TY - JOUR
T1 - The effect of δ9-tetrahydrocannabinol on 5-HT3 receptors depends on the current density
AU - Yang, K. H.S.
AU - Isaev, D.
AU - Morales, M.
AU - Petroianu, G.
AU - Galadari, S.
AU - Oz, M.
N1 - Funding Information:
The authors wish to thank Dr. David Julius for providing 5-HT 3A -cDNA, and Dr. Mary Pfeiffer of NIDA/IRP for careful editing of the manuscript. This work was supported in part by the Intramural Research Program of the National Institutes of Health , National Institute on Drug Abuse , and by start-up grants from FMHS/UAEU . The experiments comply with the current laws of the U.S. and the authors have no financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.
PY - 2010/11/24
Y1 - 2010/11/24
N2 - The effects of δ9-tetrahydrocannabinol (THC), the psychoactive component of cannabis, on the function of 5-HT type 3 (5-HT3) 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-HT3A receptor, THC reversibly inhibited currents evoked with 5-HT (1 μM) in a concentration-dependent manner (IC50=1.2 μM). The extent of THC inhibition was inversely correlated with the amount of cRNA injected and the mean 5-HT3A receptor current densities. Pretreatment with actinomycin D, which inhibits transcription, decreased the mean 5-HT3 receptor current density and increased the extent of THC inhibition on 5-HT3 receptor-mediated currents. The IC50 values for THC increased from 285 nM to 1.2 μM in oocytes injected with 1 and 3 ng of 5-HT3A cRNA, respectively. In radioligand binding studies on membrane preparations of oocytes expressing 5-HT3A receptors, THC did not alter the specific binding of a 5-HT3A receptor antagonist, [3H]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-HT3 receptors. In adult rat nodose ganglion neurons, application of 1 μM THC caused a significant inhibition of 5-HT3 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-HT3 receptors by THC may contribute to its pharmacological actions in nociception and emesis.
AB - The effects of δ9-tetrahydrocannabinol (THC), the psychoactive component of cannabis, on the function of 5-HT type 3 (5-HT3) 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-HT3A receptor, THC reversibly inhibited currents evoked with 5-HT (1 μM) in a concentration-dependent manner (IC50=1.2 μM). The extent of THC inhibition was inversely correlated with the amount of cRNA injected and the mean 5-HT3A receptor current densities. Pretreatment with actinomycin D, which inhibits transcription, decreased the mean 5-HT3 receptor current density and increased the extent of THC inhibition on 5-HT3 receptor-mediated currents. The IC50 values for THC increased from 285 nM to 1.2 μM in oocytes injected with 1 and 3 ng of 5-HT3A cRNA, respectively. In radioligand binding studies on membrane preparations of oocytes expressing 5-HT3A receptors, THC did not alter the specific binding of a 5-HT3A receptor antagonist, [3H]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-HT3 receptors. In adult rat nodose ganglion neurons, application of 1 μM THC caused a significant inhibition of 5-HT3 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-HT3 receptors by THC may contribute to its pharmacological actions in nociception and emesis.
KW - 5-HT receptor
KW - Cannabinoid
KW - Nodose ganglion neuron
KW - Xenopus oocytes
KW - δ-tetrahydrocannabinol
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U2 - 10.1016/j.neuroscience.2010.08.044
DO - 10.1016/j.neuroscience.2010.08.044
M3 - Article
C2 - 20800662
AN - SCOPUS:77957874829
VL - 171
SP - 40
EP - 49
JO - Neuroscience
JF - Neuroscience
SN - 0306-4522
IS - 1
ER -