Magnesium involvement in sleep: genetic and nutritional models.

Alterations of peripheral magnesium (Mg) concentration have been reported in association with several behavioral disorders and sleep organization. Blood Mg regulation is under a strong genetic control, whereas brain Mg regulation does not seem to be affected. We have studied peripheral and central levels of Mg and analyzed sleep in two lines of mice selected for low (MGL) and high (MGH) red blood cell (RBC) Mg levels. The same variables were also studied in C57BL/6J mice before and after 3 weeks of Mg deficiency. Whereas blood Mg was highly affected by the selection, brain Mg exhibited only small differences between the two lines. In contrast, Mg deficiency strongly decreased both central and peripheral Mg levels. Sleep analysis indicated that in both models the amount of paradoxical sleep was lower in mice with higher Mg levels. The amplitude of daily variation in sleep and slow-wave sleep delta power was markedly decreased in MGH line. Quantitative electroencephalogram (EEG) analysis also revealed a faster theta peak frequency in MGH mice, irrespective of behavioral states. Central Mg showed significant correlations with the amount of paradoxical sleep and sleep consolidation. However, because the direction of these correlations was not consistent, it is concluded that optimal, (physiological) rather than high or low, Mg levels are needed for normal sleep regulation.

Blood and brain magnesium in inbred mice and their correlation with sleep quality.

A strong genetic component in the regulation of blood magnesium (Mg) levels has been demonstrated. The regulation and distribution of brain Mg levels, however, have never been assessed. Herein we report on the genetic variation of peripheral and central Mg levels in six inbred strains of mice. In addition, the possible involvement of Mg in sleep regulation was assessed by establishing correlations between Mg and sleep parameters obtained before and after a 6-h sleep deprivation. Although genotype strongly determined blood Mg levels, it did not affect brain Mg, suggesting that central and peripheral Mg are regulated differently. Central Mg displayed a highly structure-specific distribution with frontal cortex having the highest and brain stem the lowest values. Whereas for the amount and distribution of baseline sleep only marginal correlations with Mg were found, Mg contents in four of nine brain structures were highly positively correlated with the length of slow-wave sleep episodes during recovery. This relationship suggests that higher levels of Mg in specific brain sites promote sleep quality as part of a recovery process.

[Not Available]. / Relationship between blood magnesium and psychomotor retardation in drug-free patients with major depression.

In previous reports, we have observed that blood magnesium was significantly higher in drug-free patients with major depression when compared to healthy controls. This was especially true for erythrocyte magnesium. Furthermore, the most severely depressed patients had the highest intracellular magnesium content, showing that intracellular magnesium rate was related to the intensity of symptoms. We report here the results of blood magnesium measured in 88 major depressed patients as compared to 61 controls. We show that the mean erythrocyte and also plasma magnesium contents are both increased in these patients. We observe that about 40% of male and female patients have a very significant increase (25%) in intracellular magnesium content as compared to controls. However, about 60% of the hospitalised depressed patients have normal values. None of the controls has high erythrocyte magnesium. This is less evident concerning the plasma magnesium. No differences are observed between patients when classified according to the intensity of moral pain or anxiety. In contrast, the patients with mild to high psychomotor retardation score, which is an index of hypoexcitability, have significant higher erythrocyte magnesium values compared with other patients. The results of male patients without psychomotor retardation do not differ from control values. Our study suggests that central hypoexcitability might be related to an increase in intracellular magnesium observed at the peripheral level, keeping in mind that hyperexcitability, as observed in various conditions such as stress and cardiovascular disorders, is frequently associated, in contrast, with a decrease in blood magnesium.

Weak association between blood sodium, potassium, and calcium and intensity of symptoms in major depressed patients.

In previous reports, we showed that plasma and erythrocyte magnesium were increased in many drug-free hospitalized depressed patients. Furthermore, we observed that erythrocyte magnesium content was related to the intensity of the symptoms. Highly depressed patients had the highest magnesium values. Today, we report the results of plasma and erythrocyte sodium and potassium, and of total and ultrafilterable plasma calcium in 66 hospitalized patients with major depression compared to 58 healthy controls. No consistent differences in these biochemical parameters are observed between patients when separated according to intensity of anxiety, psychomotor retardation, and moral distress. Plasma sodium is higher and plasma potassium lower in female patients of all subgroups as compared to controls. Both male patients and controls have erythrocyte sodium and potassium levels that are significantly different from those of females. This clearly suggests a separation into genders in such studies. In conclusion--in contrast to blood magnesium--sodium, potassium, and calcium levels do not seem to be related to the intensity of the main clinical symptoms in hospitalized patients with major depression.

Relationship between erythrocyte magnesium, plasma electrolytes and cortisol, and intensity of symptoms in major depressed patients.

53 male and female drug-free major depressed patients were separated into three groups according to the severity of the depression. In the entire regrouped population, plasma and erythrocyte magnesium (Mg) were shown to increase as compared with 48 healthy controls, confirming our previous studies. The middle and highly depressed patients had higher erythrocyte and also plasma Mg levels than either lowly depressed patients or controls. Only, a few differences were noticed in plasma sodium, potassium and calcium (Ca) in the three groups of patients, except for ultrafiltrable plasma Ca, measured for the first time in affective disorders. Thus, erythrocyte and also plasma Mg are shown to be associated with the intensity of the depression. As blood hypomagnaesemia is often related to hyperexcitability, further investigations are actually in process to shown whether hypermagnesaemia might be, in contrast, associated with psychomotor retardation as observed in many depressed patients.

Sodium-magnesium exchange in erythrocyte membranes from patients with affective disorders.

The Vmax of erythrocyte sodium-magnesium exchange was measured for the first time in 63 patients suffering from affective disorders and compared to that in 33 healthy subjects. Depressed patients had a significantly higher Vmax (215 +/- 13 vs. 151 +/- 14 mumol/l.cells/h; p < 0.005; mean +/- SEM). This tendency was conserved after division of the 63 patients into three clinical subgroups according to the DSM-III-R criteria. Thirty-four patients from this panel were divided into three subgroups according to the chemical class of the antidepressant drug used and were followed up during a 3-month period of drug treatment. Mood improvement over the 3-month period was associated with a slow increase in Vmax of Na/Mg exchange (delta increase approximately 25 mumol/l.cells/h), except in the subgroup of patients treated with non-tricyclic antidepressants (n = 8). These results are consistent with the previously reported link between high erythrocyte magnesium content and affective disorders. Indeed, enhanced Na/Mg exchange Vmax, which probably results from an increased number of transport units per cell, contributes to the normalization of red blood cell magnesium content correlated with mood improvement.

Blood magnesium, potassium, sodium, calcium and cortisol in drug-free depressed patients.

Many biochemical variables, including plasma and erythrocyte magnesium, were simultaneously measured in drug-free depressed patients (n = 34), compared to healthy controls (n = 35). Higher plasma and erythrocyte magnesium concentrations were observed in patients than in controls (+12 per cent, P < 0.0001 and 14 per cent, P < 0.0001, respectively). In contrast, patients showed a lower plasma potassium level (-10 per cent; P < 0.007). Cortisol secretion was much higher in patients (+35 per cent; P < 0.02), particularly in females, showing overactivity of the hypothalamo-hypophyseo-adrenal axis in the patients. Except in a few cases, plasma sodium and calcium in patients did not differ from control values. Significant differences in magnesium and cortisol levels were observed between patients classified in diagnostic groups and by sex, whereas little variation in the other biochemical indices was noted. The increase in blood magnesaemia and its possible association with central hypocatecholaminergic deficiency in affective disorders are discussed.

Evolution of blood magnesium, sodium and potassium in depressed patients followed for three months.

No consensus has been obtained about blood electrolyte status, especially about magnesium, in affective disorders. This is mainly due to the lack of information about the distribution of the patients in clinical subgroups, sex, type of treatment and about the severity of their illnesses. Most of these studies concerned treated patients. We confirmed in this study that drug-free depressed patients have higher erythrocyte and plasma magnesium than controls, as shown in previous reports. Significant differences are observed in as shown in previous reports. Significant differences are observed in patients for sex and between clinical subgroups. Low plasma potassium levels are described in both male and female depressed patients. The erythrocyte magnesium level tends to normalize in parallel with clinical improvement, depending on sex and clinical subgroup, and seems then to be related to the intensity of the depression. Plasma magnesium in male and female patients, except for female unipolars, remains higher than controls in all conditions and might be related to the diagnosis of affective disorders.

Reversible in vitro decrease of L-tyrosine and L-tryptophan influx across the human erythrocyte membrane induced by cytochalasin B, the specific inhibitor of D-glucose transport.

For many years, we have been studying, in psychiatric conditions, the influx of tyrosine (TYR) and tryptophan (TRP), the two amino acid precursors of monoamines, across the membrane of human blood cells. We have also attempted to characterize better the transport mechanisms. In a previous paper, we suggested a close relationship between glucose and the two neuter amino acid transports in vitro. The purpose of the present study is to test the effect of cytochalasin B, the specific and potent inhibitor of glucose transport. Our data show that at high concentrations, the cytochalasin B induces a reversible inhibition of about 70% or more on the temperature-dependent influx of the two amino acids, depending on the medium of incubation. The effect of cytochalasin B was about 200 times less for TYR and TRP transport than for glucose. The cytochalasin E, claimed to be a nonspecific inhibitor, decreased both these transports only when used at very high concentrations, as described for sugar influx in the same structure. In conclusion, we suggest that there is a relationship between the transport of glucose and nucleosides, both carried into the cells by the glycoprotein band 4.5, and the two amino acid precursors of monoamines.

In vitro effects of short-chain aliphatic alcohols, benzyl alcohol and chlorpromazine on the transport of precursors of monoamines across the human erythrocyte membrane.

In previous papers we reported a deficit of tyrosine (TYR) and tryptophan (TRP) transport across the erythrocyte membrane in depressed patients. To investigate further the transport mechanism of both monoamine precursors, we tested in healthy subjects the role played by membrane fluidity, using different fluidizing agents such as alcohols and the neuroleptic chlorpromazine. We found that the transport of both amino acids depended on the length of the chain of each alcohol tested (number of carbon atoms = C). No inhibition was observed after methanol (C1) preincubation, in contrast to benzyl alcohol (C6), which produced an inhibition of about 80% of amino acid basal transport. In a condition of incubation by suspension of cells in an artificial medium, we observed a dose response of these transports with ethanol used at doses of 0.1-1.3 M. Finally we found in this study that the effect of ethanol on membrane fluidity, and therefore on inhibition of basal amino acid transport, was totally reversible after having washed the suspended cells, suggesting a superficial, noncovalent ethanol binding on such biological membranes.

In vitro effects of ionophores and inhibitors of main sodium and calcium movements on tyrosine and tryptophan transport by human erythrocytes.

Peripheral models using blood cells might be biochemical markers in various psychiatric illnesses. In previous papers we reported a deficit of tyrosine and tryptophan transport in red cells incubated in plasma from depressed patients. In the present study we investigated the role played by sodium and calcium in these transports by using inhibitors and ionophores of the main movements of these electrolytes. We also studied the contribution of phloretin-sensitive countertransport, which has been described as low in psychiatric conditions.

[Endogenous 3-O-methyldopa in man: normal level and effect of an inhibitor of aromatic amino-acid decarboxylase (Benserazid) (author's transl)]. / 3-O-Méthyldopa plasmatique endogène chez l'homme: taux normaux et effet d'un inhibiteur des décarboxylases des acides amines aromatiques (Bensérazide).

The fasting level of 3-O-methyldopa in human plasma is 120 +/- 18 nmol/1. Four hours after a single dose of 425 mumol benserazid, the level increased to 313 +/- 69 nmol/1.