抑郁症患者自杀与脑脊液单胺代谢产物的关系

目的：探讨抑郁症患者自杀与脑脊液单胺代谢产物之间的关系。方法：应用高效液相色谱法，测定24例抑郁症患者(自杀组10例，无自杀组14例)及25例对照组5-羟色胺(5-HT)代谢产物5-羟吲哚乙酸(5-HIAA)，去甲肾上腺素(NE)代谢产物3-甲基-4-羟苯乙二醇(MHPG)及多巴胺(DA)代谢产物高香草酸(HVA)的浓度。结果：抑郁症自杀组5-HIAA浓度显著低于对照组，男性自杀组5-HIAA浓度、HVA浓度和HVA／MHPG比值均显著低于男性对照组，女性则无显著差异：结论：抑郁症患者自杀可能与5-HT和DA功能低下以及DA和NE之间的关系改变有关。     

Variations of monoamines and their metabolites in the human brain putamen

The levels of the monoamines dopamine (DA), serotonin (5-HT) and norepinephrine (NE) and the monoaminergic metabolites 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) were measured with HPLC-ECD in 42 samples from human brain putamen. The influence of gender and of age was investigated and correlations between the monoamines were established. The DAergic system shows a significant difference between males and females, with females having lower DA and higher DOPAC levels and a higher DOPAC/DA ratio than males. No gender-related differences of 5-HT and its metabolites were observed, nor of NE. Three different age groups (group 1: 0–9.9 years; group 2: 10–59.9 years; group 3: 60 years and older) were defined according to previous studies on ontogenesis and senescence in human brain. An increase in 5-HT levels, decrease in 5-HIAA levels a d a decrease in the 5-HIAA/5-HT ratio were observed after the first decade of life. Changes in the DAergic system were seen in senescence, with decreasing DA levels and an increase in the HVA/DA ratio. DOPAC, HVA and the DOPAC/DA ratio are unaffected. NE is similar in all age groups. The analysis of the relation of the levels of the three monoamines proved a strong correlation between the DAergic and 5-HTergic systems. The nature of this relationship might have an impact on neuro-psychiatric disorders and brain function.     

Comparative evaluation of 5-HIAA (5-hydroxy indoleacetic acid) and HVA (homovanillic acid) in infantile hydrocephalus

Background Infantile hydrocephalus is a common congenital problem. Functional and behavioral disturbances associated with hydrocephalus may be due to altered neurotransmitters in the brain. The role of neurotransmitters has been established in various psychiatric and neurological conditions. Therefore, we decided to study the role of 5-hydroxy indoleacetic acid (5-HIAA) and homovanillic acid (HVA) in cerebrospinal fluid (CSF) of hydrocephalic patients as diagnostic and prognostic marker. Materials and methods Ventricular CSF samples were taken from hydrocephalic patients peroperatively and at days 7 & 30. Control CSF samples were taken from nonhydrocephalic patients operated for other conditions. Samples were analyzed for 5-HIAA and HVA, and results were obtained accordingly. Results Values of 5-HIAA and HVA showed a highly significant decrease after shunt insertion. No significant difference in values of 5-HIAA and HVA were observed in relation to age and duration of disease. The CSF ventriculo-lumbar gradient for both 5-HIAA and HVA done in six patients was statistically significant only in the noncommunicating group. Conclusion Both the neurotransmitter metabolites 5-HIAA and HVA are found to be significantly high in the hydrocephalus, but 5-HIAA is a more sensitive parameter. These markers levels decrease after shunt insertion. Thus, estimation of these metabolites could be valuable markers for its diagnosis and follow-up.     

A double-blind study of zimelidine, a serotonin uptake inhibitor, and desipramine, a noradrenaline uptake inhibitor, in endogenous depression. II. Biochemical findings

In a comparative evaluation of zimelidine, a potent serotonin (5-HT) uptake inhibitor, and desipramine, a potent noradrenaline (NA) uptake inhibitor, 65 hospitalized patients with endogenous depression were evaluated for the following biochemical variables: 5-HT uptake in platelets, 5-HT concentration in whole blood, inhibition of the 5-HT and NA accumulation in rat hypothalamic synaptosomes incubated in the patients' plasma, the excretion of 4-hydroxy-3-methoxyphenyl glycol (HMPG) in urine and the pretreatment levels of the amine metabolites 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA) and HMPG in cerebrospinal fluid (CSF). results of the biochemical studies confirmed that zimelidine and desipramine have different profiles with respect to monoamine uptake. Thus zimelidine caused more marked inhibition of 5-HT uptake than desipramine, especially in rat brain synaptosomes incubated in the patient's plasma. Desipramine plasma was much more effective than zimelidine plasma in inhibiting NA uptake in the same preparation. The urinary excretion of HMPG decreased significantly during desipramine treatment but remained unchanged during zimelidine treatment. The combined clinical and biochemical results indicated that patients with low pretreatment levels of 5-HIAA and HVA in CSF responded significantly better to zimelidine than patients with high levels of 5-HIAA and HVA. On the other hand, patients with high levels of 5-HIAA and HVA. On the other hand, patients with high levels of HMPG in CSF tended to respond better to desipramine than those with low levels of this NA metabolite.     

Characterization of monoamine release in the lateral hypothalamus of awake, freely moving rats using in vivo microdialysis

Extracellular levels of serotonin (5-HT), dopamine (DA) and their major metabolites 5-hydroxyindoleacetic acid (5-HIAA), 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA), were measured in the lateral hypothalamus of awake, freely moving rats using microdialysis combined with HPLC and electrochemical detection. To characterize the factors which control 5-HT release, the effects of various drugs were assessed. TTX had a reversible inhibitory effect on the basal levels of 5-HT, 5-HIAA, DOPAC and HVA. Infusion of K+ concomitantly increased 5-HT and DA and decreased 5-HIAA and HVA. Imipramine increased extracellular levels of 5-HT and DA and decreased 5-HIAA levels; this effect was TTX-sensitive. Systemic pargyline increased extracellular 5-HT and markedly decreased the metabolic levels. Pargyline pretreatment in the presence of imipramine, infused through the dialysis probe, slowly increased 5-HT levels above that produced by the reuptake blocker alone. Infusion with AMPH produced a dramatic, TTX-insensitive, increase in 5-HT and DA and a decrease in the metabolic levels. These results provide evidence that (1) basal release of 5-HT in the lateral hypothalamus results from neuronal activity, (2) the metabolites in the extracellular fluid derive primarily from intracellular monoamine oxidase (MAO) activity, (3) 5-HT is mainly removed from the extracellular space by a reuptake mechanism, with minimal contribution of an extracellular MAO, and (4) the AMPH-evoked release of 5-HT and DA is a Na+ channel-independent process.     

精神分裂症患者的中枢多巴胺和5—羟色胺浓度及其性别差异

目的 了解精神分裂症中枢多巴胺（DA）与5－羟色胺（5－HT）相互作用的变化及其性别影响的程度。方法 应用高效液相色谱对符合CCMD－2精神分裂症诊断标准的30例男性病人、37例女性病人、21例男性对照组、9例女性对照组脑脊液中DA、5－HT及其代谢产物高香草酸（HVA）、5－羟吲哚乙酸（5－HIAA）进行测试,并应用5－HT／DA、5－HIAA／HVA作为它们的相互作用的指标。结果 5－HT／DA、5－HIAA／HVA在4组中有显著性差异（F＝3．567,P＝0．032;F＝12．464,P＝0．001）,进一步分析提示;女性分裂症5－HT／DA显著低于男性对照组,且男性、女性分裂症及男性对照组5－HIAA／HVA均显著低于女性对照组。在男性病例组的相关分析中,5－HT／DA与BPRS及其阳性症状呈显著负漠、非特异性症状呈显著负、正相关;5－HIAA／HVA与思维形式障碍呈显著正相关。结论 精神分裂症患者存在中枢DA和5－HT相互作用的失平衡,这种失平衡与某些重要精神症状有关,且受性别因素的影响。     

Cerebrospinal fluid monoamine precursor and metabolite levels in children treated for leukemia: age and sex effects and individual variability

Lumbar cerebrospinal fluid (CSF) was obtained from children during and following treatment for acute lymphoblastic leukemia (ALL). One hundred ninety-two CSF samples from 50 subjects, which were selected to minimize the effects of the disease and its treatment (i.e., to approach "normality" as closely as possible), were analyzed for the monoamine precursors tyrosine (Tyr) and tryptophan (Trp) and the metabolites homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA). Levels of HVA (p less than 0.0001), 5-HIAA (p less than 0.002), and Tyr (p less than 0.05) decreased with age from 3 to 17 years. Significant correlations were observed between the acid metabolites HVA and 5-HIAA (r = 0.79) and between the amino acid precursors Tyr and Trp (r = 0.71). Within individuals, levels of all four compounds were relatively stable over time, with total mean coefficient of variation ranging from 20% to 25%. No significant sex differences for CSF levels of HVA, 5-HIAA, Tyr, or Trp were found. Assessment of CSF monoamine precursors and metabolites in children treated for ALL may provide a method for understanding the chronic effect of CNS trauma on the ontogeny of monoamine systems.     

CSF monoamine patterns in pathological gamblers and healthy controls

Previous reports on compounds in the cerebrospinal fluid (CSF) of pathological gamblers have focused on disturbed NA, DA and 5-HT function in the central nervous system. We have analysed precursors, transmitters and transmitter metabolites in 3 x 6 ml of CSF obtained from one female and 11 male pathological gamblers and 11 healthy male controls lumbar punctured at the L4-5 level after 8 h of fasting without preceding strict bedrest. Pathological gamblers displayed lower CSF levels of tryptophan and 5-HT while the opposite was the case for 5-HIAA, tyrosine, DA, HVA, DOPAC and HMPG. In contrast to previous studies, the NA level did not differ between pathological gamblers and healthy controls. A disrupted CSF gradient was noted for tryptophan, 5-HT, DA, HVA, DOPAC, NA and HMPG, but only in pathological gamblers. A disrupted gradient was found for 5-HIAA in both pathological gamblers and healthy controls. The results are in line with the presence of altered indoleamine and catecholamine function in pathological gamblers as well as an altered CSF transport from the brain to the lumbar compartment in such gamblers.     

Levels of biogenic amines and their metabolites in rat whole brain after rapid tissue fixation with microwave irradiation (author's transl)]

Levels of norepinephrine (NE), dopamine (DA), serotonin (5-HT), 3, 4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxy-indoleacetic acid were measured fluorometrically in the whole brain of rats killed either by decapitation or by 5kW microwave irradiation for 1.6 sec. which inactivates the relevant brain enzymes rapidly and irreversibly. There were statistically no differences in the levels of NE, DA, 5-HT and 5-HIAA between the two methods of sacrifice, while the level of DA increased slightly in irradiated brains. On the other hand, the level of DOPAC, an oxidative deaminated metabolite of DA, increased significantly and the level of HVA, a final metabolite of DA, reduced markedly in the irradiated brains compared to that in the decapitated brains, respectively. These findings suggest that the turnover rates for metabolism of DA at synaptic nerve terminals and synaptic clefts may be relatively rapid. Therefore, it may be concluded that rapid inactivation of the brain enzymes involved in metabolism of DA is necessary prior to analysis of DA and its metabolites and microwave irradiation is the most suitable method available at the present time.     

Brain monoaminergic and neuropeptidergic variations in human aging

Summary The effect of age on the monoamines 5-hydroxytryptamine (5-HT), noradrenaline (NA) and dopamine (DA), their metabolites 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), 3,4-dihydr-oxyphenylacetic acid (DOPAC), and the 5-HT precursor 5-hydroxy-L-tryptophan (5-HTP), together with the peptides neuropeptide Y (NPY), somatostatin (SOM), and corticotropin-releasing factor (CRF), was studied in frontal cortex, gyrus cinguli and hypothalamus from 23 healthy control subjects, aged 16–75 years. After correcting for postmortem interval, significant decreases in gyrus cinguli NA, NPY and CRF, and hypothalamic DA, HVA, and 5-HIAA concentrations were obtained with advancing age. The involvement of the monoaminergic system in several functional abnormalities appearing in senescence is suggested. Furthermore, evidence is given of the participation of the peptidergic systems in the aging process.     

Late chronic dyskinesia from neuroleptic drugs (CSF and pharmacological data) (author's transl)]

CSF values of dopamine and serotonine metabolites (homovanillic acid and 5-hydroxy-indoleacetic acid) have been studied in 4 patients suffering from late dyskinesia due to neuroleptics. Trazodone (which acts on all monoaminergic systems, namely noradrenergic, dopaminergic and serotoninergic) induced a marked clinical improvement associated with CSF HVA increase and 5-HIAA decrease. The Authors suggest that involuntary movements could be due to an impairment of 5-HT e DA link.     

Naltrexone administration effects on regional brain monoamines in developing rats

The effects of the opioid antagonist naltrexone (NALTX) daily administration (1 mg/kg SC) from birth on the levels of dopamine (DA), serotonin (5-HT), and their respective major metabolites, in the striatum, midbrain, and hypothalamus of 7-, 14-, and 22-day-old rats were investigated. Naltrexone treatment increased the striatal HVA/DA ratio on postnatal day 7. At day 14, two subpopulations (A and B) were found among the treated animals. The subpopulation A showed decreased HVA/DA and increased DOP AC/DA ratios, whereas the subpopulation B presented a higher DA concentration. No significant effect appeared on the striatal dopaminergic system in 22-day-old pups. The serotonergic system was affected by exposure to naltrexone only from day 14. The subpopulation A showed a reduction in all the parameters measured in the three regions studied, although in the subpopulation B, lower 5-HIAA/5-HT ratios appeared in the midbrain and hypothalamus. At 22 days of age NALTX treatment elevated striatal 5-HT and 5-HIAA and the ratio of 5-HIAA/ 5-HT in the midbrain and hypothalamus. These data suggest an endogenous opioid modulation on the central aminergic systems during the neonatal period and point out the consequences of opioid plasticity on related neurotransmitter systems.     

Changes of monamine metabolites in the cerebral cortices and hippocampi following prolonged administration of diphenylhydantoin in the developing mice]

It was previously reported by the authors that long-term diphenyl-hydantoin (DPH) administration impaired the learning behavior in the developing mice. The aim of the present study was to find out whether prolonged administration of DPH would affect the levels of monamine metabolites in the cerebral cortices and hippocampi of the developing mice. Each of the experimental animals was treated intraperitoneally with a dose of DPH of 25mg/kg q.d. for 50 days. The monamine metabolites were measured with high performance liquid chromatography. The results showed that chronic administration of DPH caused a significant elevation of the concentrations of 5-hydroxytryptamine(5-HT), 5-hydroxyindoleacetic acid (5-HIAA) and dihydroxy-phenyl acetic acid (DOPAC) in the cerebral cortices and hippocampi, whereas it did not raise the concentrations of dopamine (DA), homovanillic acid (HVA) and norepinephrine (NE) in these two brain regions. This suggested that DPH mainly enhanced the function of 5-HT in the brains. It was postulated that the elevation of the concentrations of 5-HT and 5-HIAA in the cerebral cortices and hippocampi might be responsible for the adverse effect of DPH on the learning behavior in the developing mice.     

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.     

Modification of gonadectomy-induced increases in brain monoamine metabolism by steroid hormones in male and female rats

Concentrations of monoamines (dopamine, DA; serotonin, 5-HT) and their major metabolites (homovanillic acid — HVA; dihydroxyphenylacetic acid — DOPAC; 5-hydroxyindolacetic acid — 5-HIAA) were measured in selected brain areas of chronically gonadectomized, steroid- or oil-treated male and female rats. Concentrations of DOPAC and HVA were markedly increased in the hypothalamus (male, female), striatum (male, female) and brainstem (male) following gonadectomy, whereas the levels of DA remained unaltered in most of the brain areas examined. Most of the changes were reversed or attenuated by chronic estradiol (EB) substitution. In contrast, chronic treatment with physiological concentrations of testosterone (TP) reduced indexes of DA turnover only in the striatum of ovariectomized (OVX) and brainstem of orchidectomized (ORDX) rats. ORDX-related increases in striatal levels of DOPAC and HVA were not reversed by either EB or TP. ORDX increased the levels of 5-HIAA (hypothalamus, striatum) and decreased those of 5-HT (hypothalamus, hippocampus). These changes were reversed by chronic treatment with either TP or EB. Brain metabolism of 5-HT remained unaltered following OVX.

Gonadectomy and chronic steroid replacement therapy appear to alter brain monoamine metabolism in a brain region and sex-dependent manner. Our data demonstrate that gonadectomy-related increases in the activity of brain monoaminergic neurons in both male and female rats was attenuated more effectively with physiological concentrations of estradiol than with testosterone. Insensitivity of monoaminergic neurons in a number of brain areas (e.g., hypothalamus, striatum) to the action of testosterone was evident in both sexes.     

Monoamine metabolites in the CSF of epileptic patients.

To assess the possible role of amine neurotransmitters in human epilepsy, we measured metabolites of serotonin (5-hydroxyindoleacetic acid [5-HIAA]), dopamine (homovanillic acid [HVA]), and norepinephrine (3-methoxy-4-hydroxyphenylethylene glycol [MHPG]) in the lumbar cerebrospinal fluid (CSF) of patients with partial complex seizures and in neurologic controls. Untreated epileptic patients had lower concentrations of 5-HIAA and HVA in the lumbar CSF than the controls, but the differences were not statistically significant. Among epileptic patients receiving effective antiepileptic drug treatment, the HVA concentration was within the control range. Mean MHPG concentrations were similar in patients and controls. From the epileptic patients whose CSF was obtained at pneumoencephalography we obtained a second sample of CSF that was originally in the basal cisterns. No significant differences between treated and untreated patients were found for any of the three metabolites. The concentrations of HVA and 5-HIAA were higher in cisternal than in lumbar CSF, but there was no such gradient for MHPG.     

Phenylethylamine and monoamine metabolites in CSF of schizophrenics: Effects of neuroleptic treatment

Phenylethylamine (PEA) and the monoamine metabolites 3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) have been measured in the cerebrospinal fluid (CSF) of nine paranoid schizophrenics before and after three weeks of neuroleptic treatment. Patients were classified according to the Research Diagnostic Criteria and rated by means of the Brief Psychiatric Rating Scale. A significant increase was seen in HVA CSF concentrations during neuroleptic treatment (p less than 0.01). No influence was found on levels of PEA, 5-HIAA, and MHPG. Concentrations of both MHPG and 5-HIAA correlated positively with those of HVA. These results in combination with previous findings do not support the contention that PEA and NA metabolisms are grossly disturbed in paranoid schizophrenics whereas involvement of other neurotransmitters i.e. dopamine, seems more probable.     

Cerebrospinal fluid monoaminergic metabolites are elevated in adults with Down's syndrome

Under conditions of rest and a low monoamine diet, brain monoamine activity was examined in young (less than 35 years) and old (greater than 35 years) adults with Down's syndrome and in control subjects by measuring the cerebrospinal fluid (CSF) and plasma concentrations of the neurotransmitter norepinephrine, and of 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy 4-hydroxyphenylglycol (MHPG), the respective metabolites of the neurotransmitters serotonin, dopamine, and norepinephrine. There were no age-related differences in metabolite concentrations in either the Down's syndrome or control subjects. CSF concentrations of 5-HIAA, HVA, and norepinephrine were significantly higher in young subjects with Down's syndrome as compared with young controls, and CSF concentrations of 5-HIAA and norepinephrine were significantly higher, by twofold or more, in old subjects with Down's syndrome as compared with older controls. The results suggest that monoamine turnover and brain functional activity involving monoamines is elevated in Down's syndrome, and that the early neuropathological changes in the disorder are not associated with a monoamine deficit.     

Concentration gradients of monoamine metabolites in human cerebrospinal fluid.

The monamine metabolites 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), vanillylmandelic acid (VMA), and 4-hydroxy-3-methoxyphenylglycol (HMPG) were analysed in CSF from different regions of the CSF system to study the caudocranial concentration gradient of the metabolites. Four consecutive 10 ml fractions of CSF were withdrawn in 17 patients during the course of four minutes. The CSF pressure was monitored through a lumbar cannula because of suspected adult hydrocephalus. A pronounced gradient of the HVA concentration was found with a ratio between the last and the first fraction of 1,7. 5-HIAA showed a slight increase while HMPG and VMA showed no increase at higher levels of the CSF system. The results suggest that lumbar HVA reflects dopaminergic activity in the brain, whereas lumbar 5-HIAA and HMPG/VMA reflect the activity of 5-hydroxytryptamine and noradrenaline secreting neurones in both the brain and the spinal cord.     

CSF monoamine metabolites and MRI brain volumes in alcohol dependence

Correlations between cerebrospinal fluid (CSF) concentrations of monoamine metabolites (MAM) and brain structure have been described in schizophrenia, but not in alcoholism. To investigate the relationship between monoaminergic transmission and brain structure in alcoholism, the metabolites of dopamine (homovanillic acid, HVA), norepinephrenine (3-methoxy-4-hydroxyphenylethyleneglycol, MHPG) and serotonin (5-hydroxyindoleacetic acid, 5-HIAA) were measured in lumbar CSF in 54 alcohol-dependent patients and 20 healthy subjects. The volumes of the cerebrum, total grey and white matter, total and ventricular CSF, left and right hippocampus, and corpus callosum area were measured with MRI. MHPG and age were positively correlated in alcoholic women. The MAM concentrations were not significantly correlated with the MRI volumes in the subject categories. There were no differences in MAM across subjects defined by diagnosis and gender, age of onset of alcoholism or comorbidity of psychiatric disorders. Total CSF, cerebrum, and white and grey matter tissue volumes differed between patients and healthy subjects. The greatest difference was the white matter reduction in alcoholic women. In alcoholic women and men, monoaminergic neurotransmission measured by the CSF MAM HVA, MHPG, and 5-HIAA is not significantly correlated with the size of different brain structures.