MONOAMINE-OXIDASE INHIBITORS INCREASE PREFERENTIALLY EXTRACELLULAR 5-HYDROXYTRYPTAMINE IN THE MIDBRAIN RAPHE NUCLEI - A BRAIN MICRODIALYSIS STUDY IN THE AWAKE RAT

We have examined the local and systemic effects of clorgyline, tranylcypromine and deprenyl on extracellular serotonin (5-HT) and 5-hydroxyindoleacetic acid in the raphe nuclei and in frontal cortex of awake, freely-moving rats using microdialysis. When administered through the dialysis probe, monoamine oxidase (monoamine: oxygen oxidoreductase (deaminating), E.C. 1.4.3.4., MAO) inhibitors increased 5-HT output in a dose-dependent manner in both brain areas. The effects were more pronounced in the raphe nuclei for the three MAO inhibitors at all doses assayed. When the monoamine oxidase inhibitors were given i.p., dialysate 5-HT increased dramatically, after tranylcypromine (15 mg/kg), in raphe nuclei and frontal cortex (area under the curve (AUC) to 4 h post-treatment: 63-fold and 11-fold, respectively) whereas the effects of clorgyline (10 mg/kg) were much less pronounced (+ 47% increase in the AUC for raphe nuclei, P < 0.09; + 18% increase in the AUC for frontal cortex, n.s.). Deprenyl (2.5 mg/kg, i.p.) induced a moderate (+ 22%) increase of dialysate 5-HT from the raphe nuclei but did not cause a change in dialysate 5-HT from the frontal cortex (+ 4%). However, clorgyline, or deprenyl, dramatically increased dialysate 5-HT in animals which had been pre-treated with the above dose of deprenyl, or clorgyline, respectively, showing that the blockade of both forms of MAO results in much larger increases of extracellular 5-HT than does the blockade of either form alone. These results indicate that: (a) deamination by MAO participates actively in the control of the extracellular concentration of 5-HT in those areas of the brain that are rich in serotoninergic nerve terminals as well as in cell bodies, (b) in vivo, brain 5-HT is deaminated preferentially by MAO-A but its full inhibition does not result in an increased release of 5-HT, in spite of a large accumulation of 5-HT in the brain tissue, (c) MAO-B deaminates 5-HT when the A-form is inhibited (in this situation, MAO-B participates actively in the control of a releasable pool of 5-HT), (d) the raphe nuclei appears to be a preferential site of action of MAO inhibitors, administered either locally or systemically. These results may help to understand the model of action of MAO inhibitors as antidepressant drugs.