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Biomedical subjects

M Scheinin

Publications and source records attributed to M Scheinin.

At least 181 records · Page 10Linked to original sources
PubMed1986

Comparison of free MHPG in rat cerebrospinal fluid with free and conjugated MHPG in brain tissue: effects of drugs modifying noradrenergic transmission.

The changes of free 3-methoxy-4-hydroxyphenylglycol (MHPG) in cerebrospinal fluid (CSF) were compared with the corresponding alterations of free and conjugated MHPG in rat brain tissue after various pharmacological treatments modifying noradrenergic neurotransmission. In addition, the effects of the drug treatments on the concentration of noradrenaline (NA) in brain were determined. alpha-Methyl-p-tyrosine (an inhibitor of tyrosine hydroxylase) induced decreases in free and conjugated MHPG in CSF and brain; the free species appeared to decline more rapidly. Reserpine caused similar biphasic changes in free MHPG in CSF and brain but the rapid and transient initial increase in MHPG-SO4 was very weak. Pargyline (monoamine oxidase inhibitor) induced a sharp decline in the concentration of free MHPG in brain and CSF while MHPG-SO4 in brain definitely decreased more slowly. Relatively similar time courses were seen for all three MHPG parameters after administration of MPV-1248 (alpha 2-antagonist) and clonidine (alpha 2-agonist) i.e., increases and decreases, respectively. The present results support the validity of monitoring drug-induced acute changes in central turnover of NA by repeated measurements of free MHPG levels in rat cisternal CSF.

Adrenergic alpha-Antagonists↗
PubMed1986

Association between increased serotonin metabolism in rat brainstem nuclei and development of spontaneous hypertension.

Spontaneously hypertensive rats have increased brain stem serotonin turnover localized to the nuclei raphe magnus, raphe pallidus, tractus solitarius and reticularis lateralis. It occurs only in young animals coinciding with the development of hypertension. In the locus coeruleus, increased serotonin metabolism is present during both the early and the established phase of hypertension. Our results provide evidence for serotonergic overactivity in specific brainstem nuclei during the development of spontaneous hypertension in the rat.

Age Factors↗
PubMed1986

alpha 2-Adrenoceptor agonists decrease free 3-methoxy-4-hydroxyphenylglycol in rat cerebrospinal fluid.

The effects of alpha 2-adrenoceptor agonists on the concentrations of monoamine metabolites in cisternal cerebrospinal fluid (CSF) of freely moving rats were determined. Clonidine and two new imidazole derivatives, detomidine and medetomidine, and diazepam (as a control substance) were administered in sedative doses and the concentrations of unconjugated 3-methoxy-4-hydroxyphenylglycol (MHPG), 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) in CSF were monitored for 48 h. The alpha 2-agonists caused a dose-dependent, statistically significant decrease in the concentration of MHPG in CSF compared to the concentration in animals treated with saline or diazepam. Detomidine caused a statistically significant increase in the concentration of 5-HIAA compared to control treatments. The present results demonstrate the usefulness of monitoring drug-induced alterations in central nervous system (CNS) noradrenergic activity by measuring free MHPG in repeatedly collected cisternal CSF samples from freely moving rats. The alpha 2-agonists reduced the concentration of MHPG in CSF, indicating a decreased release, metabolism and turnover of noradrenaline in the CNS.

Adrenergic alpha-Agonists↗
PubMed1986

Tetrahydrobiopterin administration to rhesus macaques. Its appearance in CSF and effect on neurotransmitter synthesis.

Tetrahydrobiopterin, the hydroxylase cofactor (BH4) was administered (i.v. 20 mg/kg) to Rhesus monkeys. Within 90 min of its administration CSF cofactor levels increased significantly above baseline levels. Peak CSF levels were attained at 90-180 min time period following cofactor injection and returned to baseline gradually over the next 15 hrs. The increased brain cofactor levels had no apparent effect on synthesis of dopamine, norepinephrine or serotonin as evidenced by a lack of change in the levels of the metabolites homovalillic acid, 3-methoxy-4-hydroxyphenyleneglycol, and 5-hydroxyindoleacetic acid. The present results using primates suggest no apparent effect of increased cofactor levels on monoamine biosynthesis. However, it remains to be explored whether monoamine synthesis could be affected by increased cofactor levels in the pathological situation.

Animals↗
PubMed1986

Disposition of single oral doses of E-10-hydroxynortriptyline in healthy subjects, with some observations on pharmacodynamic effects.

The active and major metabolite of nortriptyline (NT), E-10-hydroxynortriptyline (E-10-OH-NT), was taken orally as the hydrogen maleate in single doses by nine healthy subjects. The doses (10 to 100 mg) were completely absorbed, as shown by the high urinary recovery of 86.1% +/- 9.9%. Of the given dose, 51.2% +/- 8.7% was recovered as conjugated E-10-OH-NT and 23.9% +/- 4.3% was recovered as unchanged compound. The plasma t1/2 of E-10-OH-NT was 8.0 +/- 1.2 hours and total plasma clearance was 47.5 +/- 10.3 L/hr. The rate of elimination varied little between individuals. There was no indication of dose-dependent elimination. The mean apparent volume of distribution was 7.7 +/- 2.1 L/kg. Single oral doses of 50 mg E-10-OH-NT significantly increased the plasma levels of norepinephrine in both the supine and standing positions (P less than 0.01). Pulse rate increased in the standing but not the supine position. These effects might result from inhibition of neuronal uptake of norepinephrine by E-10-OH-NT. Coupled with its low affinity for muscarinic receptors, these kinetic and pharmacodynamic features of E-10-OH-NT call for further phase I studies.

Administration, Oral↗
PubMed1986

Presynaptic dopamine receptors in the pithed rat: characterization with apomorphine and comparison with central dopamine autoreceptors.

Apomorphine, a dopamine agonist with high affinity for presynaptic dopamine receptors, caused dose-dependent inhibition (10-300 micrograms/kg intravenously) of the stimulation-induced increase in diastolic blood pressure in the pithed rat. This effect of apomorphine could be antagonized with (-)-sulpiride or haloperidol but not with yohimbine or atropine, indicating the involvement of inhibitory dopamine receptors. The alpha-1-adrenoceptor mediated pressor response to phenylephrine (5 micrograms/kg intravenously) was not significantly attenuated by apomorphine. The sensitivity of peripheral presynaptic dopamine receptors was then studied in the cardiovascular system of rats treated subchronically with haloperidol (2 mg/kg, twice daily intraperitoneally for 10 days). The inhibition of sympathetic vasoconstrictor responses exerted by apomorphine was found to be enhanced after subchronic haloperidol treatment suggesting the development of presynaptic dopamine receptor supersensitivity in the periphery. In addition, the previously reported supersensitivity of central dopamine autoreceptors to low doses of apomorphine could be confirmed in behavioural experiments.

Animals↗
PubMed1986

Effects of intravenous and subcutaneous administration of apomorphine on the clinical symptoms of chronic schizophrenics.

The effects of apomorphine, a stimulant of dopamine autoreceptors, were studied in 12 chronic schizophrenics on neuroleptic treatment; both subcutaneous and intravenous administration were used. Apomorphine has been reported to have therapeutic effects in previous studies but, we were not able to confirm any significant and specific differences in psychotic symptoms or tardive dyskinesia scores with apomorphine administration, compared with placebo. These results do not support the importance of dopamine autoreceptors in the regulation of schizophrenic and dyskinetic symptoms in chronic neuroleptic-treated patients.

Adult↗
PubMed1986

Epidural and paracervical blockades in obstetrics. Catecholamines, arginine vasopressin and analgesic effect.

A comparative study of analgesic and endocrinologic effects of obstetrical epidural anesthesia (EA, n = 23) and paracervical block (PCB, n = 39) was performed. Pain intensity was assessed on a horizontal linear scale. Simultaneously, blood samples for the determination of concentrations of norepinephrine (NE), epinephrine (E) and arginine vasopressin (AVP) were obtained. NE and AVP levels did not bear any relationship to pain scores. Instead, the average plasma E profile during labor was practically identical with the profile of pain scores. Plasma levels of E decreased significantly after EA. A similar but short-lived effect was observed also after PCB. When comparable doses of bupivacaine were used (30 mg in the EA group and 25 mg in the PCB group); initial pain relief after EA and PCB was similar, though after 30 min the pain score increased for patients who received the PCB, while patients who received EA had continued pain relief. Faster absorption of bupivacaine was observed after paracervical than epidural injection. Decreased variability was seen in the fetal cardiograms in 25% after EA and in 33% after PCB. Transient bradycardia was observed in 2 cases after paracervical injection.

Adult↗
PubMed1985

Repetitive measurement of monoamine metabolite levels in cerebrospinal fluid of conscious rats: effects of reserpine and haloperidol.

A simple high performance liquid chromatographic method with electrochemical detection is described for the simultaneous determination of unconjugated 3-methoxy-4-hydroxyphenylglycol (MHPG), 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA), the principal central nervous system (CNS) metabolites of noradrenaline, serotonin and dopamine (DA), respectively, in small samples of cisternal cerebrospinal fluid (CSF) obtained repeatedly from freely moving rats. Amounts of 30-50 microliter of CSF could be collected repeatedly every 30-60 min allowing monitoring of monoamine metabolite concentration levels in CSF under physiological conditions. None of the metabolites showed any clear diurnal variation. A single injection of reserpine caused a prominent elevation in the concentrations of MHPG, 5-HIAA and HVA in CSF. However, after a rapid increase, the concentration of MHPG was decreased by 85% from the control values. Haloperidol caused a 3-fold increase in the concentration of HVA, indicating increased DA turnover in the CNS. The method enables the reliable quantitative determination of three major monoamine metabolites in small samples of CSF from freely moving rats and appears to be a useful tool in the evaluation of the validity of the clinically used research methods of monitoring drug-induced alterations in CNS monoaminergic activity by metabolite measurements in CSF.

Animals↗
PubMed1985

Selective antidepressants and cerebrospinal fluid. Lack of specificity on norepinephrine and serotonin metabolites.

Cerebrospinal fluid concentrations of the norepinephrine metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG), the serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA), and the dopamine metabolite, homovanillic acid, were measured in depressed patients before and after treatment with three putatively specific antidepressants. The expected specificity of action on these three neurotransmitter metabolites was not observed. Desipramine hydrochloride, a norepinephrine uptake inhibitor, reduced 5-HIAA as well as MHPG concentrations; zimeldine hydrochloride, a serotonin uptake inhibitor, reduced MHPG as well as 5-HIAA concentrations; and clorgyline, a selective monoamine oxidase type A inhibitor, which might be predicted to most affect 5-HIAA, dramatically reduced MHPG, moderately reduced homovanillic acid, and only modestly reduced 5-HIAA concentrations.

Adolescent↗
PubMed1985

The effect of clorgyline on noradrenergic function.

A low dosage of the specific MAO-A inhibitor clorgyline (5-10 mg/day) was administered chronically to 10 depressed patients. Peripheral noradrenergic activity, as assessed by measurements of the plasma norepinephrine (NE) concentration, heart rate, and blood pressure, was determined before and after drug treatment. The administration of a low dosage of clorgyline was associated with a decrement in peripheral presynaptic noradrenergic activity. Comparison with the results of similar studies of the effects of desmethylimipramine (DMI) suggests that antidepressant drugs with unrelated primary actions affect peripheral noradrenergic functions differently.

Adult↗
PubMed1985

Cerebrospinal fluid and plasma monoamines and their metabolites in euthymic bipolar patients.

In a search for trait markers in manic-depressive illness, we studied cerebrospinal fluid (CSF) and plasma monoamines and their metabolites in 25 lithium-treated euthymic bipolar patients (12 of whom provided unmedicated samples) and 30 normal volunteers. No group differences were found. Lithium treatment showed a trend to increase CSF hydroxy-indoleacetic acid (HIAA) (p = 0.05). Dopaminergic and serotonergic metabolites were highly correlated in the CSF of all three groups. We found no evidence of a trait marker for manic-depressive illness among CSF monoamines and their metabolites.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1985

Effects of apomorphine on blood levels of homovanillic acid, growth hormone and prolactin in medicated schizophrenics and healthy control subjects.

Two doses of apomorphine (0.005 mg/kg as a subcutaneous injection and 0.015 mg/kg as a 90 min i.v. infusion), and corresponding placebo treatments, were administered to 11 chronic medicated schizophrenic patients and to 8 healthy control subjects. The purpose of the study was to asses the usefulness of drug-induced alterations in the concentration of homovanillic acid (HVA) in plasma as indicators of dopamine autoreceptor sensitivity in the central nervous system. Growth hormone and prolactin in serum were also measured and used as indicators of postsynaptic dopaminergic drug effects. In the control subjects, i.v. apomorphine increased growth hormone in serum from 1.8 +/- 0.2 to 28.3 +/- 4.6 ng/ml and reduced prolactin by 57 +/- 7%. In the patients, apomorphine caused only weak neuroendocrine effects. HVA in plasma was not affected by apomorphine in either group of subjects. The results for growth hormone and prolactin indicate that postsynaptic dopamine receptors in the tubero-infundibular system are antagonized to a considerable degree also during chronic treatment with neuroleptics. The lack of effect of apomorphine on HVA levels suggests that HVA in plasma is not a sensitive indicator of the inhibition of dopamine release caused by small doses of apomorphine and mediated through dopamine auto-receptors. Supersensitivity of this class of receptors could not be demonstrated in our patients, which contrasts with some earlier results.

Adult↗
PubMed1985

Tofisopam and midazolam: differences in clinical effects and in changes of CSF monoamine metabolites.

The effect of two repeated oral doses of 100 mg tofisopam 15 mg midazolam and placebo on the concentrations of monoamine metabolites (MHPG, 5-HIAA, HVA) in lumbar CSF were studied in general surgical patients operated on under spinal analgesia (n = 12 in each group). Midazolam, but not tofisopam, improved the quality of sleep the night before surgery. Both active agents reduced preoperative anxiety of the patients, but tofisopam was without subjective sedative action. In the placebo group, in contrast to the active drug groups, there was a slight positive correlation between the MHPG concentration and degree of anxiety before surgery. The only significant difference in the monoamine metabolites in lumbar CSF was found in the concentrations of HVA between tofisopam and placebo treated patients. The lower HVA concentrations suggest that the curious 3,4-benzodiazepine derivative, tofisopam, modifies central dopaminergic activity.

Aged↗
PubMed1985

The hypotensive action of 4-(5,6-dimethyl-2-benzofuranyl) piperidine HCl (CGP 6085 A) in spontaneously hypertensive rats.

CGP 6085 A, [4-(5,6-dimethyl-2-benzofuranyl)piperidine HCl], has been found to be a mild to moderately potent hypotensive agent. One hour following CGP 6085 A administration (10 mg/kg, i.p.), a maximal reduction in blood pressure of approximately 20-30 mm Hg is observed in spontaneously hypertensive rats. The maximal reduction in blood pressure was observed at a dose of 3 mg/kg. CGP 6085 A blocks 5-HT uptake in the brainstem when assessed in vivo by use of the serotonin depletor, H 75/12 (3-hydroxy-4-methyl-alpha-ethyl-phenylethylamine). The maximal inhibitory effect on 5-HT uptake occurred at 10 mg/kg CGP 6085 A. The reduction in blood pressure correlates well with the ability of the drug to inhibit 5-HT uptake as assayed by H 75/12, with a correlation coefficient of 0.71 for SH rats. However, since the drug has not been widely characterized, alternate explanations for the cardiovascular pharmacological properties of CGP 6085 A are also proposed.

Amphetamines↗
PubMed1985

Monoamine metabolites in human cerebrospinal fluid: indicators of neuronal activity?

Concentrations of monoamine metabolites in human cerebrospinal fluid (CSF) have been widely used as indicators of the level of functional activity in the central monoaminergic neuronal pathways. This article reviews the relationship between the turnover of the neurotransmitter monoamines noradrenaline, serotonin, and dopamine, and the concentrations in CSF of their principal metabolites, 3-methoxy-4-hydroxyphenylglycol (MHPG), 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid (HVA). It attempts to summarise what is known of the effects of various illnesses and drug treatments on the concentrations of these metabolites.

Animals↗
PubMed1985

Neuroendocrine aspects in monitoring of dopaminergic drugs in man.

The role of plasma homovanillic acid together with serum growth hormone and prolactin in monitoring of central dopaminergic activity was studied in healthy volunteers and psychiatric patients. Both dopaminergic agonists (apomorphine, bromocriptine and L-dopa) and antagonists (metoclopramide) were used. Apomorphine, bromocriptine and metoclopramide, which exerted the expected neuroendocrine effects caused no significant changes in plasma homovanillic acid. L-dopa increased the concentration of homovanillic acid in plasma. This effect was not potentiated by L-deprenyl, although L-dopa-induced growth hormone secretion was increased after L-deprenyl premedication. There was negative correlation between growth hormone secretion and the increase of plasma homovanillic acid after L-dopa. This indicates that the L-dopa-induced rise in plasma homovanillic acid probably reflects more peripheral L-dopa metabolism than central dopaminergic activity. Thus, it seems that plasma homovanillic acid cannot be regarded as a sensitive indicator of drug-induced changes in central dopaminergic activity in man, which is in contrast with some earlier findings in animals.

Apomorphine↗