Effects of the benzodiazepine receptor ligands midazolam, Ro 15-1788, and Ro 5-4864, alone and in combinations, on platelet serotonin uptake.

The benzodiazepine (BZ) agonist midazolam, the BZ antagonist Ro 15-1788, and the peripheral BZ binding site ligand Ro 5-4864 have been assessed, separately and in combinations, as to their effect on the active uptake of serotonin (5HT) in human blood platelets in vitro, in an artificial, protein-free medium. Midazolam had a moderate noncompetitive (or mixed competitive/noncompetitive) inhibitory effect on the uptake. This effect was not influenced by Ro 15-1788, which in itself had only a very weak inhibitory effect. Ro 4-5864 showed in several independent experiments (but not always) a biphasic inhibitory effect, with a moderate but significant inhibition in the concentration range of about 10(-8) to 10(-6) M, and a stronger, noncompetitive inhibitory effect above 10(-6) M. When Ro 5-4864 was tested in the presence of a fixed concentration of midazolam (4 X 10(-6) M), the inhibitory effect of the former was markedly reduced (at higher concentrations), eliminated (at intermediate concentrations), or even reversed into a relative stimulatory effect (at low concentrations). Thus, low concentrations of Ro 5-4864 reduced the inhibitory effect of midazolam. A possible explanation of this interaction is that low concentrations of Ro 5-4864 have both an inhibitory and a stimulatory effect on platelet 5HT uptake (often seen to vary in relative strength between experiments), and that the stimulatory component is unmasked in the presence of a drug that already has an inhibitory effect, probably mediated by the same site.(ABSTRACT TRUNCATED AT 250 WORDS)