locus, and are not fully established [56]. While in vitro studies suggest CBD acts as a direct 5-HT 1A R agonist [57], in vivo studies are more consistent with CBD acting as an allosteric modulator, or facilitator of 5-HT 1A signaling [58].…”

Divergent effects of cannabidiol on the discriminative stimulus and place conditioning effects of Δ9-tetrahydrocannabinol

“…CBD has minimal affinity for CB1 receptors (Pertwee, 1997b), although it appears to interact with the endocannabinoid system via fatty acid amide hydrolase (Watanabe et al, 1996) or through the putative anandamide membrane transporter (Bisogno et al, 2001). CBD also has been found to have agonist activity at TRPV1 (Bisogno et al, 2001) and at 5-HT1A receptors (Russo et al, 2005). In addition, prior research has suggested that metabolic factors may account for interactions between CBD and THC, as inhibition of the metabolism of THC via interactions with P450 enzymes has been observed following large doses of CBD (Bornheim et al, 1993a;Bornheim et al, 1995a).…”