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Relation between brain monoamine oxidase (MAO) activity and the firing rate of locus coeruleus neurons
Abstract:
Utilizing a specific "low substrate concentration technique", intrasynaptosomal MAO-A and MAO-B activities within the rat brain noradrenaline system were studied. It was found that mainly MAO-A was localized intrasynaptosomally, whereas MAO-B contributed with less than 15% of the total intrasynaptosomal MAO activity, a phenomenon that was also observed within the central dopamine system. It is suggested that the intrasynaptosomal pool of MAO in the noradrenaline and the dopamine systems may reflect the density of innervation of the respective system throughout the brain. In addition, the effects of various selective monoamine oxidase (MAO) inhibitors on the noradrenergic intrasynaptosomal MAO activity as well as on the neuronal firing rate of noradrenaline containing cells in the locus coeruleus (LC) were investigated. Pretreatment with the MAO-A selective inhibitors clorgyline (10 mg/kg, i.p., 1 h) or (+)-FLA 336 (1 mg/kg, i.p., 1 h) caused a significant depression (40%) of mean spontaneous firing rate of LC neurones, randomly encountered throughout the LC. The MAO-B selective inhibitor pargyline (10 mg/kg, i.p., 1 h) was found to lack effect in this regard. However, pretreatment with (-)-deprenyl (10 mg/kg, i.p., 1 h), equally a selective MAO-B inhibitor, markedly suppressed the spontaneous firing rate of LC units. This inhibition by (-)-deprenyl was blocked by pretreatment with SK&F 525 A (50 mg/kg, i.p., 30 min), an inhibitor of microsomal drug metabolizing enzymes. Thus, the depression of LC units by (-)-deprenyl seems to be executed by a metabolite, e.g. l-amphetamine.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Monoamine oxidase A (MAO-A) is primarily intrasynaptosomal in rat noradrenaline and dopamine systems. Selective MAO-A inhibitors and a metabolite of a MAO-B inhibitor reduce locus coeruleus neuronal firing.
Area of Science:
- Neuropharmacology
- Enzymology
- Neuroscience
Background:
- Monoamine oxidase (MAO) enzymes are crucial for neurotransmitter metabolism.
- Understanding the localization and inhibition of MAO subtypes is vital for neurological drug development.
- The noradrenaline system, particularly the locus coeruleus (LC), plays a key role in regulating neuronal activity.
Purpose of the Study:
- To investigate the intrasynaptosomal localization of MAO-A and MAO-B in rat brain noradrenaline and dopamine systems.
- To examine the effects of selective MAO inhibitors on noradrenergic intrasynaptosomal MAO activity.
- To assess the impact of these inhibitors on the neuronal firing rate of noradrenaline-containing cells in the locus coeruleus.
Main Methods:
- Utilized a specific "low substrate concentration technique" to measure intrasynaptosomal MAO-A and MAO-B activities.
- Administered selective MAO inhibitors (clorgyline, (+)-FLA 336, pargyline, (-)-deprenyl) and an enzyme inhibitor (SK&F 525 A) to rats.
- Recorded spontaneous firing rates of locus coeruleus (LC) neurons.
Main Results:
- Intrasynaptosomal MAO activity in rat brain noradrenaline and dopamine systems was predominantly MAO-A, with MAO-B contributing less than 15%.
- Selective MAO-A inhibitors (clorgyline, (+)-FLA 336) significantly reduced LC neuronal firing rate by 40%.
- (-)-Deprenyl, a selective MAO-B inhibitor, also suppressed LC neuronal firing, an effect blocked by SK&F 525 A, suggesting mediation by a metabolite like l-amphetamine.
Conclusions:
- Intrasynaptosomal MAO in noradrenaline and dopamine systems is mainly MAO-A, potentially reflecting innervation density.
- Selective MAO-A inhibition profoundly impacts noradrenergic neuronal activity in the locus coeruleus.
- The MAO-B inhibitor (-)-deprenyl exerts its inhibitory effect on LC neurons via a metabolite, not directly.
