Re: RLS: Iron & Dopamine

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Putative biological mechanisms of the effect of iron deficiency on brain

biochemistry and behavior

Author: Youdim MB; Ben-Shachar D; Yehuda S

Address: Department of Pharmacology, Faculty of Medicine, Technion Medical

School, Haifa, Israel.

Source: Am J Clin Nutr, 1989 Sep, 50:3 Suppl, 607-15; discussion 615-7

Abstract: An animal model of nutritional iron deficiency (ID) is described

that demonstrates a reduction of brain nonheme iron. The most prominent

feature of ID is the significant and selective diminution of central dopamine

neurotransmission resulting from the decreased number of dopamine D2 receptors

in the caudate nucleus, nucleus accumbens, pituitary, and in all probability

the frontal cortex. The consequences of diminished dopaminergic

neurotransmission is a modification of dopamine-dependent behaviors and

biochemical reactions, the most important of which is the reduction in

learning processes.

The role of iron in maintaining the homeostasis of normally functioning

dopamine neurons and their involvement in cognitive processes cannot be

excluded. An interference with iron metabolism at an early age can result in

irreversible damage to developing dopamine neurons, with consequences that may

manifest themselves in adult life.

IRON DEFICIENCY AND THE BRAIN

Author: Parks YA; Wharton BA

Address: Community Health and Mental Handicap Services, Canterbury, UK.

Source: Acta Paediatr Scand Suppl, 1989, 361:, 71-7

Abstract: There is increasing evidence both from 'association' and

'intervention' studies that iron deficiency has an adverse effect on brain

function in animals and children. The severity and duration of iron deficiency

are important in determining the effect on development. Iron replacement

therapy has immediate (within 14 days) and long-term (over 3 months)

beneficial effects on behaviour and psychomotor development. The mechanisms

for this probably involve a number of biochemical pathways in which iron is

essential. These include mitochondrial enzymes and various neurotransmitters.

Cytochrome C is reduced by iron deficiency but brain tissue is relatively

spared until the deficiency is severe. Levels of neurotransmitters such as

noradrenaline, serotonin and dopamine are all altered during iron deficiency

and this may explain some of the behavioural and developmental changes that

occur.

Modulation of dopamine receptor in the striatum by iron: behavioral and

biochemical correlates

Author:Youdim MB; Ashkenazi R; Ben-Shachar D; Yehuda S

Source: Adv Neurol, 1984, 40:, 159-70

Abstract: The present study has shown that in the rat brain iron is unevenly

distributed and may be associated with the dopaminergic neuron. The function

of the large amounts of iron in certain brain areas, such as the pallidum,

caudate nucleus, substantia nigra, nucleus accumbens, and olfactory tubercule,

is not known. But it is obvious that by reduction of brain iron, as in the

case of nutritional iron deficiency, certain dopamine-mediated behavioral

phenomena and biochemical reactions are altered. These changes have been

attributed to the selective reduction in dopamine D2 receptors and function in

brain areas rich in dopamine neurons and iron. If iron is especially important

to dopaminergic modulatory systems in the brain, its deficit might explain the

increasing number of reports on behavioral disturbances, EEG, and event-

related potentials (ERPs) associated with nutritional iron deficiency in

children.

Minimal brain damage induced by early iron deficiency:

modified dopaminergic neurotransmission

Author: Youdim MB; Ben-Shachar D

Source: Isr J Med Sci, 1987 Jan-Feb, 23:1-2, 19-25

Abstract: The reports that iron-deficiency anemia in human subjects induces

behavioral changes was investigated in rats made nutritionally iron-deficient.

The most prominent features of these animals were: the unchanged metabolism of

the neurotransmitters noradrenaline, dopamine and serotonin, profound

reduction of brain nonheme iron, the selective diminution of dopamine D2

receptor number (measured by Bmax), modification of dopamine-dependent

behaviors and reduction of learning processes. The induction of these changes

and their recovery with iron supplementation are age- and time-dependent

phenomena.

In newborn rats, however, the consequences of iron deficiency are

irreversible, even after long-term iron supplementation. The results point to

the profound effect iron metabolism can have on the long-term development and

function of dopaminergic neurotransmission. These findings may not be totally

unexpected, since iron distribution in the brain is highly localized in

dopaminergic-peptidergic regions, such as the globus pallidus, substantia

nigra, red nucleus, thalamus, caudate nucleus and nucleus accumbens. In some

regions its concentration is higher than that found in the liver, the site of

iron metabolism.

Effect of iron chelators on dopamine D2 receptors

Author: Ben-Shachar D; Finberg JP; Youdim MB

Source: J Neurochem, 1985 Oct, 45:4, 999-1005

Abstract: Nutritional iron deficiency induced in rats causes a selective

reduction of [3H]spiperone binding in caudate nucleus. This effect can be

reversed by iron supplementation in vivo. The possibility that iron may be

involved in the dopamine D2 receptor was investigated by examining the effect

of various iron and noniron chelators on the binding of [3H]spiperone in rat

caudate nucleus. Iron chelators 1,10-phenanthroline, 2,4,6-tripyridyl-s-

triazine, alpha, alpha'-dipyridyl, and desferrioxamine mesylate inhibited the

binding of [3H]spiperone.

The inhibition by 1,10-phenanthroline was noncompetitive and reversible. In

the presence of FeCl2 or FeCl3, the inhibitory effect of 1,10-phenanthroline

was potentiated. Iron salts or chelators were without effect on the binding of

[3H]dihydroalprenolol to beta-adrenoreceptors in caudate nucleus; thus the

action of iron chelators on the dopamine D2 receptor tends to be selective.

Incubation of caudate nucleus membrane prepared from iron-deficient rats with

FeCl2 or FeCl3 did not reverse the diminished binding of [3H]spiperone. The

present study indicates that if iron is involved in the physiological

regulation of dopamine D2 agonist-antagonist binding sites, it is more complex

than hitherto considered.