Psychotropic and nonpsychotropic cannabis derivatives inhibit human 5-HT(3A) receptors through a receptor desensitization-dependent mechanism.
W Xiong, B-N Koo, R Morton, L Zhang
Neuroscience June 16, 2011 DOI: 10.1016/j.neuroscience.2011.03.066 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro experimental study Peer reviewed |
|---|---|
| Population | Human 5-HT3A receptors expressed in HEK 293 cells and Xenopus oocytes |
| Interventions | Cannabidiol (CBD) Tetrahydrocannabinol (THC) |
| Topics | Cannabis Serotonin |
| Key findings | CBD and THC inhibited human 5-HT3A receptor function with EC50 values of 110 nM and 322 nM, respectively, and the inhibition was not mediated by a G-protein-dependent mechanism. Both compounds accelerated receptor desensitization, and reducing desensitization decreased the inhibition, indicating that the effect depends on receptor desensitization. |
Abstract
Δ⁹ tetrahydrocannabinol (THC) and cannabidiol (CBD) are the principal psychoactive and nonpsychoactive components of cannabis. While most THC-induced behavioral effects are thought to depend on endogenous cannabinoid 1 (CB1) receptors, the molecular targets for CBD remain unclear. Here, we report that CBD and THC inhibited the function of human 5-HT(3A) receptors (h5-HT(3A)Rs) expressed in HEK 293 cells. The magnitude of THC and CBD inhibition was maximal 5 min after a continuous incubation with cannabinoids. The EC₅₀ values for CBD and THC-induced inhibition were 110 nM and 322 nM, respectively in HEK 293 cells expressing h5-HT(3A)Rs. In these cells, CBD and THC did not stimulate specific [³⁵S]-GTP-γs binding in membranes, suggesting that the inhibition by cannabinoids is unlikely mediated by a G-protein dependent mechanism. On the other hand, both CBD and THC accelerated receptor desensitization kinetics without significantly changing activation time. The extent of cannabinoid inhibition appeared to depend on receptor desensitization. Reducing receptor desensitization by nocodazole, 5-hydroxyindole and a point-mutation in the large cytoplasmic domain of the receptor significantly decreased CBD-induced inhibition. Similarly, the magnitude of THC and CBD-induced inhibition varied with the apparent desensitization rate of h5-HT(3A)Rs expressed in Xenopus oocytes. For instance, with increasing amount of h5-HT(3A)R cRNA injected into the oocytes, the receptor desensitization rate at steady state decreased. THC and CBD-induced inhibition was correlated with the change in the receptor desensitization rate. Thus, CBD and THC inhibit h5-HT(3A) receptors through a mechanism that is dependent on receptor desensitization.
Comparable studies
Other preclinical and animal studies on cannabis, most cited first.