Saturation of monoamine oxidase by intraneuronal noradrenaline accumulation

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Abstract
Summary After pretreatment of the rats with reserpine and pargyline (to inhibit vesicular uptake and MAO), after an additional in vitro treatment with pargyline, and in the presence of U-0521 (to inhibit COMT), the adrenergic nerve endings of vasa deferentia were loaded with 3H-(-)-noradrenaline by exposure to various concentrations of this amine. Subsequently, tissues were washed out with amine-free solution, and the neuronal efflux of tritium was analysed. 1. During 180 min of wash-out the apparent rate constant for the efflux of tritium decreased with increasing tritium content of the tissue. 2. Prolongation of the wash-out period to 305 min revealed that efflux curves for tritium from heavily loaded tissues became steeper after the 180th min of wash-out. This phenomenon is indicative of saturation (followed by desaturation) of a process that limits the efflux of tritium from heavily loaded tissues. 3. Analysis of the radioactivity of the efflux revealed a characteristic efflux curve for DOPEG: the formation of DOPEG appears to be saturated when the 3H-(-)-noradrenaline content of the tissue is high, in order to become desaturated during prolonged wash-out. These results cannot distinguish between MAO and alcohol dehydrogenase as the saturable enzyme. 4. The formation of the mainly deaminated metabolites (during 60 min of wash-out) was determined in lightly and in heavily loaded tissues. The ratio “formation of metabolites/3H-(-)-noradrenaline content” was lower in heavily than in lightly loaded tissues; the relative decline in DOPEG formation was not accompanied by a compensatory increase in the formation of DOMA. Hence, in heavily loaded tissues, MAO must have been saturated by the pronounced accumulation of axoplasmic 3H-(-)-noradrenaline. 5. From the 100th to the 115th min of wash-out, the fractional rate of loss of DOPEG was negatively correlated with the 3H-(-)-noradrenaline content of the tissue; but no such correlation was observed for the fractional rate of loss of 3H-(-)-noradrenaline. 6. The results are interpreted as indicating that any very pronounced inhibition of intraneuronal MAO (by pargyline) enables the nerve ending to achieve such very high axoplasmic noradrenaline concentrations that two phenomena occur simultaneously: a) there is very little obvious sign of any inhibition of MAO, since the great loss of enzyme activity is largely compensated for by the greatly increased intraneuronal substrate concentration; consequently, DOPEG continues to be formed at a brisk rate; b) the axoplasmic noradrenaline concentration then reaches levels that saturate the intraneuronal enzyme.

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