In vivo evidence for the reversible action of the monoamine oxidase inhibitor brofaromine on 5-hydroxytryptamine release in rat brain

We have used intracerebral microdialysis to examine the reversibility of the action of brofaromine, a selective inhibitor of monoamine oxidase-A (MAO, E.C. 1.4.3.4.), on 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) output in rat frontal cortex. Brofaromine significantly increased the 5-HT output to about 200% of basal values 4 h after the s.c. administration of 10 and 30 mg/kg (but not 3 mg/kg) and reduced the concentration of 5-HIAA in the dialysate dose-dependently (61%, 53% and 41% of basal value with doses of 3, 10 and 30 mg/kg, respectively). At this time, cortical 5-HT concentration was increased and cortical 5-HIAA concentration was decreased in a dose-dependent manner.Treatment of rats with 10 mg/kg brofaromine plus 2.5 mg/kg of the irreversible MAO-B inhibitor l-deprenyl increased the concentration of 5-HT in the dialysate more than did brofaromine alone (503% vs 206% of the basal value, 4 h after administration). Similarly, clorgyline (5 mg/kg) plus l-deprenyl (2.5 mg/kg) increased the concentration of 5-HT in the dialysate to 461 % of the control value. This indicates that the concurrent inhibition of both types of MAO increases 5-HT output more than the selective blockade of either enzyme subtype. We have used this characteristic to examine, in vivo, the reversibility of the interaction of brofaromine with MAO-A. The output of 5-HT and 5-HIAA was examined 19–21 h after treatment with l-deprenyl plus clorgyline or l-deprenyl plus brofaromine. At this time, the concentration of 5-HT in the dialysate was increased six-fold in the clorgyline plus l-deprenyl group, as compared to pre-treatment values, but did not differ significantly from these in the brofaromine plus L-deprenyl group. Also, 5-HIAA concentration in the dialyste was still reduced (48% of basal value) in the clorgyline plus l-deprenyl group but not in the brofaromine plus l-deprenyl group. Cortical 5-HT and 5-HIAA concentrations in these animals, measured at the end of the microdialysis experiments (21 h after treatment), displayed changes that paralleled those in the extracellular compartment.These results indicate that: (a) as with clorgyline, the inhibition of MAO-A with brofaromine has a more pronounced effect on tissue 5-HT concentrations than on extracellular 5-HT concentrations; (b) the simultaneous inhibition of both forms of MAO with l-deprenyl and either brofaromine or clorgyline increased the concentration of 5-HT in the dialysate shortly (1–4 h) after administration more than did treatment with either of the MAO-A inhibitors alone; (c) dialysate and tissue 5-HT concentrations were greatly increased one day after the irreversible inhibition of MAO by clorgyline plus l-deprenyl, whereas they had returned to pretreatment values in those animals treated with brofaromine plus l-deprenyl. These transient effects on 5-HT and 5-HIAA in vivo provide further support for the conclusion that the interaction of brofaromine with brain MAO-A is reversible.