CHRONIC INHIBITION OF MONOAMINE-OXIDASE TYPE-A INCREASES NORADRENALINE RELEASE IN RAT FRONTAL-CORTEX

Chronic but not acute treatment of rats with MAO inhibitors, as with o ther antidepressant drugs, has been shown to down-regulate the number of cerebro-cortical beta-adrenoceptors. In order to establish whether this effect is associated with an increase in cortical noradrenaline r elease, 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 fro ntal cortex was then per fused by microdialysis in the awake animal. C ontrol animals were injected with saline. The concentration of noradre naline in the microdialysate increased only slightly after 1 or 3 days of clorgyline treatment but increased fourfold over control levels af ter 21 days treatment. Yohimbine (20 mumol/1) added to the perfusing s olution caused a similar degree of enhancement in microdialysate norad renaline concentration in all groups of rats. Tetrodotoxin (10 mumol/1 ) reduced noradrenaline concentration to low levels in all groups of a nimals, but noradrenaline was still detectable in the microdialysate i n rats treated with clorgyline for 21 days. Concentrations of the deam inated metabolites dihydroxyphenylacetic acid, dihydroxyphenylglycol a nd 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 th an 10% inhibition of MAO-B. The results indicate that cerebrocortical noradrenaline release increases gradually during chronic MAO inhibitio n. This may be the result of more complete inhibition of the enzyme wi th time, not detectable by the ex vivo assay, but shown by the progres sive reduction in metabolite levels. The intraneuronal consequence of this effect could be increased vesicular packaging of noradrenaline, t ogether with reduction in net uptake from the synaptic cleft because o f increased axoplasmatic noradrenaline levels. Modification of neurona l firing rate may also play a role in the net change in cortical norad renaline release. The increase in extracellular fluid noradrenaline co ncentration occurs over a time period similar to that required for bet a-adrenoceptor down-regulation, and for the onset of clinical antidepr essant action.