Displacement of the binding of 5-HT1A receptor ligands to pre- and postsynaptic receptors by (-)pindolol.: A comparative study in rodent, primate and human brain

Using receptor autoradiography we examined the displacement of the binding of [H-3]8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and [H-3][N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridyl)cyclohexanecarboxamide . 3HCl] (WAY 100635) to 5-HT1A receptors by (-)pindolol in the brain of four different species, rat, guinea pig, monkey and human. (-)pindolol completely displaced the binding of both tritiated ligands at 10(-6) M in all species and regions examined. The affinity of (-)pindolol for presynaptic 5-HT1A receptors in the dorsal raphe nucleus was similar to that observed in postsynaptic locations, such as hippocampus (areas CA1, CA3 and dentate gyrus) or entorhinal cortex. Affinity values (K-i) were in the range 3.8 - 15.9 nM for [H-3]8-OH-DPAT and 5.8 - 22.3 nM for [H-3]WAY 100635. In human brain, the K-i values using [H-3]8-OH-DPAT as ligand were 10.8 nM in the dorsal raphe nucleus and 6.5 - 13.5 in postsynaptic sites. The present data do not support the hypothesis that (-)pindolol may displace 5-HT1A ligands preferentially from presynaptic 5-HT1A receptors in the dorsal raphe nucleus, as suggested by electrophysiological evidence. The affinity of (-)pindolol for human 5-HT1A receptors is below the mean plasma concentration attained in depressed patients treated with a combination of fluoxetine and pindolol, which indirectly supports an action of pindolol at 5-HT1A receptors in these patients. (C) 1999 Wiley-Liss, Inc.