Catecholamine alterations in basal ganglia after hippocampal lesions

Rats were given sham, cortical, or hippocampal lesions and sacrificed 7 or 28 days following surgery. Levels of norepinephrine, dopamine, and the major dopamine metabolites, 3, 4-dihydroxyphenylacetic acid and homovanillic acid (HVA), were assayed in 3 brain regions. At day 7 there was a decrease in dopamine utilization and a decrease in norepinephrine levels in the nucleus accumbens after hippocampal damage but both of these measures returned to normal levels by day 28. In the neostriatum HVA levels decreased at day 7 after hippocampal damage. The utilization of dopamine in the neostriatum was decreased at day 28 in animals that received neocortical lesions but this was not observed in animals with hippocampal destruction. No effects of any lesion at any day were found in the olfactory tubercle region, the third brain region analyzed. It is thought that the removal of hippocampal and neocortical input to the basal ganglia influences catecholamine function reflected in the loss and subsequent recovery of dopamine utilization.     

Effect of chronic nicotine administration on monoamine and monoamine metabolite concentrations in rat brain

The effects on rat brain tissue monoamine and monoamine metabolite concentrations of chronic nicotine administration at two doses (3 and 12 mg/kg/day) using constant infusion were studied. After 21 days of treatment, tissue concentrations of dopamine (DA), norepinephrine (NE), 5-hydroxytryptamine (5-HT), and several metabolites in striatum, hypothalamus, and frontal cortex were determined by high performance liquid chromatography with electrochemical detection. Compared with a control group, nicotine treatment significantly decreased NE in frontal cortex but not in other regions. The concentration of 5HT also was decreased in frontal cortex but increased in the hypothalamus at the higher dose of nicotine. The 5HT metabolite 5-hydroxyindoleacetic acid (5-HIAA) was not significantly altered in any region. The 5HT index (5-HIAA/5-HT) was significantly decreased in the hypothalamus and increased in frontal cortex at the higher dose. Concentrations of DA and the metabolite homovanillic acid (HVA) were not significantly altered by nicotine. Nevertheless, significant decreases in the DA metabolite dihydroxyphenyl-acetic acid (DOPAC) were observed in both striatum and hypothalamus. Moreover, the DA index [(DOPAC + HVA)/DA] was significantly decreased in all three brain regions. In contrast to other studies using acute dose and in vitro perfusion paradigms that have reported increased CNS catecholamine release stimulated by nicotine, chronic administration appears to be associated with decreased catecholamine turnover in some brain regions.     

Catecholamine metabolism in kinky hair disease

Kinky hair disease is a progressive neurologic disease associated with decreased copper absorption. Because dopamine-beta-hydroxylase, an essential enzyme in norepinephrine biosynthesis, is copper-dependent, we studied norepinephrine metabolism in vivo in 5 affected children. Patients with kinky hair disease had decreased plasma norepinephrine concentrations (196 +/- 25 pg/ml) in comparison to control patients (325 +/- 20 pg/ml, p less than 0.001). The ratio of total urinary norepinephrine metabolites to total dopamine metabolites was 0.25 +/- 0.04 in kinky hair patients and 0.52 +/- 0.03 in controls p less than 0.001). These data indicate that dopamine-beta-hydroxylation in vivo is decreased in patients with kinky hair disease; however, there was no correlation between serum copper concentration and catecholamine abnormality.     

Conjugates of biogenic amines in ventriculocisternal perfusates of conscious african green monkeys

To determine the importance of conjugation relative to alternate metabolic pathways for the inactivation of catecholamines and serotonin, free and conjugated norepinephrine, dopamine and serotonin, together with the acid metabolites homovanillic acid and 5-hydroxyindoleacetic acid, were measured in ventriculocisternal perfusions in awake African green monkeys. Measurements were made of endogenous transmitters and their metabolites using high performance liquid chromatography with electrochemical detection. Efflux of amines and metabolites was measured both under conditions of spontaneous overflow and during release evoked by 40 mM K+ or by 5 X 10(-5) M amphetamine. Conjugated amines were of greater importance under basal conditions than during evoked release. Although more conjugated amines were produced in African green monkey than has been previously detected in other species, conjugation was still minor relative to O-methylation and oxidative deamination. When nomifensine (5 X 10(-5) M), a blocker of neuronal uptake of dopamine, was added to perfusion fluids, the efflux of free dopamine was increased. Efflux of conjugated dopamine was not decreased in the presence of nomifensine, suggesting that conjugation did not occur subsequent to reuptake of transmitter into dopaminergic neurons. Evidence is also presented that different enzymes are responsible for the conjugation of catecholamines and serotonin.     

Dietary induced changes in catecholamine metabolites in rat urine

Summary The influence of dietary conditions on the excretion of catecholamine metabolites has been investigated in rats. Four groups of rats were nourished over several days, with the usual cereal rat chow (A) or a synthetic complete food (B) or 15% milk (C) or 12% sucrose solution (D),Interference from cereal-rich diet was observed on most metabolites: dopamine (DA), 3-0-methyldopamine (3-MT), 3, 4-dihydroxyphenylacetic acid (DOPAC), norepinephrine (NE) and epinephrine (E). The cerealinduced interference was the highest for conjugated DA metabolites.Sucrose diet suppressed the chemical dietary interferences on DA metabolites but induced sympathetic hyperactivity, together with sustained changes in lipid metabolism, as previously observed in sucrose overfeeding.Milk diet induced too catecholamine release but did not reduce dietary interference on DA and 3-MT.From these results, we conclude that the synthetic cereal-free meal B is convenient in studies including most catecholamine metabolites, except for conjugated DOPAC. In the latter case, sucrose diet proofs more appropriate, provided it is used over a short period.This work was supported from grants of CNRS (ER 96) and IFFA-CREDO.     

Plasma amine metabolites before and after withdrawal from neuroleptic treatment in chronic schizophrenic inpatients

Plasma catecholamine metabolites were measured in paired blood samples from 22 subjects with chronic schizophrenia. One sample was drawn while patients were on a stable dose of neuroleptic medication; the second was drawn 6 weeks after discontinuation of medication. In comparison with baseline values during neuroleptic treatment, there was a significant increase in the plasma concentration of the norepinephrine metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG), and a trend toward an increase in the plasma concentration of the dopamine metabolite, homovanillic acid (HVA), in the medication-free subjects. There were no significant correlations between plasma MHPG or HVA concentrations and the corresponding ratings of psychopathology for these patients.     

3,4-Dihydroxyphenylacetaldehyde and hydrogen peroxide generate a hydroxyl radical: possible role in Parkinson's disease pathogenesis

3,4-Dihydroxyphenylacetaldehyde (DOPAL) and 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL), the monoamine oxidase (MAO) metabolites of dopamine (DA) and norepinephrine (NE), respectively, are toxic to catecholamine (CA) neurons in vitro and in vivo. DOPEGAL generates a free radical and activates mitochondrial permeability transition, a mechanism implicated in neuron death. To determine if DOPAL and other DA metabolites generate the hydroxyl radical in the presence of H(2)O(2), we used HPLC-EC to detect salicylate hydroxylation products. To determine the relative reducing capacity of DOPAL and DOPEGAL we used cyclic voltammetry to measure their reduction potentials. Results indicate that DOPAL, but not DOPEGAL, DA or other DA metabolites, generates hydroxyl radicals. Atomic absorption spectroscopy and heavy metal screening indicate that this result is not due to contamination of DOPAL with iron or other heavy metals. DOPAL reduction potential (161 mV) is lower than that of DOPEGAL (235 mV). DOPAL is present in human substantia nigra. The implications of these findings to CA neuronal death in degenerative brain diseases are discussed.     

Biochemical analysis of catecholamines in small intensely fluorescent (SIF) cell clusters of the rat superior cervical ganglion

The microlaser technique of isolating small cell clusters has been applied to groups of small intensely fluorescent (SIF) cells in rat superior cervical ganglion. Alternate cryostate sections were either incubated in glyoxylic acid monohydrate or freeze-dried. SIF cell clusters, recognized by glyoxylic acid-induced fluorescence, were re-identified in the consecutive freeze-dried section through dark-field microscopy. These clusters were dissected with a BTG microlaser unit and collected for biochemical assay. The catecholamine content of the specimens was measured by gas chromatography/mass fragmentography, using 3 deuterated catecholamines as an internal standard and calibration curves of each catecholamine. The findings indicate the presence of these 3 catecholamines in rat SIF cell clusters in a varying amount: in probes, each consisting of 5 cell clusters, the content of norepinephrine averaged approximately 7.3 pmol, of epinephrine below 1 pmol, and of dopamine from below 1 pmol to 14.6 pmol.     

Age changes in concentrations of monoamines and related substances in the cerebrospinal fluid]

We studied age changes of concentrations of thirteen substances including monoamines, their precursors and metabolites in the cerebrospinal fluid, using high performance liquid chromatography. Cerebrospinal fluid was obtained from 106 subjects without neurological diseases (44.2 +/- 17.3 years) who underwent minor operations under lumbar anesthesia. Concentrations of dopamine, norepinephrine, tyrosine and 3-methoxy-4-hydroxy-phenylalanine were significantly increased with age, while concentrations of other monoamine precursors and metabolites were unchanged. There was a significant positive correlation between concentrations of the following substances: dopamine and norepinephrine; tyrosine and tryptophan; tyrosine and 3-methoxy-4-hydroxy-phenylalanine; tyrosine and 5-hydroxytryptophan; homovanillic acid and 5-hydroxyindoleacetic acid. Norepinephrine concentrations were positively correlated with concentrations of 3-methoxy-4-hydroxy-phenylglycol, whereas dopamine concentrations were not with homovanillic acid concentrations. The significance of these results was discussed with regard to age changes of transmitter secretion and metabolism, the binding capacity of receptors and cerebrospinal fluid kinetics of the measured substances.     

Catecholamine metabolism in rat brain following the intracerebroventricular administration of cyclic nucleotides

Summary The dibutyryl analogues of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) were administered into the lateral ventricles and catecholamine metabolites were determined in brain 40 min later.Dibutyryl cAMP elevated the level of homovanillic acid in whole brain and dihydroxyphenyl acetic acid levels in striatum, the dopamine-rich part of the limbic system and hemispheres but neither affected the accumulation of 3-methoxytyramine following inhibition of MAO with pargyline nor dopamine and noradrenaline levels. Normetanephrine accumulating after MAO inhibition was elevated markedly by dibutyryl cAMP. Dibutyryl cGMP was without effect on the catecholamine metabolites investigated.Dibutyryl cAMP appears to stimulate dopamine metabolism within dopaminergic nerve endings but does not stimulate dopamine release. Dibutyryl cAMP-induced activation of noradrenaline metabolism, however, appears to coincide with a stimulation of noradrenaline release.     

A study of CSF catecholamine and its metabolites in acute and convalescent period of encephalitis

AIMS: To evaluate cerebrospinal fluid (CSF) catecholamine (CA) and its metabolites in encephalitis patients in acute and convalescent period and correlate these with clinical and magnetic resonance imaging (MRI) features. SUBJECTS AND METHODS: Patients with acute encephalitis diagnosed on the basis of clinical, CSF, MRI and virological parameters underwent detailed neurological evaluation including Glasgow Coma Scale (GCS), Unified Parkinson's Disease Rating Scale (UPDRS) and Dystonia Rating Scale. Cranial MRI was carried out and CSF dopamine (DA), norepinephrine (NE), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxytryptamine (5HT) levels were estimated by High Performance Liquid Chromatography (HPLC). The CSF catecholamine levels were compared with convalescent phase as well as with controls. These levels were also correlated with parkinsonian features, dystonia and radiological abnormalities. RESULTS: There were 29 encephalitis patients; whose age ranged between 2 and 65 years, 4 were females and 11 children. 25 patients had Japanese encephalitis (JE) and 4 nonspecific encephalitis. The mean GCS score was 8 and 13 had seizures. Movement disorders were present in 13 patients and included parkinsonian features in 5, dystonia in 1 and combination of both in 7 patients. MRI revealed abnormalities in 15 out of 21 patients and included thalamic lesion in 10, globus pallidus in 4, putamen in 5, caudate in 4 and midbrain in 9 patients. In acute stage NE, DOPAC, 5HT and HVA levels were significantly lower compared to controls. NE levels significantly correlated with dystonia and thalamic lesions. Convalescent CSF study revealed significantly lower levels of DOPAC compared to acute phase. CSF catecholamine levels in encephalitis patients with and without movement disorders were not significantly different. CONCLUSION: In encephalitis, catecholamine and its metabolites are lower in acute and convalescent phase. Norepinephrine level correlates with dystonia and thalamic lesions.     

Neurotoxicity of MAO metabolites of catecholamine neurotransmitters: role in neurodegenerative diseases

The monoamine oxidase (MAO) metabolites of norepinephrine (NE) or epinephrine (EPI) and of dopamine (DA) are 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL) and 3,4-dihydroxyphenylacetaldehyde (DOPAL), respectively. The toxicity of these catecholamine (CA) MAO metabolites was predicted over 50 years ago. However, until our recent chemical synthesis of these CA aldehyde metabolites, the hypothesis about their toxicity could not be tested. The present paper reviews recent knowledge gained about these compounds. Topics to be reviewed include: chemical synthesis and properties of DOPEGAL and DOPAL; in vitro and in vivo toxicity of CA aldehydes; subcellular mechanisms of toxicity; free radical formation by DOPEGAL versus DOPAL; mechanisms of accumulation of CA aldehydes in Alzheimer's disease (AD) and Parkinson's disease (PD) and potential therapeutic targets in Alzheimer's disease and Parkinson's disease.     

Interaction between the long-latency stretch reflex and voluntary electromyographic activity prior to a rapid voluntary motor reaction

In vivo electrochemical detection of endogenous neurotransmitters was done in the dorsal raphe nucleus of urethane-anesthetized male Sprague-Dawley rats. Stereotaxically implanted carbon paste electrodes were scanned using a cyclic voltammetry amplifier with semiderivative signal processing over the potential range--0.2 to +0.5 V at the rate of 10 mV/s. Two distinct peaks were observed at +0.15 V (peak 1) and +0.25 V (peak 2), respectively. Peak identification was assessed by comparing the oxidation potential observed in vivo with those observed in in vitro experiments using pure catecholamines, indoleamines and their metabolites as well as ascorbic acid. Further characterization of in vivo peaks was done by observing changes in electrochemical peaks as well as tissue neurotransmitter concentrations after pharmacological manipulations. p-Chlorophenylalanine, m-hydroxybenzylhydrazine (NSD-1015), pargyline, alpha-methyl-p-tyrosine and fusaric acid were administered in an effort to block catecholamine or serotonin synthesis or degradation. Results of these experiments revealed that peak 1 primarily represents extracellular norepinephrine, while peak 2 is primarily produced by extracellular 5-hydroxyindoleacetic acid (5-HIAA).     

Catecholamines in murine bone marrow derived mast cells

Cultured murine bone marrow derived mast cells (BMMC) were found to store high levels of dopamine (3753+/-844 pg/10(7) cells) and occasionally produce norepinephrine and epinephrine. The catecholamine synthesis inhibitor, alpha-methyl-para-tyrosine, decreased intracellular catecholamine concentrations, and activation with ionomycin stimulated dopamine release. Neither dopaminergic receptor antagonists nor exogenous dopamine < or =10 microM affected IL-3-induced cell proliferation. High exogenous dopamine (20-100 microM) decreased proliferation and increased apoptosis, and the anti-oxidant ascorbic acid prevented these effects. Increased expression of the anti-apoptotic factor Bcl-2 or loss of pro-apoptotic Bax expression attenuated dopamine-induced apoptosis, suggesting the apoptosis proceeds through a mitochondrial pathway.     

In vivo electrochemical detection of extraneuronal 5-hydroxyindole acetic acid and norepinephrine in the dorsal raphe nucleus of urethane-anesthetized rats

In vivo electrochemical detection of endogenous neurotransmitters was done in the dorsal raphe nucleus of urethane-anesthetized male Sprague-Dawley rats. Stereotaxically implanted carbon paste electrodes were scanned using a cyclic voltammetry amplifier with semiderivative signal processing over the potential range—0.2 to +0.5 V at the rate of 10 mV/s. Two distinct peaks were observed at +0.15 V (peak 1) and +0.25 V (peak 2), respectively. Peak identification was assessed by comparing the oxidation potential observed in vivo with those observed in in vitro experiments using pure catecholamines, indoleamines and their metabolites as well as ascorbic acid. Further characterization of in vivo peaks was done by observing changes in electrochemical peaks as well as tissue neurotransmitter concentrations after pharmacological manipulations. p-Chlorophenylalanine, m-hydroxybenzylhydrazine (NSD-1015), pargyline, a-methyl-p-tyrosine and fusaric acid were administered in an effort to block catecholamine or serotonin synthesis or degradation. Results of these experiments revealed that peak 1 primarily represents extracellular norepinephrine, while peak 2 is primarily produced by extracellular 5-hydroxyindoleacetic acid (5-HIAA).     

Regional differences in catecholamine formation and metabolism in the rat spinal cord

Catecholamine metabolism was assessed from the content of norepinephrine (NE), dopamine (DA) and their metabolites in various regions of the rat spinal cord during steady-state conditions and following treatment with alpha-methyl-p-tyrosine. The content of NE was rather uniform along the cord while DA was higher in the rostral portion of the cord than in the caudal portion.For both NE and DA there was a rostrocaudal decrease of their turnover rates along the cord. In the cervical cord, DA was formed at a faster rate than NE. There was no correlation between the content of catecholamine metabolites and amine turnover rates. The non-uniformity of catecholamine turnover in the cord probably arises from the fact that different regions of brain project to different regions of cord, each having a specific physiological function. Furthermore, our study provides added support for the presence of an independent DA-containing neuronal system in the spinal cord.     

Neurotoxic catecholamine metabolite in nociceptors contributes to painful peripheral neuropathy

The neurotoxic effects of catecholamine metabolites have been implicated in neurodegenerative diseases. As some sensory neurons express tyrosine hydroxylase and monoamine oxidase (MAO), we investigated the potential contribution of catecholamine metabolites to neuropathic pain in a model of alcoholic neuropathy. The presence of catecholamines in sensory neurons is supported by capsaicin-stimulated epinephrine release, an effect enhanced in ethanol-fed rats. mRNA for enzymes in dorsal root ganglia involved in catecholamine uptake and metabolism, dopamine beta-hydroxylase and MAO-A, were decreased by neonatal administration of capsaicin. Ethanol-induced hyperalgesia was attenuated by systemic and local peripheral administration of inhibitors of MAO-A, reduction of norepinephrine transporter (NET) in sensory neurons and a NET inhibitor. Finally, intradermal injection of 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL), a neurotoxic MAO-A catecholamine metabolite, produced robust mechanical hyperalgesia. These observations suggest that catecholamines in nociceptors are metabolized to neurotoxic products by MAO-A, which can cause neuronal dysfunction underlying neuropathic pain.     

Catechols in post‐mortem brain of patients with Parkinson disease

Background: Dihydroxyphenylacetaldehyde (DOPAL), a cytotoxic metabolite of dopamine, is the focus of the ‘catecholaldehyde hypothesis’ about the pathogenesis of Parkinson disease. This study explored whether DOPAL is detectable in human striatum – especially in the putamen (Pu), the main site of dopamine depletion in Parkinson disease – and is related to other neurochemical indices of catecholamine stores and metabolism in Parkinson disease. Methods: Putamen, caudate (Cd), and frontal cortex (Ctx) catechols were measured in tissue from patients with pathologically proven end‐stage Parkinson disease (N = 15) and control subjects (N = 14) of similar age with similar post‐mortem intervals. Results: Putamen DOPAL (3% of dopamine in controls) correlated with dopamine and dihydroxyphenylacetic acid both across all subjects and within the Parkinson disease and control groups. Pu dopamine was decreased by 93% and dihydroxyphenylacetic acid 95% in Parkinson disease vs. controls, with smaller decreases of DOPAL (83%) and norepinephrine (73%) in Pu and of dopamine (74%) and dihydroxyphenylacetic acid (82%) in Cd. In Parkinson disease, Pu DOPAL:dihydroxyphenylacetic acid averaged 3.4 times and DOPAL:dopamine 4.4 times control (P = 0.03 each). The main catecholamine in Ctx was norepinephrine, which was decreased by 51% in Parkinson disease patients. Conclusions: Correlated decreases of DOPAL, dopamine, and dihydroxyphenylacetic acid in Parkinson disease reflect severe loss of Pu dopamine stores, which seems more extensive than loss of Pu norepinephrine or Cd dopamine stores. Increased Pu DOPAL:dihydroxyphenylacetic acid ratios in Parkinson disease suggest decreased detoxification of DOPAL by aldehyde dehydrogenase. Elevated levels of cytosolic DOPAL might contribute to loss of dopaminergic neurons in Parkinson disease.     

Indomethacin prevents increased catecholamine turnover in rat brain following systemic endotoxin challenge

1. Key features of the acute phase response to infection are replicated by systemic administrations of lipopolysaccharide and may be mediated via the production of lymphokines and cytokines, including interleukin-1. Inhibition of prostaglandin synthesis may attenuate certain features of the acute phase response. 2. In the present study, the effects of systemic administration of the lipopolysaccharide (LPS, 250 micrograms/rat) and interleukin-1 (IL-1, 10 micrograms/rat) on catecholamine metabolism in different brain regions were compared and the effects of indomethacin, a cyclooxygenase inhibitor was determined. 3. The ratio of metabolite to parent amine was used as an index of turnover of catecholamines. 4. In hypothalamus, both epinephrine and norepinephrine concentrations were decreased and their major metabolite, 3-methoxy,4-hydroxyphenylglycol (MHPG), was elevated at 4, 8 and 24 hr following LPS. The major metabolite of dopamine (homovanillic acid, HVA) was increased at 8 hours in striatum, hypothalamus and medulla. LPS increased dopamine turnover at 8 and 24 hr and norepinephrine turnover at 4, 8 and 24 hr. 5. In all regions examined, IL-1 produced effects similar to LPS on amine and metabolite contents and norepinephrine and dopamine turnover. 6. Significantly, co-administration of a single dose of indomethacin (50 mg/kg) completely blocked LPS-induced changes in hypothalamic catecholamines and metabolites and the increase in turnover at 4 and 8 hr. Furthermore, the effects of IL-1 on hypothalamic MHPG content and norepinephrine turnover were also blocked by indomethacin, although the effects of IL-1 on regional catecholamines and HVA content and turnover were either not modified or partially antagonized by indomethacin. 7. The present results suggest that in the rat, activation of noradrenergic, dopaminergic and epinephrine-containing neurons in hypothalamus, as well as dopaminergic neurons in other regions is associated with the acute phase response to endotoxin and that synthesis of prostaglandins plays a pivotal role in catecholamine responses in all brain regions examined.     

Effect of low-dose clorgyline on 24-hour urinary monoamine excretion in patients with rapidly cycling bipolar affective disorder

Effects of clorgyline on urinary excretion of norepinephrine, dopamine, tyramine, and their major metabolites, 5-hydroxyindoleacetic acid and phenylethylamine, were studied in four women who suffered from primary, bipolar affective disorder. All patients had rapid mood cycles and were nonresponsive to lithium carbonate. During placebo administration, a strong correlation was found between the excretion rates of norepinephrine and dopamine and their respective metabolites. Clorgyline, 5 to 10 mg every or every other day, reduced overall-body norepinephrine turnover by 55% and increased tyramine but did not alter 5-hydroxyindoleacetic acid, phenylethylamine, or p-hydroxyphenylacetic acid excretion. These findings demonstrate the clinical actions of low-dose clorgyline and clorgyline's specificity as a monoamine oxidase A (MAO-A) inhibitor in vivo in humans, as well as the effects of specific MAO-A inhibition on monoamine metabolism.