Waldmeier P C, Stöcklin K
Research Department, Ciba-Giegy Ltd., Basel, Switzerland.
Eur J Pharmacol. 1989 Oct 10;169(2-3):197-204. doi: 10.1016/0014-2999(89)90016-2.
The inhibition of the binding of [3H]cyanoimipramine in the rat brain in vivo, with and without pretreatment with proadifen (SK & F 525 A) to prevent its metabolism, has recently been shown to reflect inhibition of 5-HT uptake. This method has been suggested to be more sensitive than other more indirect methods. We have used this method to study the reversible MAO-A inhibitor, brofaromine, which has been shown previously to inhibit 5-HT uptake into synaptosomal preparations in vitro and ex vivo at doses about 30 times higher than those that inhibited MAO-A, and a number of 5-HT uptake inhibitors. The effects of orally administered clomipramine, imipramine, citalopram, CGP 6085 A, fluoxetine and brofaromine on [3H]cyanoimipramine binding were similar to those obtained in the synaptosome ex vivo model in the absence of proadifen; ifoxetine seemed to be more potent in inhibiting [3H]cyanoimipramine binding. The effects of clomipramine, imipramine, citalopram and ifoxetine were moderately to markedly enhanced by proadifen, indicating a first-pass effect. The effect of brofaromine on [3H]cyanoimipramine binding showed a time course similar to that on MAO-A, and was not altered upon repeated treatment. The inactivity of another MAO-A inhibitor, moclobemide, suggest that the effect of brofaromine was due to true inhibition of 5-HT uptake and not to displacement of [3H]cyanoimipramine by elevated synaptic 5-HT. The possible role of inhibition of 5-HT uptake in the antidepressant effect of brofaromine is discussed.
