精神分裂症异质性及其中枢去甲肾上腺素功能初步研究

本文采用高压液相色谱（ＨＰＬＣ）对４２例阳性精神分裂症、２５例阴性精神分裂症及１０例健康对照组进行了脑脊液中去甲肾上腺素（ＮＥ）及其代谢产物３－甲基－４－羟基苯乙二醇（ＭＨＰＧ）的测定，同时引入ＮＥ相对代谢率（ＭＨＰＧ／ＮＥ）加以比较，研究结果提示：６７例精神分裂症脑脊液中ＭＨＰＧ明显低于正常对照组，４２例阳性精神分裂症脑脊液中ＮＥ及ＭＨＰＧ亦明显低于正常对照组，同时还发现，阴性精神分裂症相对代谢率ＭＨＰＧ／ＮＥ也明显低于阳性精神分裂症．本文针对以上结果、结合ＮＥ与多巴胺（ＤＡ）的相互关系进行了讨论，同时分析了精神分裂症的异质性问题。     

Evidence against specificity of electrical stimulation of the nucleus locus coeruleus in activating the sympathetic nervous system in the rat

Electrical stimulation of the central nucleus locus coeruleus (LC) was previously shown to increase activity of the peripheral sympathetic nervous system (SNS) as measured by increases in plasma levels of the norepinephrine (NE) metabolite 3-methoxy-4-hydroxyphenthyleneglycol (MHPG) in the rat⁵. Four experimental approaches were designed to test the specificity of the LC cell group in activating the SNS in the stimulation paradigm. Varying the stimulation current amplitude, varying the site of stimulating electrode placement, and electrolytic lesions of the LC yielded results consistent with the hypothesis that the site of SNS activation was within the anatomical region of the LC cell group. Neurochemical lesioning with intraventricular 6-hydroxydopamine, however, did not effectively block the plasma MHPG increase observed after stimulation of the LC region. The possibility that non-noradrenergic cells, fibers of passage, or terminals in the LC region of the midbrain may be responsible for SNS activation when the LC is electrically stimulated is discussed. These studies are pertinent to all studies of LC function which employ electrical stimulation of the LC nucleus, including investigations of the role of the LC in social behavior, intracranial self-stimulation, and blood pressure regulation.     

Monoamines (norepinephrine,dopamine, serotonin) in the rat medial vestibular nucleus: endogenous levels and turnover

Summary Monoamine (norepinephrine, dopamine, serotonin) and metabolite endogenous levels were determined in the rat medial vestibular nucleus (MVN) using HPLC with electrochemical detection. As a comparison, the locus cruleus (LC) and dorsal raphe nucleus (RD) which contain the cell bodies of MVN noradrenergic and serotoninergic neurons respectively were also analyzed. Norepinephrine (NE) and serotonin (5-HT) basal levels of MVN were high (33.8 and 39.2pmol/mg protein respectively) but lesser than in LC or RD. Great amounts of MHPG and 5-HIAA were also present in the MVN. The turnover of NE assessed both from the ratio MHPG/NE and by the decrease in the NE content after treatment with -methylparatyrosine was faster in the MVN (half-life 1.5h) than in LC (half-life 3.6h). On the other hand, the ratio 5-HIAA/5-HT was lower in the MVN (0.58) than in the RD (0.85) indicating a smaller 5-HT turnover in the MVN. In addition, like LC and RD, the MVN contained meaningful amounts of dopamine (DA) and DOPAC. The high ratio DA/NE (0.27) suggests the presence of non precursor specific dopaminergic pools. However, individualized dopaminergic neurons have not yet been demonstrated. The data are discussed in line with the possible neurotransmitter function of monoamines in the MVN.     

Patterns of cerebrospinal fluid catechols support increased central noradrenergic responsiveness in aging and Alzheimer's disease.

BACKGROUND: High cerebrospinal fluid (CSF) norepinephrine (NE) concentrations in aging and Alzheimer's disease (AD) could reflect decreased NE clearance from central nervous system (CNS) extracellular fluid or increased release of NE into CNS extracellular fluid. Measuring CSF concentrations of the intraneuronal NE metabolite dihydroxyphenylglycol (DHPG), an estimate of NE clearance, and the NE precursor dihydroxyphenylacetic acid (DOPA), an estimate of NE biosynthesis, can help differentiate these mechanisms. METHODS: NE, DHPG, and DOPA were determined by HPLC in CSF and plasma obtained following yohimbine, clonidine, and placebo. Ten AD, 10 older, and 11 young subjects were studied. RESULTS: CSF DOPA following yohimbine was higher in older and AD than in young subjects. CSF DHPG did not differ among groups. Plasma DOPA following yohimbine was higher in AD than in young subjects. CONCLUSIONS: During alpha-2 adrenoreceptor blockade in both aging and AD, there are increased responses of CNS NE biosynthesis and release with unchanged CNS NE clearance. This pattern is consistent with partial loss of CNS noradrenergic neurons with compensatory activation of remaining CNS noradrenergic neurons. Given the marked loss of locus coeruleus (LC) noradrenergic neurons in AD, achievement of high CSF NE suggests particularly prominent compensatory activation of remaining LC neurons in this disorder.     

Corticotropin-releasing factor administered into the locus coeruleus, but not the parabrachial nucleus, stimulates norepinephrine release in the prefrontal cortex

Previous studies have indicated that intracerebroventricular application of corticotropin-releasing factor (CRF) activates noradrenergic neurons in the brain stem locus coeruleus (LC) and norepinephrine (NE) metabolism in several brain regions. To assess whether CRF has direct effects on LC noradrenergic neurons, CRF was infused into the LC and concentrations of NE and its metabolites were measured in microdialysates collected from the medial prefrontal cortex (PFM). Infusion of 100 ng of CRF into the LC significantly increased dialysate concentrations of NE and of its catabolite MHPG in the ipsilateral PFM, whereas no significant changes were observed following infusion of artificial CSF. No response was observed when the infusions of CRF occurred outside of the LC, including those in the parabrachial nucleus. Although CRF administered into the LC slightly increased dialysate concentrations of NE in the contralateral PFM, this effect was not statistically significant. The effect of CRF injected into the LC on dialysate NE was prevented by combination with a 10-fold excess of the CRF antagonist, alpha-helical CRF_9–41 indicating some specificity in the response. These results are consistent with anatomical and electrophysiological evidence suggesting that CRF may directly activate noradrenergic neurons in or close to the LC.     

Activation of the locus coeruleus induced by selective stimulation of the ventral tegmental area

The effects of selective stimulation of perikarya, but not axons of passage, within the ventral tegmental area (VTA) on the locus coeruleus (LC) noradrenergic system were examined. Anterograde and combined retrograde-immunohistochemical studies indicated both dopaminergic and non-dopaminergic projections to the region of the LC originating from the VTA. Kainic acid (KA) stimulation of the VTA resulted in a dose-dependent increase in the levels of the dopamine metabolite dihydroxyphenylacetic acid (DOPAC) in the prefrontal cortex, and also elevated levels of the norepinephrine (NE) metabolite 3-methoxy-4-hydroxyphenolglycol (MHPG). Prefrontal cortical MHPG levels did not increase in response to vehicle injection or KA infusion into the hippocampus, nor did concentrations of this metabolite increase in the prefrontal cortex in response to intra-VTA KA in animals with neurotoxic lesions of the VTA. KA injection into the VTA resulted in increased MHPG levels in the hippocampus, but not the hypothalamus. Dorsal noradrenergic bundle knife cuts prevented the KA-elicited prefrontal cortical MHPG increase. These data suggest that stimulation of the mesocoeruleo dopaminergic projection arising from the VTA results in selective excitation of the LC-derived dorsal bundle noradrenergic system.     

Increased activity of surviving locus ceruleus neurons in Alzheimer's disease

In Alzheimer's disease (AD) there is neuronal loss in the locus ceruleus (LC), and the noradrenergic system may be even more affected in depressed AD patients. However, this neuronal loss may go together with an increase in activity of the remaining noradrenergic neurons. We prospectively evaluated 16 AD patients (6 depressed, 5 transiently depressed, and 5 nondepressed) and 10 controls. We determined norepinephrine and its metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) in various brain areas, and compared these data with previously established neuron numbers in the LC in the same patients. We could not confirm earlier studies reporting lower norepinephrine concentrations in depressed than in nondepressed dementia patients. The mean norepinephrine concentrations in AD patients were significantly lower than those in control patients, whereas the mean concentrations of MHPG were not different. Moreover, we found significant inverse relationships between the number of remaining pigmented LC neurons and the MHPG/norepinephrine ratio in the frontal cortex and LC. These data are the first to provide direct evidence for the hypothesis that remaining LC neurons are activated to compensate for decreased cerebral norepinephrine levels in AD, by demonstrating that the MHPG/norepinephrine ratio is significantly higher in AD, indicating increased metabolism. Ann Neurol 1999;45:82–91     

Locus Coeruleus Stimulation Modulates the Nociceptive Response in Parafascicular Neurons: An Analysis of Descending and Ascending Pathways

The nociceptive responses in parafascicular neurons (PF) were recorded and studied following electrical stimulation of locus coeruleus (LC) combined with intrathecal (IT) or intracerebroventricular (ICV) administration of phentolamine (Ph), an

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-adrenoceptor antagonist. The results revealed the following. (1) Three different PF neuronal populations were observed according to their response pattern following noxious stimulation: nociceptive-on, nociceptive-off, and nonresponsive units. Only the nociceptive-on units were studied further. (2) The nociceptive discharges in majority of PF neurons (66/87) were inhibited by electrical stimulation of the LC. (3) The inhibitory effect of LC stimulation was prevented and even reversed by pretreatment of IT Ph (40 nmol) in 22 units, or by dorsolateral funiculi transection in 24 units tested. (4) The inhibitory effect of LC stimulation was strengthened by preadministration of ICV Ph (40 nmol) in 17 units tested. (5) ICV administration of norepinephrine (NE 30 nmol) resulted in PF neurons a biphasic response to nociceptive stimulation: an early brief inhibition and a late long-lasting facilitation. (6) Pretreatment of ICV Ph (40 nmol) prior to NE injection prevented the NE-induced biphasic response. The results suggest that stimulation of LC modulates the nociceptive response of PF neurons through both ascending and descending routes. These two diverse routes exert two different effects: a predominantly inhibitory role on the nociceptive transmission at the spinal cord level by descending NE-ergic fibers, and a facilitatory role on the responsiveness of PF to noxious inputs by ascending fibers.     

Selective study of sulfate and glucuronide conjugates of urinary MHPG in nervous depression. Peripheral and central influences

The determination of urinary MHPG (3-methoxy-4-hydroxyphenyl glycol) has been extensively performed to confirm the noradrenergic hypothesis of some depressions. However, owing to the double origin, central and peripheral, of this norepinephrine metabolite, the validity of total MHPG assay as an index of central noradrenergic activity may be challenged. MHPG exists in human urine in two conjugated forms, at equal amounts: sulfate and glucuronide. A number of arguments suggest that MHPG sulfate and MHPG glucuronide respectively reflect central and peripheral norepinephrine metabolism. In this work, we have selectively estimated both MHPG conjugates in 24 h-urine samples of 36 severely depressed women in view to assess the extent and frequency of central or/and peripheral norepinephrine dysfunction. On the basis of MHPG sulfate and glucuronide values, we conclude that in the examined population (6 endogenous, 19 neurotic, 11 reactive depressions) about 80% of patients exhibited a central NE functional deficit, and many of them had also a diminished sympathetic activity. Clinical symptoms related to psychic factors (melancholia) or associated to sympathetic activity changes (anxiety, retardation) respectively alter sulfate or glucuronide MHPG excretion. These data altogether validate the concept of the independent origin of the two MHPG conjugated and show that their selective assay is able to provide a more satisfactory reflection of the psychobiological state in depressed patients than total MHPG determination.     

Disposition and metabolism of MHPG in humans: application to studies in depression

MHPG is formed from norepinephrine metabolized throughout the body; its levels in plasma reflect total norepinephrine metabolism. Over half of the MHPG, is converted to VMA. Less than 20% of MHPG is derived from brain norepinephrine and urinary excretion of this metabolite cannot be used as a measure of brain norepinephrine metabolism. Because unconjugated MHPG is readily diffusable, there is a free exchange of this metabolite among plasma, cerebrospinal fluid, and nerve tissues (including brain and spinal cord). The CSF MHPG levels, after appropriately correction for the plasma contribution of the metabolite, reflect its rate of formation in the central nervous system.     

Bilaterally diverging axon collaterals and contralateral projections from rat locus coeruleus neurons,demonstrated by fluorescent retrograde double labeling and norepinephrine metabolism

Summary Evans Blue (EB) and a mixture of 4-6-diamidino-2-phenylindol 2 HCl and primuline (DAPI-Pr), fluorescing at different wave-lengths were injected into the rat hippocampus, frontal cortex or lateral part of the thalamus. After unilateral injection either of the two substances was retrogradely transported not only to ipsilateral but also to contralateral locus coeruleus (LC) neurons. Moreover after simultaneous injections of EB and DAPI-Pr respectively into the opposite brain structures of individual animals double-labeled neurons were observed in the bilateral LC.Unilateral electrical stimulation of the LC induced significant decreases of norepinephrine and increases of 3-methoxy-4-hydroxyphenylethyleneglycol in both the ipsi- and contralateral frontal cortex and whole forebrain, respectively. These ipsi- and contralateral alterations of the amine and its metabolite correlated highly significantly.These results indicate that several LC neurons have both contralateral and bilateral projections to the brain areas mentioned above.     

Effects of dopamine and norepinephrine on neuronal activity of the olfactory tubercle

The effects of iontophoretic administration of norepinephrine (NE) and dopamine (DA) on olfactory tubercle (OT) neurons that respond to lateral hypothalamus (LH) or locus coeruleus (LC) electrical stimulation were studied. NE and DA decreased the frequency of OT neurons which were increased or decreased by the LH stimulation. An increased firing of OT neurons following NE or DA administration was less frequently observed. NE administration decreased the firing of OT neurons that responded to LC stimulation. These results suggest that the LC fibers which reach the OT use NE as a neurotransmitter. DA administration also suppressed the unitary discharge of OT neurons responding to LC stimulation. The increase in frequency of OT neurons observed following LH stimulation cannot be attributed to DA. The possibility that other suspected neural transmitters are involved in this effect is discussed.     

Norepinephrine and its metabolites in cerebrospinal fluid, plasma, and urine. Relationship to hypothalamic-pituitary-adrenal axis function in depression

Among 140 depressed and control subjects, there were significant positive correlations between indexes of noradrenergic activity in cerebrospinal fluid (CSF), plasma, and urine. Among the depressed patients, CSF levels of the norepinephrine (NE) metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) and urinary outputs of NE and its metabolites normetanephrine, MHPG, and vanillylmandelic acid correlated significantly with plasma cortisol levels in relation to dexamethasone administration. Also, CSF levels of MHPG were significantly higher among patients who were cortisol nonsuppressors than among either patients who were cortisol suppressors or controls. Urinary outputs of NE and normetanephrine were significantly higher among patients who were cortisol nonsuppressors than among controls. Patients who were cortisol suppressors had indexes of NE metabolism similar to those of controls. These results in the depressed patients extend recent observations suggesting that dysregulation of the noradrenergic system and hypothalamic-pituitary-adrenal axis occur together in a subgroup of depressed patients.     

Impaired presynaptic regulation of norepinephrine in schizophrenia. Effects of clonidine in schizophrenic patients and normal controls

Recent studies have found elevated levels of norepinephrine (NE) in CSF and brain specimens from schizophrenic patients. Presynaptic inhibitory alpha 2-adrenergic receptors regulate NE release in the brain. The hypothesis that the functional sensitivity of this presynaptic regulation of NE is impaired in schizophrenia was tested by evaluating, in schizophrenic patients and age-matched normal controls, the ability of clonidine, an alpha 2 agonist, to lower plasma levels of the NE metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) and to lower blood pressure (BP). Clonidine produced a significant decrease in plasma MHPG levels in the normal control group, but did not lower plasma MHPG levels in the schizophrenic patients. Clonidine decreased BP equally in both groups. These results suggest that there is a functional subsensitivity of the inhibitory presynaptic alpha 2-adrenergic receptor in schizophrenia, which may relate to an impaired regulation of NE turnover.     

Characterization of the isolated perfused mouse brain as a system for neurochemical studies

The preparation of the isolated perfused mouse brain (IPMB) is described along with its electrophysiological, morphological, biochemical and pharmacological properties. Using high performance liquid chromatography with electrochemical detection, the primary metabolite of mammalian central nervous system norepinephrine, 3-methoxy-4-hydroxyphenethyleneglycol (MHPG), was measured in the perfusate at 15-min intervals. The rate of MHPG production was similar to literature values of the rate of norepinephrine turnover in mouse brain. MHPG production rate in the IPMB was blocked by pretreatment with 6-hydroxydopamine and was increased by pretreatment with reserpine.     

3-Methoxy-4-hydroxyphenylethyleneglycol concentrations in discrete hypothalamic nuclei reflect the activity of noradrenergic neurons

An analytical technique is described which permits the quantitation of picogram concentrations of 3-methoxy-4-hydroxyphenylethylene-glycol (MHPG) in acid hydrolyzed extracts of microdissected regions of the rat brain, and this procedure is used to determine if alterations in the activity of noradrenergic neurons are reflected by changes in the concentrations of MHPG in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) of the rat hypothalamus. MHPG was not detected in non-hydrolyzed samples of either the PVN or SON, but following acid hydrolysis (heating of samples at 94 degrees C for 5 min in 0.16 M perchloric acid) MHPG was detected in both of these regions. These results indicate that MHPG exists primarily as a conjugate in the PVN and SON. Neurotoxin-induced lesions of the ventral noradrenergic bundle decreased norepinephrine (NE) and MHPG concentrations in the PVN and SON, demonstrating that tissue levels of MHPG in these brain regions are dependent upon the presence of noradrenergic neurons. Electrical stimulation of the locus coeruleus increased MHPG concentrations in the PVN, but not in the SON, whereas electrical stimulation of the medial forebrain bundle increased MHPG concentrations in both of these regions. The alpha 2-adrenergic receptor antagonist idazoxan increased, while the alpha 2-adrenergic receptor agonist clonidine decreased MHPG concentrations in both the PVN and SON, but neither idazoxan nor clonidine altered NE concentrations in these regions. Immobilization of rats in the supine position increased MHPG concentrations in the PVN and SON, and this was accompanied by a decrease in NE concentrations in the SON.(ABSTRACT TRUNCATED AT 250 WORDS)     

帕金森病患者立体定向手术前后脑脊液单胺类递质含量的改变

目的　研究帕金森病 (PD)患者脑立体定向手术前后脑脊液 (CSF)中单胺类递质含量的变化。方法测定 2 6例原发性PD患者 (PD组 )脑立体定向术前、后CSF中多巴胺 (DA)、5 羟色胺 (5 HT)、去甲肾上腺素 (NE)及其代谢产物高香草酸 (HVA)、5 羟吲哚乙酸 (5 HIAA)、3 甲氧基 4羟基苯乙二醇 (MHPG)的含量 ,另外测定 2 5例外科疾病腰麻手术患者 (对照组 )CSF中HVA、5 HIAA、MHPG含量。结果　PD组CSF中HVA、5 HIAA、MHPG含量明显低于对照组 (P <0 0 0 1、P <0 0 5、P <0 0 0 1) ;手术后组的CSF中DA、HVA ,、5 HT、5 HIAA、NE、MHPG含量明显高于手术前组 (其中DA、HVA、5 HT、5 HIAA和NE均P <0 0 0 1;MHPGP <0 0 5 )。结论　PD患者CSF单胺类神经递质代谢产物含量明显降低 ,脑立体定向术可提高PD患者脑部单胺类神经递质及其代谢产物的含量 ,其发生机制可能与DA能神经元的保护作用有关     

Cerebrospinal fluid norepinephrine, 3-methoxy-4-hydroxyphenylglycol and neuropeptide Y levels in Parkinson's disease, multiple system atrophy and dementia of the Alzheimer type

Summary Neuropeptide Y, one of the most abundant polypeptides within the nervous system, is co-stored with catecholamines, especially norepinephrine (NE), thus suggesting its possible involvement in pathologies characterized by a noradrenergic impairment. In Parkinson's disease (PD), as well as in multiple system atrophy (MSA), a central noradrenergic deficit has been demonstrated, and in the dementia of Alzheimer type (DAT) an impaired noradrenergic transmission has been postulated. In this study we determined CSF NE and MHPG levels in 29 PD, 15 MSA, 22 DAT patients and in 36 controls, while CSF NPY-immunoreactivity (NPY-ir) levels were measured in 10 PD, 7 MSA, 10 DAT patients and 20 controls. PD, MSA, and DAT patients showed a significant reduction in CSF NPY-ir and NE levels compared with controls, while CSF MHPG levels resulted in a reduction in only the MSA group.Furthermore, an inverse correlation between either NE or MHPG levels and the duration of the orthostatic hypotension was found in MSA patients while for DAT patients the MHPG levels were directly correlated to the severity of cognitive impairment, and inversely to the duration of illness.     

Clonidine treatment of schizophrenia: can we predict treatment response?

Four out of 13 drug-free relapsed schizophrenic patients improved with double-blind clonidine treatment. All responders were paranoid schizophrenic patients. Pretreatment growth hormone (GH) response to the clonidine challenge test (CCT) correlated significantly with clonidine treatment improvement in psychosis, anxiety, and negative symptom ratings. Spontaneous GH peaks following placebo correlated significantly with the behavioral change with clonidine treatment. Our data suggest that patients with normal or high alpha 2-receptor activity and "normal" cerebrospinal fluid (CSF) norepinephrine (NE) are likely to respond to clonidine treatment. Patients with either high or low CSF NE levels did not respond to clonidine treatment. CSF NE and 3-methoxy-4-hydroxyphenylglycol (MHPG) decreased significantly with clonidine treatment. Changes in CSF NE and MHPG did not correlate significantly with improvement in psychosis, but they correlated with changes in other behaviors.     

CSF GABA and neuropeptides in pathological gamblers and normal controls

We previously reported that pathological gamblers may have increased central noradrenergic activity. Neurons releasing gamma-aminobutyric acid (GABA) are known to be a part of an inhibitory system regulating the activity of central noradrenergic neurons. Therefore, we examined cerebrospinal fluid (CSF) levels of GABA in pathological gamblers and normal controls. There was no significant difference between the groups. Also, depressed and nondepressed gamblers did not differ significantly in their CSF levels of GABA. Among controls, however, there was a significant negative correlation between CSF levels of GABA and the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) and a significant positive correlation between CSF levels of GABA and corticotropin releasing hormone (CRH). Also, CSF levels of CRH showed a significant positive correlation with CSF levels of adrenocorticotropic hormone in both pathological gamblers and controls.