Eran Graff

The influence of meal composition on plasma serotonin and norepinephrine concentrations

Reports concerning changes in plasma neurotransmitter values that result from dietary manipulations have not been published so far. The influence of various meal compositions on platelet-poor plasma (PPP) serotonin (5-HT) and norepinephrine (NE) levels was investigated. Healthy volunteers were subjected to three test meals: a carbohydrate-rich meal (86% carbohydrates), a protein-rich meal (70% protein), and a fat-rich meal (92% fat). After a carbohydrate-rich meal, PPP 5-HT values increased significantly (4.47-fold, P less than .02), whereas a smaller increase (1.66-fold, P = NS) was observed after a fat-rich meal. These effects on PPP 5-HT values could be correlated with insulin plasma levels. A protein-rich meal significantly reduced (P = 0.0011) PPP 5-HT to 28% of initial values, despite an increase in plasma insulin levels. This study has shown that (1) changes in meal compositions influence PPP 5-HT and, to a lesser extent, NE values; (2) the resulting changes in PPP 5-HT levels parallel those reported for brain neurotransmitters; and (3) these results seem to indicate that PPP 5-HT levels may be a model for brain synthesis and release of 5-HT.

Cys 618 Arg mutation in the RET proto-oncogene associated with familial medullary thyroid carcinoma and maternally transmitted Hirschsprung's disease suggesting a role for imprinting

The multiple endocrine neoplasia type 2 (MEN2) syndromes and Hirschsprungs disease (HSCR) are inherited neurocristopathies characterized by medullary thyroid carcinoma (MTC), pheochromocytoma, parathyroid disease, and gastrointestinal neuromatosis. Mutations in the RET proto‐oncogene are the underlying cause of the MEN2 syndromes and some cases of HSCR. In this report, we show that Cys 618 Arg mutation cosegregates with familial MTC and HSCR in two Moroccan Jewish families in which no involvement of pheochromocytoma or parathyroidism was observed. A single haplotype shared by chromosomes bearing the Cys 618 Arg mutation in both families strongly suggests a founder effect for this mutation. We have observed in our and in several other previously reported families, an excess of maternal over paternal mutated RET alleles in offsprings affected by HSCR. We suggest that parental imprinting may play a role in the ethiology of HSCR caused by mutations in the RET protooncogene. Hum Mutat 10:155–159, 1997.

Single Oral High-Dose Vitamin D3 Prophylaxis in the Elderly

A poor vitamin D status is common in the elderly during the winter months. Because it is possible that hypovitaminosis D may be a cause of senile osteopenia, a simple method of prophylaxis would be useful. The single, oral, high‐dose method was tested in two old‐age homes, and the efficacy of vitamin D3 was compared with that of 25‐hydroxyvitamin D3 (25‐OHD3). The trials showed that 25‐OHD3 caused a higher peak value in the serum 25‐OHD levels in the second week than did vitamin D3. However, follow‐up after four to five months showed that in those patients who received a single, oral dose of 25‐OHD3, the serum 25‐OHD levels had returned to the baseline low values, whereas in those patients who had had oral vitamin D3, the serum 25‐OHD levels still remained significantly raised compared with the baseline values and were within normal limits, It is concluded that the single, oral, high‐dose method using vitamin D3 is a safe and simple method of prophylaxis and could be used easily in large populations of elderly persons. J Am Geriatr Soc 34:515–518, 1986

Cortisol, ACTH, and beta-endorphin after dexamethasone administration in Parkinson's dementia

The dexamethasone suppression test (DST) has been suggested as an effective tool for differentiating between depression and dementia. After administering 1 mg dexamethasone, we measured cortisol, ACTH, and beta-endorphin levels in 32 nondepressed patients with idiopathic Parkinsons disease (PD) (14 also with dementia) and 20 healthy, age-matched controls. Four of the 20 controls, 9 of the 18 with PD alone, and 8 of the 14 with PD and dementia were dexamethasone nonsuppressors (cortisol value greater than or equal to 5 micrograms/100 ml). PD patients without dementia (nonsuppressors) showed higher basal plasma values of cortisol (22.06 +/- 5.30 micrograms/100 ml) compared with the suppressors (13.38 +/- 3.30 micrograms/100 ml). Plasma ACTH and beta-endorphin responded in a coupled way to dexamethasone challenge. Higher basal levels of both peptides were found among PD patients (demented and nondemented), nonresponders to DST. Thus, the DST does not appear to be effective in differentiating between depression and dementia in PD. In addition, PD nonsuppressors showed higher basal values of plasma ACTH, beta-endorphin, and cortisol (similar to patients with major depression). This suggests that although the depression is clinically undetectable, both disorders may share some pathophysiological features at the hypothalamic hypophyseal adrenal level.

Prospective evaluation of circulatory levels of catecholamines and serotonin in neuroleptic malignant syndrome.

Objective: Neuroleptic malignant syndrome (NMS) may be associated with a dysregulation of the catecholaminergic and serotonergic systems. The objective of the present study was to evaluate prospectively the circulatory levels of serotonin (5‐HT), epinephrine (E) and dopa in patients suffering from NMS.

Bromocriptine blood levels after the concomitant administration of levodopa, amantadine and biperiden in Parkinson's disease

We recently demonstrated that when different drugs (mainly used for the treatment of Parkinsons disease) are administered in combination they interfere with the availability of bromocriptine in the brain of rats (striatum and hypothalamus). In the present study performed with parkinsonian patients, we measured plasma levels of bromocriptine (RIA) over 4h after giving orally 5 mg bromocriptine alone; together with levodopa 250 mg plus 25 mg DCI (10 patients); with 100 mg amantadine HC1 (5 patients) and with biperiden 5 mg (5 patients). Amantadine and biperiden did not interfere with the pharmacokinetics of bromocriptine. However, levodopa significantly diminished plasma levels (a mean increment of 1.78 mg ± 0.30 vs 0.92 ± 0.18 mg/ml). We postulate that levodopa may interfere with the metabolism of bromocriptine in the liver. Although we did not observe substantial clinical differences among the patients (Webster scale), this study supports our previous findings and suggests that one of the advantages of combined treatment may result from a modification of the plasma levels of bromocriptine by levodopa. A “smoothing”of the plasma bromocriptine curve possibly avoids sudden oscillations of the drug availability and enables a more “stable”penetrability of the medication into the central nervous system.

Selective regional effect of various neuroactive drugs on bromocriptine concentration in the brain of rats

Abstract Bromocriptine (2‐Br‐alpha‐ergocryptine), a partial ergoline derivative, is a dopamine agonist which has been used successfully in the treatment of hyperprolactinemia, acromegaly and Parkinsons disease. The main targets for the action of the drug are the hypothalamic, hypophyseal pathway and the striatum. These regions contain different populations of neurons which interact with each other in a complex way. In order to check the mechanism of these interactions in rats, we administered different neuroactive durgs together with bromocriptine. After a single intraperitoneal injection, bromocriptine concentration in the striatum was 13.1 ± 2.9 ng/mg protein, and in the hypothalamus 13.9 ± 0.8 ng/mg protein. The largest increase in the bromocriptine content in the striatum was found after the concomitant administration of naloxone, an opiate receptor blocker (21.2 ± 2.5 ng/mg protein). The largest increase of the bromocriptine content in the hypothalamus was found after the concomitant injection of methysergide, a serotonin receptor blocker (27.8 ± 2.6 ng/mg protein). Amantadine, diazepam and haloperidol caused the largest decrease in the two regions. The mechanism of interaction and therapeutic implication of these findings are discussed.