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 Tourette's 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.

Decreased dopamine uptake into platelet storage granules in Gilles de la Tourette disease.

The movement disorder of Gilles de la Tourette (GdlT) disease may reflect hyperactivity of the basal ganglionic dopamine system. Since platelets have been suggested as peripheral models for the study of catecholamine neurons, we developed a method to measure the uptake of [3H]-DA into platelet storage granules (PSG). In the present report, PSG were incubated with [3H] DA, and Vmax and Km values were calculated by linear regression analysis (Lineweaver Burke plot). The uptake of DA (0.5-5 microM) by PSG from 18 GdlT patients was significantly lower (p < .0001) compared to 15 controls (Vmax mean +/- SD, 107.5 +/- 42.5 and 265.3 +/- 66.5 fmole/mg protein resp.). The decrease of DA uptake in GdlT may reflect compensatory presynaptic changes that reduce DA activity.

[3H] dopamine uptake by platelet storage granules in Parkinson's disease.

[3H] Dopamine (DA) uptake by platelet storage granules was determined in 10 never-treated patients with Parkinson's disease (PD) (in 6 of them, also after 6 months of levodopa treatment), in 18 long-term levodopa-treated patients and in 15 age-matched normal controls. Maximum velocity (Vmax) of DA uptake was significantly lower in the group of never-treated PD subjects compared to healthy controls (P < 0.001) and also lower compared to the PD long-term treated patients (P < 0.025). The Vmax of PD never-treated changed after submitting the patients to 6 months treatment (P < 0.025) and became similar to the Vmax in the treated group. The apparent Michaelis constant (Km) of DA uptake in PD never-treated was also significantly different from controls (P < 0.005) and also different (but not significantly) from PD "long-term" treated patients. Decreased DA uptake by platelet storage granules in PD may reflect a generalized defect of dopaminergic cells with an impairment in the vesicularization of DA which may contribute to the symptomatology of this motor disease.

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

Our previous observations have shown that calcitonin (CT) stimulates beta-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 beta-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. Beta-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 less than 0.001); from 39.6 +/- 6 to 88.0 +/- 3.1 pg/ml (p less than 0.0001) (from 8.7 +/- 1.3 to 19.4 +/- 0.7 pmol/L); and from 13.1 +/- 1.6 to 23.8 +/- 3.0 micrograms/dl (p less than 0.0001) [374 +/- 45 to 680 +/- 85 nmol/L], respectively. Dexamethasone suppressed almost completely the stimulatory effect of CT beta-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 microgram/dl (n.s.) (from 25.1 +/- 6.5 to 25.0 +/- 5.1 nmol/L).(ABSTRACT TRUNCATED AT 250 WORDS)

[3H]dopamine uptake by platelet storage granules in schizophrenia.

[3H]Dopamine (DA) uptake by platelet storage granules was determined in 26 schizophrenic male patients, paranoid type (14 acute stage; 12 in remission) and 20 age-matched, normal controls. Maximum velocity (Vmax) of DA uptake was significantly higher in acute patients, than patients in remission or controls (p less than 0.05). The apparent Michaelis constant (Km) of DA uptake in acute patients was also significantly different from chronic patients (p less than 0.05). Preincubation with reserpine (10(-4), 10(-5) M) produced a substantial diminution of DA uptake, while haloperidol (10(-4), 10(-5) M) did not affect the assay. Considering that a DA dysequilibrium in schizophrenia may be expressed not only in the brain, but also in the periphery and that an increased amount of DA accumulated in the vesicles, implies that an increased quantity of catecholamine is available for release, our findings suggest additional evidence for the role of DA overactivity in the pathophysiology of this disorder.

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 Parkinson's 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 4 h after giving orally 5 mg bromocriptine alone; together with levodopa 250 mg plus 25 mg DCI (10 patients); with 100 mg amantadine HCl (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.

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 Parkinson's 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.

The influence of levodopa in the pharmacokinetics of bromocriptine in Parkinson's disease.

The administration of bromocriptine in addition to levodopa in Parkinson's disease produces beneficial results. Several hypotheses have explained the advantage of the combined treatment by a pharmacodynamic interaction in the striatum. However, no study has considered the possibility that levodopa modifies the kinetics of bromocriptine. In the present study performed with parkinsonian patients, we measured blood levels of bromocriptine (by radioimmunoassay) at 0, 30, 60, 90, 120, 180, and 240 min after the oral administration of bromocriptine alone and together with 250 mg levodopa plus 25 mg DCI. After loading of bromocriptine alone, we found mean peak levels at 60 min (1.42 ng/ml) and at 90 min (1.82 ng/ml). These values were reduced by levodopa (0.97 ng/ml at 60 min and 0.93 ng/ml at 90 min). Although we did not observe substantial clinical differences among the groups after the drug challenge (Webster scale), this study supports our previous findings and suggests that one of the advantages of a 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 and enables a more "stable" penetrability of the medication into the central nervous system. Therefore long-term combined treatment is advised in preference to bromocriptine alone.

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

In a previous study we observed that calcitonin increases beta-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 100 IU Salmon calcitonin Sandoz i.v. at 8 a.m. (time 0). Plasma beta-endorphin, ACTH and cortisol were estimated every 30 min 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. beta-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 micrograms/100 ml respectively (p less than 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 beta-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.

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

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 Parkinson's 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 drugs 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.

Calcitonin induced increase in ACTH, beta-endorphin and cortisol secretion.

The response of ACTH, beta-endorphin and cortisol to calcitonin administration was investigated in 8 subjects with recent fractures of the vertebrae due to postmenopausal or senile osteoporosis (Ost) and in seven normal healthy controls (NC). A significant increase of the three hormones was observed in 13 subjects. The maximum increase was observed between 15 and 60 min.: the cortisol level (microgram/100 ml) rose from 14.3 +/- 1.9 to 24.8 +/- 3.2 (P less than 0.05) in Ost and from 7.7 +/- 0.6 to 21.7 +/- 1.7 (P less than 0.001) in NC, the beta-endorphin (pmol/l) from 5.8 +/- 0.6 and to 21.2 +/- 1.3 in OST (P less than 0.001) and from 5.9 +/- 0.4 to 21.9 +/- 4.5 (P less than 0.01) in NC and the ACTH levels (pg/ml) from 21.3 +/- 5.7 to 61.7 +/- 3.6 (P less than 0.001) in OST and from 30.0 +/- 6.2 to 58.8 +/- 7.5 (P less than 0.05) in NC. The results indicate a possible role of calcitonin in modulating the anterior pituitary function. It also suggests that the analgesic effect of calcitonin might be mediated by the increase of beta-endorphin. The possibility that this analgesic effect of calcitonin is due to its direct binding to the opiate receptors was excluded in the present study by in vitro binding assay.

Effect of various neuroactive drugs on bromocriptine concentration in the striatum of rats.

Parkinsonian patients are usually given several drugs concomitantly with bromocriptine, with variable results. The possibility of interference of these drugs with the availability of bromocriptine in the brain was investigated by measuring bromocriptine concentrations in the striatum in rats. After a single injection, bromocriptine concentration in the striatum was 13.1 +/- 2.9 ng/mg protein. Naloxone, an opiate receptor blocker, was found to produce the largest increase in bromocriptine content (21.7 +/- 2.5 ng/mg protein). Amantadine, diazepam and haloperidol produced the largest decreases (3.2 +/- 0.9, 3.3 +/- 0.8 and 4.4 +/- 1.2 ng/mg protein, respectively). Rats given L-dopa or benzodiazepine also showed slightly lower levels of bromocriptine.

Growth hormone response to L-dopa in the thinned obese.

The response of plasma growth hormone (GH) to 0.5 g L-dopa was studied in 17 obese nondiabetic subjects and in 6 normal-weight subjects, aged 16 to 46 yr. The test was repeated after the obese subjects were thinned 12 to 50 kg, either with a hypocaloric diet or by a jejunoileal shunt. All the obese subjects had a blunted response to L-dopa stimulation. Nine of the thinned obese continued to exhibit the same blunted GH response, while the other eight responded with a significant GH rise after L-dopa stimulation, although the increase was smaller than that in the controls. No correlation between the initial or final weight or the extent of weight loss and the response to L-dopa was observed. It is assumed that a hypothalamic underresponsiveness is responsible for the blunted response in the obese subjects and its persistence in some of the thinned obese.

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.

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.

Plasma dopamine beta hydroxylase activity in chronic schizophrenic patients tested with single dose of 2-bromo-alpha ergocriptine (Parlodel).

Plasma dopamine beta hydroxylase (D.B.H) activity was measured in 6 chronic schizophrenic patients. Treated with phenothiazine and butyrophenone derivatives after administering a single dose of bromocriptine (7,5 mg) orally, and compared to a matched group of 6 chronic treated schizophrenic patients without bromocriptine loading, and to a control matched group loaded with 7.5 mg of bromocriptine. A significant difference was observed in D.B.H. plasma levels of the schizophrenic patients group who received bromocriptine, by comparison with the other two control groups.

[Effect of bromocriptine on secretion of the enzyme dopamine-B-hydroxylase (DBH) in patients with Parkinson's disease]. / L'effetto della Bromocriptina sulla secrezione dell'enzima dopamina-B-idrossilasi (DBH) nei malati de Parkinson.

The activity of DBH enzyme was measured in plasma of 7 non treated patients suffering from Parkinson's disease; a 10 mg dose of Bromocryptine was administered per os to these patients. Attained results were compared to the enzyme activity in a group of control of 7 healthy individuals. It was pointed out that in patients suffering from Parkinson's disease the decrease of DBH level in plasma after the administration of Bromocryptine was of 32.6% +/- SE 4.4% while in the group of control the decrease was only of 15% +/- SE 4.9%. This decrease in the plasmatic level of the enzyme after the administration of Bromocryptine should be due to the marked antagonistic activity of Bromocryptine on pre-synaptic dopaminergic receptors. This should mean that peripheric pre-synaptic dopaminergic receptors are involved in the physiopathology of Parkinson's disease.

Plasma dopamine beta hydroxylase (D.B.H.) activity in Parkinsonian patients under L-dopa, and 2-bromo-alpha-ergocriptine loading.

Dopamine-Beta-Hydroxylase (D.B.H.)-activity was measured in the plasma of untreated Parkinsonian patients, after tretment with L-dopa and 2-Bromo-alpha-ergocriptine. The findings were compared to the D.B.H.-activity of a matched healthy control group. After L-dopa loading D.B.H.-activity decreased in the Parkinsonian patients by 27.6 +/- 3.1% compared to 16.2 +/- 3.3% (p less than 0.02) in the control group. After 2-Bromo-alpha-ergocriptine laoding the decrease in D.B.H.-activity was 32.6 +/- 4.4% in the parkinsonian patients, and 158 +/- 4.9% (p less than 0.02) in the control group. This reduced D.H.B.-activity after L-dopa loading may reflect an impairment, in the Parkinsonian patients' ability to metaoblize L-dopa. The reduced D.B.H.-activity after treatment with 2-Bromo-alpha-ergocriptine may be explained by a pronounced antagonistic influence of 2-Bromo-alpha-ergocriptine on the presynaptic dopamine receptors, suggesting that presynaptic dopaminergic receptors are involved in Parkinson's disease.

Low cortisol and growth hormone secretion in response to methoxamine administration in obese subjects.

To investigate the hypothalamic responsiveness in obesity, changes in the levels of plasma cortisol and growth hormone (GH) were studied in 11 obese and six normal-weight subjects after hypothalamic alpha-adrenergic stimulation with methoxamine, 20 mg i.v. To allow for dose/body weight differences, five additional obese subjects received 30 mg methoxamine. Plasma GH, cortisol, insulin, free fatty acid and glucose levels were determined during the 3-h infusion of methoxamine. The responses of cortisol and GH were reduced in the obese subjects as compared with the normal-weight subjects. No significant changes in plasma glucose, free fatty acids or insulin were observed in any of the groups. The reduced responses of plasma cortisol ang GH in the obese subjects are considered to be an expression of hypothalamic underresponsiveness, since the stimuli for the secretion of these hormones are at least partially controlled by an alpha-adrenergic mechanism.