Cerebrospinal fluid monoamine and monoamine metabolite concentrations in melancholia

Cerebrospinal fluid levels of norepinephrine and six monoamine metabolites were measured in 28 medication-free depressed patients. Patients with a major depressive episode with melancholia (n = 15) had significantly lower levels of the three dopamine metabolites: homovanillic acid (HVA), dihydroxyphenylacetic acid (DOPAC), and conjugated dihydroxyphenylacetic (CONJDOPAC), when compared with a combined group of patients with a major depressive episode or dysthymic disorder (n = 13). In patients with major depressive episode with melancholia, levels of HVA and of the serotonin metabolite 5-hydroxyindoleacetic acid significantly correlated with the severity of depression. In the total group of 28 depressed patients, cerebrospinal fluid (CSF) levels of norepinephrine significantly correlated with symptoms of anxiety. In both patients with major depressive episode and major depressive episode with melancholia, those who were non-suppressors on the dexamethasone suppression test had significantly higher CSF levels of the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol compared to those who were suppressors.     

Effects of chronic nicotine administration on nitric oxide synthase expression and activity in rat brain

Although there is substantial evidence concerning the influence of nicotine on nitric oxide (NO) synthesis in the vascular system, there are fewer studies concerning the central nervous system. Although NO metabolites (nitrates/nitrites) increase in several rat brain regions after chronic injection of nicotine, the cellular origin of this rise in NO levels is not known. The aim of the present work was to assess the effects of repetitive nicotine administration on nitric oxide synthase (NOS) expression and activity in male and female rat brains. To determine levels of nitrate/nitrite, the Griess reaction was carried out in tissue micropunched from the frontal cortex, striatum, and accumbens of both male and female rats untreated (naïve) or injected with saline or nicotine (0.4 mg/kg for 15 days). In parallel, coronal sections of fixed brains from equally treated animals were immunostained for neuronal NOS or histochemically labelled for NADPH‐diaphorase activity. Nicotine treatment increased NO metabolites significantly in all brain regions compared with naïve or saline‐treated rats. By contrast, analysis of the planimetric counting of NOS/NADPH‐diaphorase‐positive neurons failed to demonstrate any significant effect of the nicotine treatment. A significant decrease was observed with both techniques employed in saline‐injected female rats compared with naïve animals, suggesting a stress response. The mismatch between the biochemical and the histological data after chronic nicotine treatment is discussed. The up‐regulation of NO sources other than neurons is proposed. © 2002 Wiley‐Liss, Inc.     

Region-specific transcriptional response to chronic nicotine in rat brain

This study was aimed to investigate the possible involvement of neurons in the cuneate nucleus (CN) in the processing of A beta afferent inputs evoked by electrical stimulation of constricted median nerve in rats with behavioral signs of neuropathic pain. Immunohistochemical localization of Fos protein was used to examine the neuronal activation, and the combination of Fos immunohistochemistry with the retrograde labeling of Fluoro-Gold (FG) injected into the ventrobasal complex of the thalamus was used to characterize the activated neurons. Two weeks after unilateral median nerve constriction injury, the rats exhibited behavioral signs of neuropathic pain in the affected forepaws. In rats after nerve injury but without electrical stimulation, some Fos-like immunoreactive (Fos-LI) neurons were detected in the dorsal horn of the seventh cervical segment (C7) but none was found in the CN. Similar features were also noted when the stimulation of the intact median nerve served as an additional control. After A beta-fiber intensity stimulation of the previously constricted median nerve, an increase in number of Fos-LI neurons occurred in the medial half of the ipsilateral C7 dorsal horn as well as in the ipsilateral CN. In the latter, the Fos-LI neurons were located in the median nerve projection territory throughout the nucleus. Most of the Fos-LI neurons were distributed in the middle region of the CN, with about 78% of them emitting FG fluorescence indicating that they were cuneothalamic projection neurons. The results of this study suggest that the dorsal column-medial lemniscal system may contribute to the transmission and modulation of A beta-fiber mediated neuropathic pain signals.     

Effect of maternal methadone administration on the development of multiple forms of monoamine oxidase in rat brain and liver

The development of total monoamine oxidase (MAO) and MAO-A and MAO-B in the forebrain, brainstem, cerebellum and liver of methadone-treated and normal rats were monitored with tryptamine, serotonin and benzylamine, respectively. Daily administration of methadone (10 mg/kg, s.c.) to pregnant and nursing rats substantially retarded the development of total and the A-form of MAO in the brain regions of pups but had no effect on that of MAO-B. The effect of methadone on the development of total MAO and MAO-A in the liver was only transient and less significant. This finding indicates that the perinatal opiate syndrome associated with maternal exposure to methadone is caused by the inhibition in MAO-A development in monoaminergic neurons in the brain.     

4-Methoxytranylcypromine, a monoamine oxidase inhibitor: effects on biogenic amines in rat brain following chronic administration.

4-Methoxytranylcypromine (MeOTCP), a ring-substituted analogue of the monoamine oxidase (MAO)-inhibiting antidepressant tranylcypromine (TCP), was investigated in the rat after chronic (28-day) administration and the results compared with those observed with TCP using equimolar doses of both drugs. At the dose tested, MeOTCP produced a greater inhibition of type A MAO in brain, liver, and heart than did TCP. Both drugs caused a reduction in the specific binding to beta-adrenergic and tryptamine receptors in cortex from brain. MeOTCP produced a marked increase in 5-hydroxytryptamine levels in pons-medulla, hypothalamus, and hippocampus relative to values in vehicle-treated rats and also produced a significant increase in these levels over those observed in the TCP-treated rats.     

Muscarinic agonist binding in rat brain following chronic nicotine treatment

Carbamylcholine binding was determined from competition experiments with [3H] quinuclidinyl benzilate in the rat brain chronically treated with nicotine. The nicotine group exhibited about two-fold lower affinity for the agonist binding toward a high-affinity site (or state) in the cerebral cortex, as compared with the control group. However, no alteration in the agonist binding was observed in the hypothalamus/thalamus and brainstem after chronic nicotine treatment.     

Effect of microwave irradiation on monoamine metabolism in dissected rat brain

The effect of 5 kW microwave irradiation on monoamine metabolism was investigated in dissected regions of rat brain. Concentrations of intracerebral monoamines and their metabolites were stimultaneously determined by means of high performance liquid chromatography with electrochemical detection. The concentrations of noradrenaline, dopamine and 5-hydroxytryptamine were reduced by a 0.5 s irradiation in comparison with those of decapitated animals. When the duration of irradiation was prolonged by 1.5 s, on the other hand, the levels of monoamines were increased. The changes of metabolite concentrations were generally opposite direction for those of parent transmitters. These findings suggest that the microwave irradiation affects those concentrations and that a 1.5 s irradiation is recommended in order to completely inactivete the corresponding enzyme prior to the simultaneous determination of monoamines' related substances in dissected brain regions.     

Sleep and brain monoamine changes produced by acute and chronic acetaldehyde administration in rats

Acetaldehyde, the most toxic metabolite of ethanol, has been implicated in many toxic effects of ethanol. In the present study, we used rats to investigate the possible changes on the sleep-wake cycle and brain regional concentrations of noradrenaline and serotonin after intraperitoneal administration of several doses of acetaldehyde. Results showed that acetaldehyde significantly decreases the time spent in rapid eye movements sleep and wakefulness and increases the time spent in slow-wave sleep. The neurochemical analysis showed that acetaldehyde significantly increases the 5-hydroxyindolacetic acid content and 5-hydroxyindolacetic acid/serotonin ratio at the bulb and pons. These results suggest that acetaldehyde modifies the metabolism of serotonin which has been implicated in the onset and sustaining of the sleep episodes occurring along the sleep-wake cycle.     

Effect of chronic phenobarbital administration upon brain growth of the infant rat

Administration of 0.06 mg/g of phenobarbital daily to infant rats during the first three weeks of life retarded body and brain growth during this period. Analysis of data suggests that these effects are not solely due to impaired nutrition. Accumulation of cholesterol in the cerebellum was slowed to a greater extent than was accumulation of other brain constituents measured (DNA, RNA, protein). These findings raise the possibility that chronic administration of phenobarbital delays brain development of infant rats.     

Pineal melatonin and brain transmitter monoamines in CBA mice during chronic oral nicotine administration

The effects of chronic oral nicotine administration on the pineal melatonin and brain transmitter monoamines were studied in male CBA mice, which possess a clear daily rhythm of melatonin secretion. On the 50th day of nicotine administration, pineal melatonin as well as cerebral dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), norepinephrine (NE), 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) concentrations were determined at various times. The chronic nicotine treatment did not alter the timing of the pineal melatonin peak, which occurred at 10 h after the light offset. However, in mice drinking nicotine solution, the nocturnal pineal melatonin levels were lower than in control mice drinking tap water. The chronic nicotine treatment increased the striatal DA, DOPAC, HVA and 5-HIAA levels, the hypothalamic NE, MHPG and 5-HIAA and the cortical MHPG. Most prominent effects of nicotine were found at 8 h after the light offset, when the striatal levels of DA and HVA, hypothalamic NE and MHPG as well as cortical MHPG were significantly elevated in the nicotine-treated mice compared with the control mice. No direct correlation between nicotine's effects on brain transmitter monoamines and on pineal melatonin levels was apparent. The results suggest that chronic nicotine treatment slightly suppresses the melatonin production but does not alter the daily rhythm of pineal melatonin in mice maintained on a light-dark cycle. However, the results indicate that nicotinic receptors might be involved in the regulation of pineal function.     

Effects of blinding and pinealectomy on regional brain monoamine concentrations

The effects of blinding with or without pineal ablation on brain monoamine levels were studied in male rats. Brain dopamine (DA), norepinephrine (NE), epinephrine (E), and serotonin (5-HT) were measured by radioenzymatic assays. Four weeks following pinealectomy, E levels were significantly enhanced in the frontal cortex. Chronic blinding decreased striatal DA levels and increased striatal 5-HT levels in both sham-operated and pinealectomized (Px) animals. In a second experiment Px animals were sacrificed 1 or 7 d after pinealectomy in order to examine the short-term effects of pinealectomy. There were no differences between controls and Px animals in their cortical levels of DA, NE, and E and their hippocampal and hypothalamic 5-HT levels. However, the E concentrations measured 1 d after surgery were significantly greater than after 7 d. The implications of these findings with regard to the reported role of the pineal and melatonin in brain homeostasis and endocrine regulation are discussed.     

Lateralized effect of cerebral infarction on spinal fluid monoamine metabolite concentrations in rats

Using a rat model of stroke, we studied the effect of unilateral middle cerebral artery ligation on cerebrospinal fluid monoamine metabolites at different intervals over a 40-day postoperative period. Male Sprague-Dawley rats were divided into four groups: an unoperated control group (n = 9), a sham-operated group (n = 9), a right middle cerebral artery ligation group (n = 10), and a left middle cerebral artery ligation group (n = 10). One hundred microliters of cerebrospinal fluid were collected percutaneously from the cerebellomedullary cistern just before and 5, 20, and 40 days after the surgical procedure. Monoamine metabolites--3-methoxy-4-hydroxyphenylglycol (MHPG), 5-hydroxy-indoleacetic acid (5-HIAA), and homovanillic acid (HVA)--were measured using high-performance liquid chromatography. MHPG concentration in the right lesion group was significantly depleted from control levels 5, 20, and 40 days after surgery. No such depletion was observed in the left lesion rats. Concentration of 5-HIAA was relatively lower at Days 5 and 20 in the right lesion group than in the left lesion group. HVA concentration did not differ among the groups at any time. Our study has demonstrated a differential effect of unilateral ischemia on cerebrospinal fluid neurochemistry in rats dependent on the cerebral hemisphere involved.     

Effect of chronic administration of duloxetine on serotonin and norepinephrine transporter binding sites in rat brain.

BACKGROUND: Chronic treatment of rats with certain selective serotonin or norepinephrine reuptake inhibitors produces significant decreases, respectively, in serotonin and norepinephrine transporter binding sites in brain. Duloxetine may be a dual serotonin/norepinephrine reuptake inhibitor, as it is only a slightly more potent inhibitor of serotonin than norepinephrine uptake in vitro. Consequently, we hypothesized that chronic duloxetine treatment, at doses producing serum levels within its therapeutic range, would affect both monoamine transporters dose-dependently, with a higher dose causing greater reductions of binding sites for both transporters. METHODS: Rats were treated with either 4 or 8 mg/kg/d of duloxetine, paroxetine, desipramine, or vehicle via subcutaneous osmotic minipumps for 21 days. Binding sites for serotonin and norepinephrine transporters were measured in amygdala and hippocampus using quantitative autoradiography. RESULTS: Both doses of duloxetine and paroxetine produced equivalent and significant decreases in [3H] cyanoimipramine binding to serotonin transporters, but only desipramine treatment significantly reduced [3H] nisoxetine binding to norepinephrine transporters. CONCLUSIONS: At doses producing rat serum concentrations in the range achieved in patients at recommended daily doses of the drug, duloxetine behaves in vivo more as a selective serotonin reuptake inhibitor than a dual reuptake inhibitor in its capacity to selectively reduce serotonin transporter density.     

Neither short-term nor long-term administration of oral choline alters metabolite concentrations in human brain.

BACKGROUND: This study reexamined conflicting proton magnetic resonance spectroscopy (MRS) reports of increased or unaffected choline-containing compounds (Cho) in human brain in response to a single dose of 50 mg/kg choline bitartrate. METHODS: The present work was based on a well-established strategy for quantitative proton MRS (2.0 T, STEAM localization sequence, TR/TE/TM = 6000/20/10 ms, LCModel automated spectral evaluation) that allows the determination of cerebral metabolite concentrations rather than T1-weighted resonance intensity ratios. Moreover, the investigations were extended to a possible long-term effect of oral choline by monitoring the continuous ingestion of 2 x 16 g of lecithin per day for 4 weeks. Six young healthy volunteers participated in each study and metabolite concentrations were determined in standardized locations in gray matter, white matter, cerebellum, and thalamus. RESULTS: Neither for short-term nor for long-term administration of choline do the data reveal statistically significant deviations from the basal concentrations of Cho, total N-acetyl-containing compounds (neuronal markers), total creatine, and myo-inositol (glial marker) in any of the investigated brain regions. CONCLUSIONS: Previous reports of increased Cho are not confirmed.     

Effect of MCI-186 on ischemia-induced changes in monoamine metabolism in rat brain

We examined the effects of MCI-186 (3-methyl-1-phenyl-2-pyrazolin-5-one), a novel free radical scavenger and an inhibitor of ischemia-induced brain edema, on monoamine metabolism in the brains of both normal and ischemic rats. In normal rats, 3 mg/kg i.v. MCI-186, a dose that prevents ischemic brain edema, had no significant effect on brain concentrations of dopamine, norepinephrine, 5-hydroxytryptamine, or their metabolites. After the injection of 5 microliters of 3% polyvinyl acetate into the left internal carotid artery, concentrations of 3,4-dihydroxyphenylacetic acid and homovanillic acid markedly increased, but that of norepinephrine decreased, in the left telencephalon of embolized rats compared with control rats injected with vehicle; the concentration of 5-hydroxyindoleacetic acid also increased slightly. These effects were maximal 2 hours after embolization. The turnover rate of dopamine between 6 and 8 hours after embolization was significantly higher but that of norepinephrine was slightly lower than that in vehicle-treated rats. When rats were treated with 3 mg/kg i.v. MCI-186 immediately after the injection of polyvinyl acetate, the embolization-induced changes in monoamine metabolism were less marked. Our results suggest that MCI-186 attenuates ischemia-induced changes in brain monoamine metabolism, probably due to its free radical scavenging action, although it has no marked effect in normal rats.     

Effects of chronic ethanol treatment on alpha-MSH concentrations in rat brain and pituitary

Male Sprague-Dawley rats were chronically treated with a liquid diet containing 6.5% (v/v) ethanol or equicaloric sucrose. Rats were killed after 21 days of treatment. alpha-MSH-like immunoreactivity was measured in the intermediate lobe of the pituitary gland and in several brain regions. Chronic ethanol treatment significantly reduced alpha-MSH-like immunoreactivity in the pituitary gland; in the arcuate nucleus of the hypothalamus and in the substantia nigra. The results of this study confirm the earlier findings that chronic ethanol treatment reduces POMC biosynthesis in the pituitary gland and in the central nervous system.     

Effect of progesterone on monoamine turnover in the brain of the estrogen-primed rat

The effect of progesterone (P) on monoamine levels and turnover was evaluated in 8 brain nuclei in estrogen-primed rats. Animals were subcutaneously (SC) injected with P or vehicle 21 hours after SC treatment with 5 micrograms of estradiol benzoate (EB). EB-primed animals treated with P showed high levels of lordosis behavior and an LH surge three hours later. Initial concentrations of norepinephrine (NE), dopamine (DA), serotonin (5HT) and 5-hydroxyindole acetic acid were determined in EB-saline treated controls 3 hours after P or vehicle. NE and DA turnover was estimated from the exponential decline of these amines 2 hours after IP injection of alpha-methyl-p-tyrosine (5 hours after P or vehicle). The accumulation of 5HT 20 min following IP injection of pargyline was used as an index of 5HT turnover. P did not affect the initial NE, 5HT or 5HIAA concentrations in any of the brain nuclei studied, but decreased DA content in the arcuate-median eminence region (Ar-ME). The DA rate constant was elevated in the nucleus of the diagonal band of Broca and the DA turnover rate was decreased in the Ar-ME. In the periventricular region (PVE, anterior hypothalamic level) the NE turnover rate (K, pg/microgram protein/hr) and rate constant (k, hr-1) decreased following P treatment. Progesterone treatment decreased the accumulation of 5HT in the ventromedial hypothalamus (VMN, pars lateralis) and the dorsal midbrain central grey (MCG). Progesterone effects on monoamine turnover were not found in the lateral septal, medial preoptic, anterior hypothalamic or dorsal raphe nuclei.(ABSTRACT TRUNCATED AT 250 WORDS)     

Regional monoamine and metabolite levels in a feline brain tumor model

The presence of a brain tumor alters regional cerebral blood flow, oxygen consumption, and glucose utilization in adjacent and remote brain tissue, but its effect on brain neurotransmitter levels is unclear. In the present report, the levels of noradrenaline (NA), dopamine (DA), 5-hydroxytryptamine (5-HT), 3,4-dihydroxyphenyl-acetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindole-acetic acid (5-HIAA) in tumor tissue and gray and white matter obtained from cats with induced brain tumors were measured. Glioma cells (9L) were xenotransplanted into the central white matter of the right hemisphere, and 15 d later the brains were frozen in vivo. Samples of tumor, parietal (peritumor), temporal, and frontal gray and white matter were divided for analysis of water content and quantification of amines and their metabolites. The water content of white matter, but not gray matter, adjacent to the tumor was increased. Neurotransmitter amine and metabolite levels were much lower in the tumor than in brain tissue. In gray matter adjacent to the tumor, concentrations of DA and its metabolites HVA and DOPAC were significantly decreased from control, whereas 5-HIAA was increased. The NA, DA, HVA, and DOPAC levels were decreased in temporal gray matter, whereas all amine and metabolite levels were unchanged in frontal gray matter. These results indicate that altered neurotransmitter metabolism is one of the effects of the presence of a brain tumor.