Dopaminergic supersensitivity at distant sites following induced epileptic foci

Csernansky, John G.; Holman, Cynthia A.; Bonnet, Kenneth A.; Grabowsky, Kari L.; King, Roy; Hollister, Leo E.

doi:10.1016/0024-3205(83)90084-x

Cited by 35 publications

(7 citation statements)

References 15 publications

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“…The positive relationship between iron transport into the brain cells and the tendency of the typical neuroleptic drug to induce side effects is strongly in favor of a role for iron in neuroleptic-induced side effects. Indeed, the intraamygdala injection of iron is associated with dopamine D, receptor supersensitivity and enhanced dopamine-dependent behavioral responses (Csernansky et al, 1983). The present results, indicating a 196.90 f 25.77" ~ Liver nonheme iron concentrations in the various treatments were determined as described in Materials and Methods.…”

Section: Discussionmentioning

confidence: 60%

“…Iron sup-plementation restores dopaminergic function to normal (Ben-Shachar and Youdim, 1990;Ben-Shachar et al, 199 1). In contrast, intracerebral iron injection causes biochemical and behavioral postsynaptic dopamine supersensitivity (Csernansky et al, 1983). The apparent relationship between neuroleptics and iron is supported further by the high levels or even significant increase of iron in the basal ganglia of patients with T D (Hunter et al, 1968;Campbell et al, 1985; Bartzokis et al, 1990).…”

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confidence: 99%

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Typical and Atypical Neuroleptics Induce Alteration in Blood‐Brain Barrier and Brain ⁵⁹FeCl₃ Uptake

Ben‐Shachar¹,

Livne

Spanier³

et al. 1994

Journal of Neurochemistry

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Long‐term neuroleptic medication of schizophrenic patients induces extrapyramidal motor side effects, of which tardive dyskinesia (TD) is the most severe. The etiology of TD is still obscure. Recently, it was suggested that abnormal iron metabolism may play a crucial role in neuroleptic‐induced dopamine D2 receptor super‐sensitivity. The apparent relationship between neuroleptics and iron is further supported by the increase of iron in the basal ganglia of patients with TD. We now report on the ability of neuroleptics to alter the blood‐brain barrier in the rat and to potentiate the normally limited iron transport into the brain. Thus, chronic treatment of rats with chlorpromazine and haloperidol facilitated 59Fe3+ uptake into brain cells. In contrast, clozapine, an atypical antipsychotic neuroleptic with little extrapyramidal motor side effects, caused iron sedimentation in brain blood vessels with no sign of detectable iron in the cells. Moreover, chronic treatment with chlorpromazine and haloperidol caused a 43% and 24% reduction, respectively, in liver nonheme iron, whereas clozapine induced an 81% increase. The apparent different potentials of chlorpromazine, haloperidol, and clozapine to increase iron transport into the brain from its peripheral stores may be linked to the severity of extrapyramidal motor side effects they induce and to the pathophysiology of TD.

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Section: Discussionmentioning

confidence: 60%

mentioning

confidence: 99%

Typical and Atypical Neuroleptics Induce Alteration in Blood‐Brain Barrier and Brain ⁵⁹FeCl₃ Uptake

Ben‐Shachar¹,

Livne

Spanier³

et al. 1994

Journal of Neurochemistry

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“…The increase in binding of dopamine D, receptor and brain iron level may, of course, be coincidental. However, direct injection of ferric chloride into the left amygdaloid nucleus of the rat caused a time-dependent increase in [3H]spiperone binding sites in contralateral amygdala and striatum and ipsilateral nucleus accumbens (Csernansky et al, 1983) with a supersensitivity behavioral response to apomorphine. These results suggest that iron may have a selective effect on the dopamine D, receptors in the CNS of the rat.The present study was carried out to investigate the effect of iron salts and iron chelators on the binding of [3H]spiperone to the D, receptor in vitro and to examine whether the in vivo reduction in binding of D, receptors observed as a result of iron deficiency could be reversed in vitro by addition of iron salts.…”

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confidence: 98%

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confidence: 98%

Effect of Iron Chelators on Dopamine D₂ Receptors

Ben‐Shachar

Finberg

Youdim

1985

Journal of Neurochemistry

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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.

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“…The animals' suscep-tibility to apomorphine is significantly diminished. In contrast, increased apomorphine-induced behaviour and [3H] spiperone binding sites in the caudate nucleus are observed following injection of ferric chloride into either the amygdala-hippocampus complex (Csernansky et al, 1983) or intraventricularly (Ben-Shachar and Youdim, 1987). This also results in a time-dependent biochemical and behavioural supersensitivity of dopamine Dz receptors (BenShachar et al, 1985).…”

Section: Introductionmentioning

confidence: 90%

Injection of a minuscule dose of FeCl3 within the ventrolateral striatum causes a chronic disturbance of the integrative function within the limbic part of the ventral striatum

Kolasiewicz

Jaros

Heim

et al. 1995

J Neural Transm Gen Sect

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The present study shows that low amounts of applied iron have a potent effect on the ventrolateral striatum. This is reflected by an influence on spontaneous night activity, cognitive behaviour during the water maze navigation task, exploratory activity and in response to postsynaptic apomorphine stimulation. Such functional disturbances could be observed up to months after a single application of either 0.3 microgram or 1.5 micrograms FeCl3. The low dose of iron stimulates while 1.5 micrograms inhibits the spontaneous dopaminedependent locomotor night and explorative activity. The low concentration of ionic iron injected intrastriatally also increases lipid peroxidation in striatal and hippocampal tissues. These results suggest that the functional integrity of the ventral striatum and the regulation of the iron metabolism are critical for the sensorimotor performance.

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Dopaminergic supersensitivity at distant sites following induced epileptic foci

Cited by 35 publications

References 15 publications

Typical and Atypical Neuroleptics Induce Alteration in Blood‐Brain Barrier and Brain ⁵⁹FeCl₃ Uptake

Typical and Atypical Neuroleptics Induce Alteration in Blood‐Brain Barrier and Brain ⁵⁹FeCl₃ Uptake

Effect of Iron Chelators on Dopamine D₂ Receptors

Injection of a minuscule dose of FeCl3 within the ventrolateral striatum causes a chronic disturbance of the integrative function within the limbic part of the ventral striatum

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Dopaminergic supersensitivity at distant sites following induced epileptic foci

Cited by 35 publications

References 15 publications

Typical and Atypical Neuroleptics Induce Alteration in Blood‐Brain Barrier and Brain 59FeCl3 Uptake

Typical and Atypical Neuroleptics Induce Alteration in Blood‐Brain Barrier and Brain 59FeCl3 Uptake

Effect of Iron Chelators on Dopamine D2 Receptors

Injection of a minuscule dose of FeCl3 within the ventrolateral striatum causes a chronic disturbance of the integrative function within the limbic part of the ventral striatum

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Typical and Atypical Neuroleptics Induce Alteration in Blood‐Brain Barrier and Brain ⁵⁹FeCl₃ Uptake

Typical and Atypical Neuroleptics Induce Alteration in Blood‐Brain Barrier and Brain ⁵⁹FeCl₃ Uptake

Effect of Iron Chelators on Dopamine D₂ Receptors