The effect of Δ9-tetrahydrocannabinol on 5-HT3 receptors depends on the current density.
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.
Yang
K H S
KH
Department of Biological Sciences, Schmid College of Science, Chapman University, One University Drive, Orange, CA 92866, USA.
Isaev
D
D
Morales
M
M
Petroianu
G
G
Galadari
S
S
Oz
M
M
D018712:Analgesics, Non-Narcotic / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D001703:Biophysics / Q000379:methods; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000494:pharmacology*; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004558:Electric Stimulation / Q000379:methods; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D008845:Microinjections / Q000379:methods; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D009620:Nodose Ganglion / Q000166:cytology; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D009865:Oocytes; D018408:Patch-Clamp Techniques / Q000379:methods; D011869:Radioligand Assay / Q000379:methods; D051381:Rats; D044406:Receptors, Serotonin, 5-HT3 / Q000235:genetics / Q000378:metabolism*; D012701:Serotonin / Q000494:pharmacology; D013460:Sulfur Isotopes / Q000378:metabolism; D013997:Time Factors; D014982:Xenopus laevis
D018712:Analgesics, Non-Narcotic; D002614:Chelating Agents; D019384:Nucleic Acid Synthesis Inhibitors; D044406:Receptors, Serotonin, 5-HT3; D013460:Sulfur Isotopes; D003609:Dactinomycin; D012701:Serotonin; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D004533:Egtazic Acid; D013759:Dronabinol; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid