Displacement of the binding of 5-HT(1A) 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 [(3)H]8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and [(3)H][N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridyl)cy clohexanecarboxamide. 3HCl] (WAY 100635) to 5-HT(1A) 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-HT(1A) 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 [(3)H]8-OH-DPAT and 5.8 - 22.3 nM for [(3)H]WAY 100635. In human brain, the K(i) values using [(3)H]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-HT(1A) ligands preferentially from presynaptic 5-HT(1A) receptors in the dorsal raphe nucleus, as suggested by electrophysiological evidence. The affinity of (-)pindolol for human 5-HT(1A) 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-HT(1A) receptors in these patients. Copyright 1999 Wiley-Liss, Inc.