Chronic inhibition of monoamine oxidase type A increases noradrenaline release in rat frontal cortex

Summary Chronic but not acute treatment of rats with MAO inhibitory, as with other antidepressant drugs, has been shown to down-regulate the number of cerebro-cortical ß-adrenoceptors. In order to establish whether this effect is associated with an increase in cortical noradrenaline release, rats were treated for 1, 3 or 21 days with clorgyline (2 mg/kg i.p. single injection; 1 mg/kg i.p. repeated injections), and the frontal cortex was then perfused by microdialysis in the awake animal. Control animals were injected with saline.The concentration of noradrenaline in the microdialysate increased only slightly after 1 or 3 days of clorgyline treatment but increased fourfold over control levels after 21 days treatment. Yohimbine (20 mol/1) added to the perfusing solution caused a similar degree of enhancement in microdialysate noradrenaline concentration in all groups of rats. Tetrodotoxin (10 mol/1) reduced noradrenaline concentration to low levels in all groups of animals, but noradrenaline was still detectable in the microdialysate in rats treated with clorgyline for 21 days. Concentrations of the deaminated metabolites dihydroxyphenylacetic acid, dihydroxyphenylglycol and methoxy-hydroxyphenylglycol were lowest after the 21 day clorgyline treatment. Determination of enzyme activity ex vivo showed that MAO-A was inhibited more than 95% by all clorgyline treatments with less than 10% inhibition of MAO-B.The results indicate that cerebrocortical noradrenaline release increases gradually during chronic MAO inhibition. This may be the result of more complete inhibition of the enzyme with time, not detectable by the ex vivo assay, but shown by the progressive reduction in metabolite levels. The intraneuronal consequence of this effect could be increased vesicular packaging of noradrenaline, together with reduction in net uptake from the synaptic cleft because of increased axoplasmatic noradrenaline levels. Modification of neuronal firing rate may also play a role in the net change in cortical noradrenaline release. The increase in extracellular fluid noradrenaline concentration occurs over a time period similar to that required for ß-adrenoceptor down-regulation, and for the onset of clinical antidepressant action.Abbreviations DHPG dihydroxyphenylglycol - DOPAC dihydroxyphenylacetic acid - MHPG methoxy-hydroxyphenylglycol - TTX tetrodotoxin - MAO Monoamine oxidase