Barrier mechanisms for neurotransmitter monoamines and their precursors at the blood‐brain interface

Abstract

The integrity of the endothelial cell lining of the cerebrovascular bed constitutes a morphological blood-brain barrier mechanism to neurotransmitter monoamines. Circulating monoamines are prevented from entering the brain primarily at the luminal membrane of the endothelial ling. The small percentage of amines that may pass this membrane is deaminated within the endothelial cells and pericytes of brain microvessels (capillaries, venules, and small veins) and, in the case of large parenchymal and pial vessels, in the smooth muscle layers, where O-methylation also takes place. In the choroid plexus a corresponding deamination and O-methylation takes place in the epithelial cells. The presence of these enzymes constitutes a further, enzymatic, blood-brain barrier in the brain vessels for these monoamines. The monoamine precursors L-3,4-dihydroxyphenylalanine (L-dopa) and L-5-hydroxytryptophan readily pass from the luminal endothelial cell membrane but are trapped by another enzymatic barrier mechanism. Within the endothelial cells and pericytes of the microvasculature, these compounds are decarboxylated to their corresponding amines and then immediately deaminated. One clinical implication of these enzymatic barrier mechanisms is the use of decarboxylase and monoamine oxidase inhibitors as adjuncts to L-dopa treatment of Parkinson disease; these substances facilitate the entry of L-dopa into brain and thus increase the amount of dopamine available at receptor sites. A brief hypertensive or hypertonic stimulus can transiently open the blood-brain barrier through an effect on endothelial cell linings. High circulating concentrations of monoamines can also open the morphological barrier, but probably only indirectly by inducing an acute rise in systemic blood pressure. Once the barrier is open, systemically administered monoamines enter the brain parenchyma, where they can induce pronounced changes in cerebral blood flow and metabolism.

Neurohumoral responses during prolonged exercise in humans

“…Dopaminergic neurons are considered to be important for motor activation (22), but exercise may only affect the dopamine level in small regions of the brain (10,40). Furthermore, exercise may elevate the global dopamine level in the brain without affecting the cerebral release via the jugular venous blood, because polar catecholamines do not readily penetrate the blood-brain barrier (2,26), and maybe only dopamine released into the hypophysial portal blood will appear in the jugular blood (23). However, in healthy subjects, the brain demonstrates noradrenaline spillover into both the major and the minor jugular vein (21), and, although the passage of monoamines from the bloodstream to the brain is restricted by the blood-brain barrier, the existence of a barrier to movement in the opposite direction is less certain (27).…”

“…40 for review). Dopamine transport across the brain-blood barrier may be limited (2,26), but dopamine from several hypothalamic nerve tracts is released into the hypophysial portal blood (23), and increased dopaminergic activity could result in dopamine spillover from the brain.…”

Increased norepinephrine spillover into the jugular veins in essential hypertension.

“…The existence of a blood-brain barrier to monoamines, however, that blocks the passage of neurotransmitters between the bloodstream and the brain would invalidate any efforts to assess CNS norepinephrine release using measurements of norepinephrine spillover to plasma. Although there are strong grounds for believing that such an impediment to norepinephrine passage from the bloodstream to the brain exists, 14 the evidence supporting the existence of a barrier to norepinephrine movement in the reverse direction, from the brain to the circulation, is less compelling. In an early study in rats, Glowinski and coworkers 15 reported that 25% of tritiated norepinephrine injected into the lateral cerebral ventricle reached the systemic circulation unchanged.…”

An Inhibitor of Cerebral Uptake of Noradrenaline in Jaundiced Blood Plasma

“…noradrenaline may be incorporated into vesicles in neuronal endings, may be deaminated by MAO (a mitochondrial enzyme which is present in neu rones) in smooth muscle and in endothelial cells (Hardebo and Owman, 1980b), or may be methyl ated by COMT, a cytoplasmic enzyme which is cer tainly present in smooth muscle but probably also occurs in cerebral parenchymal cells (Axelrod, 1971).…”