Z. Oberman

Changes in serum dopamine-beta-hydroxylase activity during cold pressor test in subjects with high and low basal activity of this enzyme

Twenty-seven healthy subjects, eight with high levels, eight with low levels and eleven with intermediate levels of serum dopamine-beta-hydroxylase (DBH) activity, were investigated. Serum DBH activity and blood pressure were measured in their response to the cold pressure test (CPT). Plasma renin activity (PRA) was also estimated. Blood pressure, systolic and dyastolic, increased equally in the three groups. PRA did not change significantly throughout the test in any of the groups. Serum DBH activity increased significantly in the group with low initial levels. No significant changes were seen in the controls and in the group with high initial serum DBH activity. It is suggested that subjects with high basal serum DBH activity might have a genetically-determined high sympathetic tone and therefore would hardly respond to a mild stress like CPT; the opposite might be true for the subjects with low basal DBH activity levels.

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.

Antiserotonergic inhibition of calcitonin-induced increase of beta-endorphin, ACTH, and cortisol secretion.

In a previous study we observed that calcitonin increases β-endorphin, ACTH, and cortisol secretion. We assumed that calcitonin might have a modulatory role on the pituitary function. The present study was initiated to clarify whether this effect is due to a direct pituitary stimulation or to an indirect stimulation through CRF (corticotropin releasing factor). Fourteen healthy subjects, aged 30–60 years were investigated. All the subjects received 100IU Salmon calcitonin Sandoz i.v. at 8a.m. (time 0). Plasma β-endorphin, ACTH and cortisol were estimated every 30min from − 30 to 120 min by specific radioimmunoassay. The same parameters were estimated a second time, at the same intervals, when cyproheptadine 8 mg (7 subjects) and 40 mg propranolol (7 subjects) were given per os at − 30 min and calcitonin i.v. at time 0. β-endorphin, ACTH and cortisol levels (Mean ±SEM) rose significantly after calcitonin (peak value at 30–90 min) from 5.2 ±0.7 to 15.1±2.6 pmol/l; from 43.0±2.7 to 70.7±4.1 pg/ml and from 10.6±1.5 to 19.6 ±2.1 μg/100 ml respectively (p< 0.0001 by analysis of variance and covariance and repeated measures). Propranolol 40 mg (per os) administered at time − 30 did not alter the response of β-endorphin, ACTH and cortisol to calcitonin (infused at time 0). Cyproheptadine, the antiserotonergic substance that inhibits the synthesis and release of CRF completely inhibited the stimulatory effect of calcitonin. We conclude that probably calcitonin has a modulatory role on the hypothalamo-pituitary adrenal axis and that it acts at the hypothalamic level probably by stimulating CRF secretion.

Failure of naloxone to antagonize metoclopramide induced prolactin rise.

Seven subjects aged 21–54 years were investigated. Serum PRL and DBH were estimated before and at 30, 60, 90 and 120 min after the administration of 20 mg clopropamide. The same parameters were estimated a second time when 0.4 mg naloxone was associated. PRL level increased and DBH decreased in all the patients in both investigations and no significant differences between the two occasions were detected. It is suggested that probably the two substances do not act on identical receptors.

Effect of diphenylhydantoin on patterns of insulin secretion in obese subjects.

SummaryThe effect of short-term treatment with diphenylhydantoin (DPH) on the insulin secretion patterns during OGTT and on the daily insulin profile was studied in obese patients. DPH treatment for 3 days with a dose of 300 mg/die (100 mg, 3 times daily) significantly decreased the insulin release after glucose ingestion, but did not alter the basal insulin level. No effect on the fasting glucose concentration as well as on the glucose profiles during OGTT was observed after short-term DPH treatment. A smaller decrease of plasma free fatty acid concentration during OGTT performed after DPH administration confirmed the inhibitory effect of the drug on insulin release. Short-term DPH treatment was also shown to decrease markedly the postprandial insulin release in obese patients. No difference was noted between plasma 11-OHCS and serum HGH concentrations during OGTT before and after DPH treatment. The possible therapeutic role of DPH in obesity is discussed.

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.

Dexamethasone suppression of the calcitonin induced β-endorphin, ACTH and cortisol secretion

Our previous observations have shown that calcitonin (CT) stimulates β-endorphin, ACTH, and cortisol secretion. In order to give further information on the supposed hypothalamic pituitary involvement in this effect, we studied the influence of dexamethasone on this stimulative influence of CT. Six healthy women aged 50–65 years were investigated. All the subjects received 100 U CT salmon (Sandoz) i.v. at 0800 (0 time). Plasma β-endorphin, ACTH, and cortisol were estimated every 30 min from −30 to 120 min by specific radioimmunoassays. The same subjects were evaluated a second time, at the same intervals, when 1 mg dexamethasone was administered per os at 11 PM the previous night and CT i.v. at 0800 the next morning. β-endorphin, ACTH, and cortisol levels (mean±SEM) rose significantly after 100 U CT from 5.6±0.17 to 16.75±1.8 pmol/L (p<0.001); from 39.6±6 to 88.0±3.1 pg/ml (p<0.0001) (from 8.7±1.3 to 19.4±0.7pmol/ L); and from 13.1±1.6 to 23.8±3.0μg/dl (p<0.0001) [374±45 to 680±85 nmol/L], respectively. Dexamethasone suppressed almost completely the stimulatory effect of CT β-endorphin rose from 4.9±0.12 to 6.3±1.3 pmol/L (n.s.), ACTH from 38.6±5.1 to 42.6±6.2 pg/ml (n.s.) (from 8.5±1.1 to 9.4±0.9 pmol/L) and cortisol from 0.88±0.23 to 0.88±0.18 ng/dl (n.s.) (from 25.1±6.5 to 25.0±5.1 nmol/L). β-endorphin and cortisol rose significantly after 50 and 25 U CT but less than after 100 U CT. 50 U CT increased the β-enorphin and cortisol levels from 4.8±0.49 to 7.98±0.4pmol/L(p<0.05) and from 10.46±1.48 to 16.4±3.3/ dl (p<0.05) (from 299±42 to 468±95 nmol/L), respectively. 25 U CT increased the β-endorphin and cortisol levels from 4.6±0.58 to 5.9±0.88 pmol/L (p<0.05) and from 10.90±1.00 to 15.35±1.8 μg/dl (p<0.05) (from 311±28 to 438±51 nmol/L). Dexamethasone is known to inhibit the hypothalamic-pituitary-adrenal axis. The inhibition of the CT stimulative effect on β-endorphin, ACTH, and cortisol observed in this study enforces our idea that CT exerts this effect by stimulating the hypothalamic-pituitary-adrenal axis.

Dopamine uptake by platelet storage granules in first-degree relatives of Tourette's syndrome patients.

BACKGROUND Considering that platelets have been established to be good peripheral markers for the study of catecholaminergic neurons, we have applied an assay to measure the uptake of (3H)-dopamine (DA) into platelet storage granules (PSG). Recently, we reported that Tourettes syndrome (TS) patients (pts) show decreased DA uptake into PSG. METHODS In the present study, 28 first-degree relatives (3 with chronic motor tics, 3 with transient tics, 6 with obsessive-compulsive behavior, and 16 without symptomatology) belonging to the families of 13 patients, and 14 unrelated healthy controls were studied. RESULTS Double reciprocal plots were constructed for each subject, and the apparent maximum velocity (Vmax) and Michaelis constant (K(m)) were determined by linear regression analysis (Lineaweaver-Burke plots). The uptake of DA (0.5-5 mumol/L) (mean +/- SEM) by PSG from relatives with symptomatology was similar to the TS patients (symptomatic relatives Vmax 181 +/- 22.2 fmol/mg protein, K(m) (mumol/L) 6.42 +/- 0.29; TS pts Vmax 108 +/- 6.9, K(m) 7.79 +/- 0.64). Relatives without symptomatology on the contrary showed DA affinity characteristics similar to the controls (t test, paired t test, multivariate analysis of variance, and log transformation). CONCLUSIONS The data presented suggest that TS is hereditary, but they do not distinguish between an autosomal dominant inheritance and a mixed or polygenic model.

Changes in plasma glucose, free fatty acids (FFA), cortisol, immunoreactive human growth hormone (IRHGH) and immunoreactive insulin (IRI) after tolbutamide-induced hypoglycemia in obese subjects

SummaryThe investigation was carried out on 30 subjects: 21 obese subjects and 9 normal weight controls. Twelve of the obese subjects and the 9 controls received 1 g tolbutamide i.v.; the other 9 obese subjects received 1.5 g tolbutamide, all in fasting condition. Plasma glucose, FFA, cortisol, serum IRI, and IRHGH were measured before and 15, 30, 60, 90 and 120 min after tolbutamide administration. A blunted response of cortisol and IRHGH to the hypoglycemic stimulus was observed in obese subjects receiving 1 g tolbutamide. The blunted response was reversed when 1.5 g tolbutamide was injected. Glucose levels were significantly higher at 60 min in the obese who received 1 g tolbutamide as compared to the controls, and were significantly lower 30, 60 and 90 min after the tolbutamide injection in obese who received 1.5 g tolbutamide. FFA showed significantly higher values 90 and 120 min after the injection in both groups of obese subjects: dose dependency was not observed. Insulin values were significantly higher 15 min after tolbutamide injection in the obese receiving 1.5 g tolbutamide when compared to those receiving 1 g and to the controls. The blunted plasma cortisol and serum IRHGH responses were reversed when larger doses were used. Some possible explanations for the results are discussed: a hypothalamo-pituitary underresponsiveness, a lower ratio of biologically active versus biologically unactive IRI, and peripheric insulin resistance in obesity.