Dorit Ben-Shachar

Transcranial magnetic stimulation induces alterations in brain monoamines.

SummaryTranscranial magnetic stimulation has been suggested as a possible therapeutic tool in depression. In behavioral models of depression, magnetic stimulation induced similar effects to those of electroconvulsive shock. This study demonstrates the effect of a single session of rapid TMS on tissue monoamines in rat brain. Alterations in monoamines were selective and specific in relation to brain areas and type of monoamine. The results imply on a biochemical basis to the suggested ECT-like treatment potential of TMS.

Nutritional iron and dopamine binding sites in the rat brain

Iron-deficiency (ID) anemia in man is associated with neurological disorders and abnormal behavior. Rats made nutritionally iron-deficient have markedly diminished behavioral responses to centrally-acting drugs (amphetamine and apomorphine) which affect monoaminergic systems. ID has no effect on either the levels of monoamines or on the activities of monoamine-metabolizing enzymes in the brain. We have investigated the possibility that ID may affect postsynaptic events at the level of receptor by measuring the specific binding sites of several neurotransmitters in different brain areas. The results clearly show that ID causes a significant (40-60%) reduction of the DA D2 binding sites in the caudate. DA-sensitive adenylate cyclase, alpha- and beta-adrenergic, muscarinic cholinergic and the benzodiazepine binding sites were not affected by ID. The effects of ID on DA D2 binding sites and the behavioral responses to apomorphine can be reversed when iron-deficient rats are placed for 8 days on an iron-deficient diet supplemented with iron. Chronic hemolytic anemia produced by repeated phenylhydrazine injections caused no change in serum iron and had no effect on either apomorphine-induced hyperactivity or 3H-spiroperidol binding in the caudate. Since the highest concentration of iron is found in DA-rich brain areas, it is possible that iron may be crucial to either the synthesis or coupling of the DA D2 binding site. The possibility that the DA supersensitivity induced by neuroleptics may be related to iron metabolism in the brain has been investigated.

Long-term consequence of early iron-deficiency on dopaminergic neurotransmission in rats

Nutritional iron‐deficiency (ID) induced in rats caused a reduction in peripheral as well as central iron metabolism. This effect was markedly greater in the liver than the brain. Although the decrease in the rate of brain non‐haem iron was slower than that of serum and liver, significant diminutions of behavioral response to apomorphine (2 mg/kg) and maximum [3H]spiperone binding (Bmax) in caudate nucleus were noted in these animals. These effects of ID can be reserved byron supplementation in young (21‐day‐old) and adult (48‐day‐old) rats. In contrast, if ID is induced in new born (10‐day‐old) animals, the diminished brain non‐haem iron, behavioral response to apomorphine and [3H]‐spiperone binding in caudate nucleus will not recover even after 6 weeks of iron supplementation. However, these animals have normal serum iron, haemoglobin and liver iron. These data point to the profound effect early ID can have on the development of dopaminergic neurotransmission, since brain iron concentration increases its maximum in the 4–5 weeks after birth. The implications of the present finding is that the prevalence of ID in children occurs in the first decade of life, when brain iron accumulation reaches values observed in adults. The profound cognitive changes associated with ID in children is thought to be dopamine‐dependent and is not always reversible with iron therapy.

Effect of Iron Chelators on Dopamine D2 Receptors

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, α,α′‐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 β‐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.

Iron, melanin and dopamine interaction: relevance to Parkinson's disease.

1. Interaction between iron and melanin may provide a reasonable explanation for the vulnerability of the melanin containing dopaminergic neurons in the substantia nigra (SN) to neurodegeneration in Parkinsons disease (PD). 2. Scatchard analysis of the binding of iron to synthetic dopamine melanin revealed a high-affinity (KD = 13 nM) and a lower affinity (KD = 200 nM) binding sites. 3. The binding of iron to melanin is dependent on the concentration of melanin and on pH. 4. Iron chelators, U74500A, desferrioxamine and to a lesser extent 1,10-phenanthroline and chlorpromazine could displace iron from melanin. In contrast, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its metabolite 1-methyl-4-phenyl-pyridinium (MPP+), which cause Parkinsonism, were unable to displace iron. 5. Melanin alone reduced lipid peroxidation in rat cortical membrane preparations. However, iron induced lipid peroxidation, which could be inhibited by desferrioxamine, was potentiated by melanin. 6. Iron bound to neuromelanin in melanized dopamine neurons was detected only in parkinsonian brains and not in controls. The interaction of iron with neuromelanin as identified by x-ray defraction technique was identical to iron interaction with synthetic dopamine melanin. 7. In the absence of an identified exogenous or endogenous neurotoxin in idiopathic Parkinsons disease, iron-melanin interaction in the SN may serve as a candidate for the oxygen-radical induced neurodegeneration of the melanin containing dopaminergic neurons.

The interplay between mitochondrial complex I, dopamine and Sp1 in schizophrenia

Schizophrenia is currently believed to result from variations in multiple genes, each contributing a subtle effect, which combines with each other and with environmental stimuli to impact both early and late brain development. At present, schizophrenia clinical heterogeneity as well as the difficulties in relating cognitive, emotional and behavioral functions to brain substrates hinders the identification of a disease-specific anatomical, physiological, molecular or genetic abnormality. Mitochondria play a pivotal role in many essential processes, such as energy production, intracellular calcium buffering, transmission of neurotransmitters, apoptosis and ROS production, all either leading to cell death or playing a role in synaptic plasticity. These processes have been well established as underlying altered neuronal activity and thereby abnormal neuronal circuitry and plasticity, ultimately affecting behavioral outcomes. The present article reviews evidence supporting a dysfunction of mitochondria in schizophrenia, including mitochondrial hypoplasia, impairments in the oxidative phosphorylation system (OXPHOS) as well as altered mitochondrial-related gene expression. Abnormalities in mitochondrial complex I, which plays a major role in controlling OXPHOS activity, are discussed. Among them are schizophrenia specific as well as disease-state-specific alterations in complex I activity in the peripheral tissue, which can be modulated by DA. In addition, CNS and peripheral abnormalities in the expression of three of complex I subunits, associated with parallel alterations in their transcription factor, specificity protein 1 (Sp1) are reviewed. Finally, this review discusses the question of disease specificity of mitochondrial pathologies and suggests that mitochondria dysfunction could cause or arise from anomalities in processes involved in brain connectivity.

Increased hepatic and reduced prostatic prolactin (PRL) binding in iron deficiency and during neuroleptic treatment: Correlation with changes in serum PRL and testosterone

Iron deficiency (ID) induced in 21 day old male rats for 28 days caused a 7 fold increase in hepatic prolactin (PRL)-specific binding and a parallel 3 fold rise in serum PRL, as expected from both the reported reduction in central dopaminergic (DA) activity and PRLs up-regulating effect on its own liver receptors. Similarly, serum testosterone was increased by 80%. Prostatic PRL binding was slightly reduced (by 27%), possibly because of masking by the raised hormone levels, although more likely by a more generalized reduction in proliferation during ID, as indicated by the 50% prostatic weight loss. Chronic treatment with neuroleptics also increased hepatic PRL binding in accord with their anti DA activity: chlorpromazine (10 mg/kg) or fluphenazine (5 mg/kg) injected daily (i.p.) for 21 days followed by a 3 day drug-free period resulted in 26 and 10 fold increases, respectively. The parallel reductions of serum levels of PRL (by 40%) and of testosterone (by 70%) by both drugs is indicative of the drug withdrawal supersensitivity normally observed in the caudate nucleus DA receptor. A testicular peripheral effect of the neuroleptics probably further accounted for the reduction in testosterone synthesis, reinforcing the induction of liver PRL binding by these drugs and explaining their negative effects on prostate PRL binding and weight. These findings stress the importance of monitoring hormone levels in ID and during treatment with neuroleptics, in order to avoid endocrine side-effects.

Mitochondrial Oxidative Phosphorylation System (OXPHOS) Deficits in Schizophrenia Possible Interactions with Cellular Processes

Mitochondria are key players in the generation and regulation of cellular bioenergetics, producing the majority of adenosine triphosphate molecules by the oxidative phosphorylation system (OXPHOS). Linked to numerous signaling pathways and cellular functions, mitochondria, and OXPHOS in particular, are involved in neuronal development, connectivity, plasticity, and differentiation. Impairments in a variety of mitochondrial functions have been described in different general and psychiatric disorders, including schizophrenia (SCZ), a severe, chronic, debilitating illness that heavily affects the lives of patients and their families. This article reviews findings emphasizing the role of OXPHOS in the pathophysiology of SCZ. Evidence accumulated during the past few decades from imaging, transcriptomic, proteomic, and metabolomic studies points at OXPHOS deficit involvement in SCZ. Abnormalities have been reported in high-energy phosphates generated by the OXPHOS, in the activity of its complexes and gene expression, primarily of complex I (CoI). In addition, cellular signaling such as cAMP/protein kinase A (PKA) and Ca+2, neuronal development, connectivity, and plasticity have been linked to OXPHOS function and are reported to be impaired in SCZ. Finally, CoI has been shown as a site of interaction for both dopamine (DA) and antipsychotic drugs, further substantiating its role in the pathology of SCZ. Understanding the role of mitochondria and the OXPHOS in particular may encourage new insights into the pathophysiology and etiology of this debilitating disorder.

Characterization of the hepatic prolactin receptors induced by chronic iron deficiency and neuroleptics

Nutritional iron deficiency (ID), like neuroleptic treatment, results in a reduction in dopaminergic activity and a rise in serum prolactin (PRL). Since PRL has been shown to regulate its own receptors, we studied PRL binding sites during the above treatments. ID induced in 21 day old male rats for 28 days, or treatment with either chlorpromazine (10 mg/kg per day i.p.) or fluphenazine (5 mg/kg per day i.p.) for 21 days or haloperidol (5 mg/kg per day i.p.) for 9 days, caused significant increases (3- to 8-fold) in [125I]oPRL specific binding to the liver membranes. The combined treatment with haloperidol and ID, as above, resulted in an additive effect on hepatic PRL receptors, suggesting that the actions of neuroleptics and ID may be either submaximal or mediated by two different mechanisms. After 7 days or recovery from ID, the induced PRL receptors were completely reduced to the control values. In vitro desaturation of the induced PRL binding sites with MgCl2 caused a further increase (1.57-fold) in PRL binding. Characterization of the hepatic PRL binding sites induced by ID showed properties similar to those reported for the classical PRL receptors, including specificity for the lactogenic hormones, a high affinity constant (2.38 X 10(10) M-1) and inhibition of PRL binding to the induced receptors by an anti-PRL receptor antibody. The results of this study further support the suggested role of endogenous PRL in inducing its own receptors.

Iron-Melanin Interaction in Substantia Nigra as the Neurotoxic Component of Parkinson’s Disease

In spite of the fashion to implicate environmental (e.g. MPTP-like) or endogenous (6-hydroxydopamine like) neurotoxins or an interaction between such factors and ageing as a process for nigra-striatal dopamine neuron loss, resulting in Parkinsonian syndrome, the primary cause of the idiopathic Parkinson’s Disease (PD) remains unknown. The nigra-striatal (SN) dopamine neurons of basal ganglia are very sensitive to many chemical insults, some of which have endogenous origin. Among these are the generation of oxygen free radicals formed from H2O2, generated by auto-oxidation and oxidative deamination of dopamine to melanin and deaminated products, respectively. The basal ganglia is endowed with highly active systems for scavenging of oxygen radicals. Among these are glutathione, glutathione peroxidase, superoxide dismutase and ascorbate, known to be present in relatively high concentrations. Theoretically a reduction in any of these could be highly damaging to the dopamine neurons (1). However, biochemical reactions which would promote the excessive formation of cytotoxic oxygen free radicals and which in turn can be highly damaging to the cell as a resultant lipid peroxidation should also be considered.Thus, ultimately, the balance between production and disposition of free radical may be the important factor. This has led a number of investigators to implicate oxidative stress as the primary cause of PD (2,3).