Agonist and antagonist effects of apomorphine enantiomers on 5-HT3 receptors.
Direct effects of the enantiomers of the classical dopamine receptor ligand apomorphine on 5-HT3 receptors were examined in NIE-115 neuroblastoma cells in whole-cell voltage clamp mode. R(-)-apomorphine (R(-)APO; 3-300 microM) evokes a small, transient inward ion current. At 30 microM, R(-)APO induces its maximum inward current, which is approximately 3% of the amplitude of the inward current induced by 10 microM 5-HT. The R(-)APO-induced current is completely and reversibly inhibited after superfusion of 50 nM of the selective 5-HT3 receptor antagonist MDL 72222 and after desensitization of the 5-HT3 receptors by 10 microM 5-HT. The results indicate that R(-)APO is a partial agonist at the 5-HT3 receptor. R(-)APO (30 microM) evokes a depolarization of the membrane potential with an amplitude which is 26% of the 10 microM 5-HT-induced depolarization. In addition, the 5-HT-induced depolarization is reduced (from 29 to 15 mV) after prolonged exposure of the cell to R(-)APO. S(+)-apomorphine (S(+)APO; 3-300 microM) does not evoke an ion current. Instead, S(+)APO antagonizes the 5-HT3 receptor with an IC50 of 32 microM. The combined results indicate that enantiomers of apomorphine act directly on 5-HT3 receptors, and suggest that the in vivo effects of apomorphine are partially attributable to a direct interaction with 5-HT3 receptors.
van Hooft
J A
JA
Research Institute of Toxicology, Utrecht University, The Netherlands.
Vijverberg
H P
HP
D000818:Animals; D001058:Apomorphine / Q000494:pharmacology*; D051379:Mice; D018408:Patch-Clamp Techniques; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000502:physiology; D044406:Receptors, Serotonin, 5-HT3; D018490:Serotonin Agents / Q000494:pharmacology*; D013237:Stereoisomerism; D014407:Tumor Cells, Cultured
D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D018490:Serotonin Agents; D001058:Apomorphine