Cerebrospinal Fluid Dopamine Research Articles

CSF dopamine turnover and positive schizophrenic symptoms after withdrawal of long-term neuroleptic treatment

Dopamine (DA), dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) were measured in cerebrospinal fluid (CSF) of 14 schizophrenic inpatients before and 2 weeks after withdrawal of long-term neuroleptic medication. Total neuroleptic-like activity (NLA) in serum was determined at the same times. DA and its metabolites (DOPAC and HVA) were significantly reduced after neuroleptic discontinuation. NLA was substantially diminished. The decrease in DA and DOPAC was positively correlated with positive symptoms of postwithdrawal deterioration, and low prewithdrawal DOPAC level predicted severe relapse. These results are compatible with the hypothesis linking an overregulated central DA system to the positive symptoms of schizophrenia.

The relationship of free and conjugated catecholamines in plasma and cerebrospinal fluid in cerebral and meningeal disease.

The concentration of free and conjugated norepinephrine (NE), epinephrine (E) and dopamine (DA) were measured by a modified radio-enzymatic assay in the plasma and in the cerebrospinal fluid (CSF) of 45 patients with normal and in 21 patients with disturbed blood-CSF barriers. In patients with an undisturbed blood-CSF barrier the free NE and E in CSF were 128 +/- 45 ng/l and 27 +/- 20 ng/l (mean values +/- S.E.), respectively, and represented about 50% of the average plasma values. Mean DA was not different in plasma (47 +/- 22 ng/l) and in CSF (41 +/- 19 ng/l). Both in plasma and in CSF, considerable higher free catecholamine (CA) levels were measured in patients with dysfunction of the blood-CSF barrier. In one patient with bacterial meningitis twofold higher concentrations of free NE and DA in CSF as compared with plasma were detectable. Sulfate conjugates of catecholamines are predominant in plasma and CSF. The contribution of conjugated CA to total CA in plasma from patients with normal blood-CSF barrier averaged 69.7%, 63.1% and 98.1% for NE, E and DA, respectively and was significantly lower in the CSF (p less than 0.001). In patients with disturbed blood-CSF barrier, the increases of conjugated CA were more pronounced in CSF than in plasma. Further, the contribution of conjugated NE and E to total NE and E in CSF was not only increased in patients with bacterial meningitis, but also in patients with renal insufficiency compared to the "control" patients (p less than 0.02 and p less than 0.001 resp.). Free and conjugated NE, E and DA in the plasma and CSF were related significantly (p less than 0.01 resp.) with stronger correlation for conjugated CA (p less than 0.001 resp.). These results together with findings in the literature, suggest that there is little or no rostral-caudal gradient in CSF CA conjugate concentrations and that even in patients with intact blood-CSF barrier plasma conjugated CA concentrations influence those in CSF. Thus only free CA levels in CSF may reflect the central adrenergic activity.

Determination of conjugated dopamine in cerebrospinal fluid from humans and non-human primates with high performance liquid chromatography using electrochemical detection.

A simple and reliable procedure for the determination of conjugated dopamine (DA) in cerebrospinal fluid (CSF) is described. The conjugate, presumably a sulfate, is conveniently hydrolyzed in 0.4 M sulfuric acid at 95 degrees. Thereafter, dopamine is quantitated using HPLC with electrochemical detection. Sensitivity (0.5 pmol/ml) is sufficient for clinical studies. Only 400 ul of CSF are required for the assay. The within assay coefficient of variation was 3.2% for conjugated DA (concentration of 11.8 pmol/ml). In a material consisting of 261 samples of lumbar CSF from unmedicated psychiatric patients and normal control subjects, a concentration range of 1.3-21.7 pmol/ml was found. No clear differences were evident between the major diagnostic groups.

Increased dopamine and serotonin metabolites in CSF during severe insulin-induced hypoglycemia in freely moving rats

The effect of insulin on dopamine (DA) and serotonin (5-HT) metabolites was determined in the cerebrospinal fluid (CSF) of the rat and compared with glucose levels in blood and CSF. CSF was continuously withdrawn from the third ventricle of freely moving rats at a constant rate of 1 μl/min. Liquid chromatography with electrochemical detection was used for the direct assay of DA and 5-HT metabolites in the CSF. The metabolites were stable during the first hour after insulin injection (6IU/Kg). A progressive increase occurred thereafter in animals which had no access to food during the time of the experiment. The maximal effect was observed 2.5 h after insulin, with respective mean increases of 80% for dihydroxyphenylacetic acid, 47% for homovanillic acid and 33% for 5-hydroxyindolacetic acid. These increases in monoamine metabolites were not observed when rats received glucose (5g/Kg ip) 45 min after insulin or when food was made available. The period for insulin-induced increase in DA and 5-HT metabolites corresponded to a maximal fall of glucose levels both in blood and CSF although the CSF glucose decrease was delayed when compared to the fall of blood glucose. The role of brain glucose and brain insulin in the control of central DA and 5-HT metabolism is discussed.

Catecholamines, Angiotensin II and Sodium Concentrations in Cerebrospinal Fluid in Young Men with Borderline Hypertension

To evaluate the role of central nervous mechanisms and their relationships to the peripheral sympathetic nervous system in borderline hypertension, we measured catecholamines, angiotensin II (AII) and sodium (Na) concentrations in cerebrospinal fluid (CSF) with plasma catecholamines concomitantly in 12 young men with borderline hypertension and 7 age-matched healthy normotensive men on ordinary salt intake. Plasma norepinephrine (NE) and epinephrine (E) were higher in the borderline hypertensives than in the normotensives (NE: 239 +/- 15 vs 190 +/- 11 pg/ml, p less than 0.05, E: 83 +/- 9 vs 43 +/- 6 pg/ml, p less than 0.01). NE levels in CSF were also higher in the borderline hypertensives than in the normotensives (200 +/- 15 vs 150 +/- 18 pg/ml, p less than 0.05). In most of the subjects, CSF E and plasma and CSF dopamine levels were below the sensitivity of the assay. CSF NE correlated positively with both plasma NE (p less than 0.01) and mean blood pressure (p less than 0.05) in all subjects. Immunoreactive AII and Na concentrations in CSF did not differ between the borderline hypertensives and normotensives. These results suggest that peripheral sympathoadrenal overactivity in young subjects with borderline hypertension may be related to an altered function of central noradrenergic neurons. AII and Na in the central nervous system do not appear to have an important role in borderline hypertension.

Changes in dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) levels in human cerebrospinal fluid after L-dopa and deprenyl administration.

The dopamine (DA) and DOPAC levels were measured in cerebrospinal fluid (CSF) using a radioenzymatic method. The influence of a specific monoamine oxidase B inhibitor (deprenyl) on changes in DA and DOPAC levels was studied in untreated patients or after L-dopa administration. A single dose of deprenyl alone did not change the CSF DA and DOPAC levels, a three days' treatment, however, decreased both the DOPAC and DA concentrations. The acute administration of L-dopa caused an increase in CSF DA and DOPAC levels. The changes were smaller following repeated treatment. Deprenyl diminished the increase in DOPAC level after repeated L-dopa administration.

Comparative analysis of indices of central dopaminergic functions in man

Various postulated indices of central dopaminergic activity - cerebrospinal fluid (CSF) dopamine (DA), dihydroxy-phenylacetic acid (DOPAC), homovanillic acid (HVA), noradrenaline (NA), plasma NA, serum prolactin, serum dopamine-β-hydroxylase (DBH), and platelet monoamine oxidase (MAO) activity - were measured in 30 drug-free inpatients. The mean values and the ranges were similar to those described in the literature. Plasma NA showed significant positive correlation with age. Significant positive correlation was found between CSF DA and its metabolites DOPAC and HVA. Serum DBH activity showed a slight but significant inverse correlation with CSF DA and its two metabolites. CSF NA showed a significant positive correlation with CSF DOPAC, but only in females. Serum DBH activity had no significant correlation either with CSF or with plasma NA levels. These findings suggest that either CSF HVA or DOPAC and DA may be useful indicators of DA metabolism in humans. Serum DBH activity may be in relationship with the central dopaminergic functions.

Cerebral hemodynamics, oxygen uptake and cerebral arteriovenous differences of catecholamines following E. coli endotoxin in dogs.

In experimental endotoxic shock in dogs, a decrease in cerebral blood flow and an increase in cerebral metabolic rate of oxygen (CMRO2) have been shown to occur. In this situation the blood levels of adrenaline and noradrenaline are markedly elevated. The aim of the present study was to investigate whether a cerebral uptake of circulating catecholamines with a possible influence on CMRO2 takes place in the brain. In eight anaesthetized dogs, arterial blood, superior sagittal sinus blood and cerebrospinal fluid were analyzed for the concentrations of adrenaline, noradrenaline and dopamine before and up to 4 h after an injection of E. coli endotoxin 1.0-1.5 mg . kg-1. The blood levels of adrenaline and noradrenaline, but not dopamine, increased in response to the endotoxin. From about 30 min after the endotoxin injection, arteriovenous adrenaline and noradrenaline differences indicating a cerebral uptake were most often seen. Increased concentrations of noradrenaline, adrenaline and dopamine in cerebrospinal fluid were observed. Noradrenaline gave the highest concentrations and these were correlated to the CMRO2. In some animals the blood and cerebrospinal fluid concentrations of adrenaline seemed to be related. These results indicate that catecholamines might be of importance for the development of an increased CMRO2 in endotoxic shock.

Initial clinical trial based on biochemical methodology of zimelidine (a serotonin uptake inhibitor) in depressed patients.

The bicyclic compound Z-1-(4-bromophenyl)-1-(3-pyridyl)-3-dimethylaminopropen (zimelidine) has a pronounced inhibitory effect on neuronal 5-hydroxytryptamine (5-HT) uptake in animals. Zimelidine was given to 6 depressed patients in doses ranging between 25 and 150 mg twice daily for about 3 wk. To get an objective assessment of its pharmacologic effects, the following variables were monitored: (1) plasma levels of parent compound and its desmethylated metabolite; (2) the 5-HT and norepinephrine (NE) uptake inhibiting activity in vitro of plasma drawn from the patients; and (3) the concentrations of the main metabolites of serotonin (5-HT), tryptamine, NE, and dopamine in cerebrospinal fluid (CSF), i.e., 5-hydroxyindoleacetic acid (5-HIAA), indoleacetic acid (IAA), 4-hydroxy-3-methoxyphenylglycol (HMPG), and homovanillic acid (HVA), respectively. Plasma from the patients markedly inhibited 5-HT uptake compared to NE uptake. The inhibitory effect of 5-HT uptake and the plasma concentration of the desmethylated metabolite correlated significantly. The 5-HIAA levels in CSF decreased markedly in 4 patients while the IAA levels increased. The levels of HMPG also decreased significantly, but less so than the 5-HIAA levels. The effects on HVA were inconsistent. Zimelidine appears to be a selective inhibitor of 5-HT uptake in central monoamine neurons and is therefore an interesting pharmacologic tool in future central nervous system (CNS) research.