Antagonist binding at 5-HT2A and 5-HT2C receptors in the rabbit:: High correlation with the profile for the human receptors

This study examined the binding of serotonin receptor antagonists at the 5-HT2A and 5-HT2C receptors of the rabbit's cerebral cortex. The 5-HT2A receptor was characterized by the binding of [H-3]MDL 100,907 (R(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine-methanol to cortical membranes and the 5-HT2C receptor by the binding of [H-3]mesulergine in the presence of the selective 5-HT2A receptor Ligand spiperone. Both [H-3]MDL 100,907 and [H-3]mesulergine demonstrated high affinity binding to single sites in rabbit membranes. Based on Scatchard plots of [H-3]MDL 100,907 binding, the mean B-max was 8.5 +/- 0.7 fmol/mg tissue and the mean K-d was 33.1 +/- 3.5 pM. For [H-3]mesulergine binding the mean B-max was 3.70 +/- 0.58 fmol/mg tissue and the mean K-d was 0.35 +/- 0.05 nM. Binding of [H-3]MDL 100,907 to the 5-HT2A receptor and of [H-3]mesulergine to the 5-HT2C receptor was confirmed by displacement studies with highly selective 5-HT2A and 5-HT2C receptor ligands. The pharmacological profile of these ligands in rabbits correlated highly with published values for 5-HT2A (r = 0.91, P < 0.001) and 5-HT2C (r = 0.94, P < 0.001) receptors in humans. There was also a high correlation between the profiles for human and rat 5-HT2C receptor(r = 0.92, P < 0.001), but not for 5-HT2A receptors (r = 0.53, P > 0.10). It was concluded that the rabbit provides an appropriate animal model for studies attempting to predict the pharmacology of human 5-HT2A and 5-HT2C receptors. (C) 2000 Elsevier Science B.V. All rights reserved.