The effect of Δ9-tetrahydrocannabinol on 5-HT3 receptors depends on the current density.

Abstract

The effects of Δ(9)-tetrahydrocannabinol (THC), the psychoactive component of cannabis, on the function of 5-HT type 3 (5-HT(3)) receptors were investigated using a two-electrode voltage clamp technique in Xenopus oocytes, and a whole-cell patch clamp technique in rat nodose ganglion neurons. In oocytes injected with 3 ng cRNA of 5-HT(3A) receptor, THC reversibly inhibited currents evoked with 5-HT (1 μM) in a concentration-dependent manner (IC(50)=1.2 μM). The extent of THC inhibition was inversely correlated with the amount of cRNA injected and the mean 5-HT(3A) receptor current densities. Pretreatment with actinomycin D, which inhibits transcription, decreased the mean 5-HT(3) receptor current density and increased the extent of THC inhibition on 5-HT(3) receptor-mediated currents. The IC(50) values for THC increased from 285 nM to 1.2 μM in oocytes injected with 1 and 3 ng of 5-HT(3A) cRNA, respectively. In radioligand binding studies on membrane preparations of oocytes expressing 5-HT(3A) receptors, THC did not alter the specific binding of a 5-HT(3A) receptor antagonist, [(3)H]GR65630. In the presence of 1 μM THC, the maximum 5-HT-induced response was also inhibited without a significant change in 5-HT potency, indicating that THC acts as a noncompetitive antagonist on 5-HT(3) receptors. In adult rat nodose ganglion neurons, application of 1 μM THC caused a significant inhibition of 5-HT(3) receptors, extent of which correlated with the density of 5-HT-induced currents, indicating that the observed THC effects occur in mammalian neurons. The inhibition of 5-HT(3) receptors by THC may contribute to its pharmacological actions in nociception and emesis.

• Authors: K H S Yang, D Isaev, M Morales, G Petroianu, S Galadari, M Oz
• Journal: Neuroscience (Neuroscience) Vol. 171 Issue 1 Pg. 40-9 (Nov 24 2010) ISSN: 1873-7544 [Electronic] United States
• PMID: 20800662 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010. Published by Elsevier Ltd.

Chemical References

• Analgesics, Non-Narcotic
• Chelating Agents
• Nucleic Acid Synthesis Inhibitors
• Receptors, Serotonin, 5-HT3
• Sulfur Isotopes
• Dactinomycin
• Serotonin
• Guanosine 5'-O-(3-Thiotriphosphate)
• Egtazic Acid
• Dronabinol
• 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid

Topics

• Analgesics, Non-Narcotic (pharmacology)
• Analysis of Variance
• Animals
• Biophysics (methods)
• Cells, Cultured
• Chelating Agents (pharmacology)
• Dactinomycin (pharmacology)
• Dose-Response Relationship, Drug
• Dronabinol (pharmacology)
• Egtazic Acid (analogs & derivatives, pharmacology)
• Electric Stimulation (methods)
• Female
• Gene Expression Regulation (drug effects, genetics)
• Guanosine 5'-O-(3-Thiotriphosphate) (metabolism)
• Membrane Potentials (drug effects, genetics)
• Microinjections (methods)
• Neurons (drug effects, physiology)
• Nodose Ganglion (cytology)
• Nucleic Acid Synthesis Inhibitors (pharmacology)
• Oocytes
• Patch-Clamp Techniques (methods)
• Radioligand Assay (methods)
• Rats
• Receptors, Serotonin, 5-HT3 (genetics, metabolism)
• Serotonin (pharmacology)
• Sulfur Isotopes (metabolism)
• Time Factors
• Xenopus laevis