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PubMed1991

Acute effects of beclamide on brain regional monoamine concentrations, their metabolites and radioligand binding studies.

The effects of beclamide on regional brain monoamine levels and radioligand binding have been studied in rats. One hour oral pre-treatment with beclamide (400 mg kg-1) increased rat striatal dopamine turnover by increasing the levels of its major metabolites (DOPAC and HVA) three-fold. Simultaneously the drug reduced the concentration of striatal dopamine by a similar factor, and the concentrations of 5-hydroxytryptamine, (5-HT), 5-hydroxyindoleacetic acid, (5-HIAA) and 3-methoxytyramine in the striatum were reduced below the detection limits of the assay. In the frontal cortex, beclamide depleted the dopamine, 5-HT and 5-HIAA content whilst having no significant effect on the noradrenaline level. The concentrations of bioamines and their metabolites in the hypothalamus were unaffected by such acute beclamide treatment. In radioligand binding studies beclamide lacked affinity and failed to displace radioligands from alpha 2, beta, 5-HT, 5-HT2 and dopamine D2 sites in selective loci of the rat brain.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1979

Influence of cerebral embolism on brain monoamines.

In baboons the right cerebral hemisphere was embolised by a shower of microemboli, immediately followed by one large embolus designed to occlude the middle cerebral artery (MCA). One hour after embolism a significant, though small, reduction in blood flow and oxygen consumption of the embolised hemisphere was recorded, at which time the animals were killed and brain monoamines measured. Dopamine was reduced in the ipsilateral caudate nucleus, the reported site of maximal ischaemic damage in this model. Dopamine levels were increased in frontal and occipital grey matter sampled from areas surrounding the occluded MCA territory and in similar brain areas of the opposite non-embolised hemisphere. Noradrenaline was increased in grey matter from both cerebral hemispheres, as well as subcortical structures bilaterally. Brain 5-hydroxytryptamine levels were unaltered, but increased 5-hydroxyindoleacetic acid in cisternal cerebrospinal fluid suggested transient alteration in 5-hydroxytryptamine metabolism after embolism. The effects of cerebral embolism on brain monoamine metabolism appear to be different from the effects of permanent surgical occlusion of major cerebral vessels. The bilaterality of effects after unilateral hemispheric embolism might be related to diaschisis. The mechanisms of the observed changes, as well as their relevance to the progression of cerebral ischaemia and the complications associated with cerebral embolism, still require to be established.

Animals↗

PubMedDate not supplied

CSF monoamines, age and impulsivity in wild grivet monkeys (Cercopithecus aethiops aethiops).

Brain monoaminergic activity has been associated with behaviors, such as impulsive risk-taking, that tend to peak during adolescence in humans and nonhuman primates. This study was designed to assess natural variation in monoamine neurotransmitter metabolism in relation to age and behavioral impulsivity in grivet monkeys (Cercopithecus aethiops aethiops) living in their native habitat and subject to natural ecological pressures. Cisternal cerebrospinal fluid, collected from 22 animals living in the Awash National Park, Ethiopia, was assayed for the major metabolites of serotonin (5-hydroxyindoleacetic acid, 5-HIAA), dopamine (homovanillic acid, HVA) and norepinephrine (3-methoxy-4-hydroxyphenylglycol, MHPG). Concentrations of HVA declined significantly from one year of age to older adulthood. Further, a significant curvilinear relationship was identified between age and the 5-HIAA/HVA ratio, with the trough coinciding with the period of adolescence. Finally, behavioral impulsivity, as measured by re-entering baited traps a second time after the animal had already been captured and sampled for CSF, was related to lower levels of MHPG. The results suggest that normal variation in central monoaminergic activity may have functional consequences in wild populations.

Aging↗

PubMed2000

Estradiol modulation of central monoamine activity in female mountain spiny lizards.

Although estradiol (E2) mediates many behaviors in females, relatively little is known about its role in female aggression. Previous studies in female mountain spiny lizards indicated that female aggression is modulated by ovariectomy and sex steroid hormone replacement and that expression of aggressive behavior is accompanied by changes in serotonin activity. This study examines if E2 modulates the activity of serotonin and other central monoamines. Free-living females were caught and housed in the laboratory and received one of 3 treatments: sham surgery (SHAM), ovariectomy plus empty implant (OVEX), or sham surgery plus a long lasting E2 implant (E2-IMP). After 3 weeks of treatment, selected brain areas were examined for levels of monoamines and their metabolites. Changes in monoamine activity were most pronounced in the septum where levels of serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), and norepinephrine (NE) were higher in E2-IMP females relative to SHAM, and levels of 5-HIAA were higher in OVEX females relative to SHAM. Changes in dopamine (DA) activity were also found, with increased DA concentration and decreased ratio of forebrain:brainstem HVA concentrations in E2-IMP relative to SHAM females. These results suggest that the actions of E2 on aggression might be mediated, in part, by dose-dependent effects on 5-HT activity in the septum.

Aggression↗

PubMed1992

Effects of nimodipine on biogenic amines in discrete brain areas.

Discrete brain sections were obtained from rats after once or repeatedly given intraperitoneal nimodipine at doses ranging from 2.5 to 40 mg/kg. The single or the last treatment was carried out at 2-8 h before killing. The biogenic amine and metabolite content of the tissue samples were determined by high-performance liquid chromatography with electrochemical detection. The nimodipine-induced effects, chiefly regarding the brainstem, the thalamus-midbrain and the striatum, consisted of both an increase in 5-hydroxyindoleacetic acid (5-HIAA) levels and a decrease in dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels. Since the 5-HIAA/5-hydroxytryptamine (5-HT) ratio was increased, whereas the DOPAC/dopamine (DA) and HVA/DA ratios were decreased, it was argued that nimodipine activated the serotonergic and inhibited the dopaminergic systems. The first effect was enhanced by fasting and, likewise, by drug administration repeated for 5 days, while the second was not affected by fasting, but disappeared after 5 days' treatment. The data obtained appeared to substantiate the usefulness of nimodipine to treat some disorders of the central nervous system.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1987

[Pharmacological studies on Y-8894 (VI). The effect on monoamine uptake and turnover in mouse brain].

The effect of Y-8894 (+/-) 2-[[o-(2-thenyl)phenoxy]methyl] morpholine maleate, which has been shown to improve experimentally induced learning and memory deficits, on cerebral monoamine uptake and turnover was studied in the mouse. The following results were obtained: 1) It inhibited in vitro norepinephrine (NE) uptake to the mouse cerebral synaptosomal fractions about 800 and 1250 times more potently than it did those of dopamine (DA) and serotonin (5-HT), respectively. 2) It dose-dependently inhibited in vivo NE uptake, but not DA or 5-HT uptake. 3) It reduced the accumulation of the NE metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG), increased that of the 5-HT metabolite, 5-hydroxyindoleacetic acid (5-HIAA), and had no effect on that of the DA metabolite, homovanillic acid (HVA). These effects were compared with those of imipramine, calcium hopantenate (Ca-hopantenate) and dihydroergotoxine. Y-8894 appeared to act by stimulating the noradrenergic receptor, and it acts to a lesser extent by blocking the serotonergic receptor in the brain.

Animals↗

PubMed1984

Serotonin in the rat sympathetic ganglion: microdetermination of monoamines and their metabolites by high-performance liquid chromatographic electrochemical detection.

We attempted to determine the existence of a functional serotonergic small intensely fluorescent (SIF) cell in the rat superior cervical sympathetic ganglion (SCG) by evaluating the effects of pargyline, decentralization and electrical stimulation on the preganglionic sympathetic fibers. The objective was to assess changes in serotonin (5-HT) metabolism compared with findings in the case of dopamine (DA) metabolism. The contents (ng/ganglion, n = 8, average +/- S.E.) in the adult male Wistar rat SCG of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) were 1.19 +/- 0.11 and 0.11 +/- 0.01, respectively, determined by our reverse-phase high-performance liquid chromatographic electrochemical method. A relatively large amount of 5-HT was detected in the capsule of the SCG (0.62 +/- 0.16 ng/capsule, n = 8) without detection of 5-HIAA. The pargyline injection increased the DA content and decreased the 3,4-dihydroxyphenylacetic acid (DOPAC) content rapidly. The increase of the 5-HT content was observed without changes in the capsule 5-HT. The mode of pargyline induced-increase in the 5-HT content and decrease of the 5-HIAA content was slow compared to that of DA and DOPAC. Decentralization did not alter the 5-HIAA content, whereas the DOPAC content was markedly reduced. Although electrical stimulation significantly increased the DOPAC content, changes in the 5-HIAA content were not observed. It would thus appear that 5-HT is produced in the rat SCG, and if so, then support for existence of a serotonergic SIF cell in the rat sympathetic ganglion can be obtained. A direct connection between pre- and postganglionic sympathetic neurons through the serotonergic SIF cell was not demonstrated.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1991

Mechanisms of veratramine-induced 5-HT syndrome in mice.

Regional monoamine assays revealed that during veratramine-induced myoclonic movements, the contents of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in the cerebral cortex were reduced with a slight increase in dopamine metabolites in the midbrain and brainstem. A similar tendency to decrease 5-HT and 5-HIAA contents was observed in the hypothalamus and hippocampus without increase in the contents of dopamine and its metabolites. Norepinephrine levels were not modified in any brain region at any time after the administration of the veratrum alkaloid. It was found that the veratramine evoked 3H-5-HT release from the frontal cortical slices was Ca+(+)-independent and persistent, and it continued approximately 20 min after the 2-min exposure to veratramine. The uptake of 3H-5-HT into the frontal cortical slices was inhibited competitively by veratramine. These results suggest that veratramine is both a releaser and uptake inhibitor of 5-HT and that the veratramine-induced involuntary movements may be mediated by serotonergic hyperfunction.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1993

Neurotransmitters in rats fed fumonisin B1.

Fumonisin B1, a toxin produced by Fusarium moniliforme, has been associated with a neurotoxic syndrome in horses known as equine leukoencephlomalacia. Previous investigations showed that F. moniliforme cultured on corn and incorporated into rat chow increased brain 5-hydroxyindoleacetic acid (5HIAA) and 5HIAA: serotonin (5HT) ratios in these animals. Therefore, this study was undertaken to determine whether fumonisin B1 would produce related neurochemical effects in the brain and pineal gland of male and female rats. Rats were fed fumonisin B1 at 15, 50, and 150 ppm for 4 weeks. No differences occurred in brain concentrations of norepinephrine, dopamine, 3,4-dihydroxyphenylacetic acid, 3-methoxytyramine, homovanillic acid, 5HT, 5HIAA, and the 5HIAA to 5HT ratios in either male or female rats, nor where there differences between the sexes. When compared across sexes, the norepinephrine to dopamine ratios were decreased (P < 0.05) in the 150-ppm-treated animals. This may suggest a fumonisin B1-induced imbalance in brain norepinephrine and/or dopamine. No differences were observed in pineal norepinephrine, 5HT, 5HIAA, and the 5HIAA to 5HT ratios. Since fumonisin B1 failed to duplicate the effects of the F. moniliforme-induced imbalances in 5HT and 5HIAA metabolism in the brains of rats, other mycotoxins from F. moniliforme may be responsible for these effects.

Animals↗

PubMed1992

Individual differences in basal cisternal cerebrospinal fluid 5-HIAA and HVA in monkeys. The effects of gender, age, physical characteristics, and matrilineal influences.

We examined the effects of gender, age, weight, length, body shape (ectomorphy), and matrilineal influences on cisternal cerebrospinal fluid 5-hydroxyindoleacetic acid (CSF 5-HIAA) and homovanillic acid (HVA) in 78 socially living adult and adolescent vervet monkeys. CSF 5-HIAA and the 5-HIAA:HVA ratio were higher (by 27% and 18%, respectively) in females. In both sexes, CSF 5-HIAA and the 5-HIAA:HVA ratio increased with age. Neither weight nor length were independently related to CSF 5-HIAA or HVA; however, shape correlated with CSF 5-HIAA and HVA in males (higher in thin, long subjects). Male offspring had CSF 5-HIAA concentrations and 5-HIAA:HVA ratios that were significantly closer to their mothers than did age-matched, maternally unrelated males. Repeated measures of CSF 5-HIAA and HVA in another 22 males living in unvarying settings showed that individual differences in these measures persisted over time. The data underscore the impact of gender, age, and matrilineal relationships on individual differences in CSF monoamine metabolites and highlight the importance of controlling for age and gender in neuropharmacological investigations of clinical populations.

Aging↗

PubMed1992

Neurochemical effects of electrically and chemically induced seizures: an in vivo microdialysis study in the rat hippocampus.

This study examined the effects of electroconvulsive shock (ECS) on interstitial concentrations of serotonin (5-HT), its metabolite 5-hydroxyindoleacetic acid (5-HIAA), acetylcholine and choline, and the dopamine metabolite homovanillic acid (HVA) in the hippocampus of freely moving rats using online brain microdialysis. The effects of ECS on 5-HT, 5-HIAA, and HVA were compared to the effects of seizures induced by the convulsant agent flurothyl. Interstitial concentrations of 5-HT increased several fold in response to ECS and this increase was accompanied by a significant increase in the concentration of HVA. Acetylcholine and choline concentrations were also increased significantly by ECS. The ECS-induced increase in interstitial 5-HT was markedly reduced when the voltage-dependent sodium channel blocker tetrodotoxin (1 mumol/L) was added in the perfusion solution, indicating that the observed increase was of neuronal origin. Interstitial concentrations of 5-HT also increased in response to flurothyl-induced seizures and this increase was accompanied by a significant increase in the concentration of HVA. These results provide direct in vivo evidence that interstitial concentrations of 5-HT increase several fold in response to both ECS- and flurothyl-induced seizures. These observations are discussed in relation to the hypothesized role of 5-HT in ECS-induced memory deficits.

Acetylcholine↗

PubMed1990

Biogenic amines distribution in the brain of nervous and normal pointer dogs. A genetic animal model of anxiety.

Nervous pointer dogs have been suggested as an animal model for pathological anxiety. In order to study possible disturbances in neurotransmitter functions in this animal model, we measured brain biogenic amines (norepinephrine, dopamine, and serotonin) and their metabolites in both nervous and normal dogs. Eight nervous and six normal dogs were behaviorally tested and later anesthetized and killed. Brains were removed and dissected while frozen using a punch technique. Samples were assayed using high-performance liquid chromatography (HPLC) with electrochemical detection. The nervous dogs had higher [NE] in the reticular formation and lower serotonin, and its metabolite 5-hydroxyindoleacetic acid, in the septal nuclei, indicating possible important differences in noradrenergic and serotonergic functions in the nervous dogs. There was a trend for lower [HVA] and [DOPAC] levels and a significantly lower [DOPAC]/[DA] ratio in the nervous dogs, suggesting decreased dopaminergic function.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1985

Comparison of 1-methyl-4-(p-chlorophenyl)-1,2,3,6-tetrahydropyridine, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and p-chloroamphetamine as monoamine depletors.

1-Methyl-4-(p-chlorophenyl)-1,2,3,6-tetrahydropyridine (PC-MPTP) failed to mimic the effects of MPTP in producing persistent depletion of striatal dopamine and its metabolites in mice one week after the last of four daily doses. MPTP was given at 20 mg/kg, whereas PC-MPTP was given at doses up to 80 mg/kg. In rats, p-chloroamphetamine (PCA) given in a single dose of 0.1 mmole/kg (20.6 mg/kg) i.p. caused marked depletion of hypothalamic serotonin and 5-hydroxyindoleacetic acid (5HIAA) concentration at 6 hrs, and the depletion persisted at 1 day and at 1 week. In contrast, PC-MPTP given at an equimolar dose failed to affect either serotonin or 5HIAA concentration at these times. Apparently the addition of a p-chloro substituent to MPTP eliminates its neurotoxicity to striatal dopamine neurons, and replacement of the aminoisopropyl side chain of PCA with a 1-methyl-1,2,3,6-tetrahydropyridin-4-yl group eliminates its neurotoxicity to brain serotonin neurons.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1987

Alcohol preference and regional brain monoamine contents of N/Nih heterogeneous stock rats.

The N/Nih heterogeneous stock rats were tested for alcohol drinking behavior. Rats that met criteria for high (greater than 5.0 g ethanol/kg body weight/day) and low (less than 0.5 g/kg/day) alcohol consumption were chosen, and the regional brain contents of monoamine neurotransmitters were determined in these animals. The primary finding was a lower content of serotonin and 5-hydroxyindoleacetic acid in the thalamus and hypothalamus of the high alcohol preferring N/Nih rats as compared with the low preferrers. The high preferrers were also found to have a lower content of dopamine and norepinephrine in the thalamus. The findings support the hypothesis that an inverse relationship exists between the density and/or metabolic functioning of regional brain serotonin systems and alcohol preference.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1987

The effect of high pressure on the kinetics of monoamine transmitters in the rat brain.

The effects of 71 ATA pressure on the turnover of serotonin (5-HT), noradrenaline (NA), and dopamine (DA) were studied. High pressure increased the concentration of the 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA) by 40%. A concomitant increase in 5-HT synthesis (measured by the accumulation of 5-hydroxytryptophan after inhibition of the decarboxylase) of 25% was found. The changes in NA and DA metabolites and synthesis were smaller and not statistically significant. The increase in 5-HT synthesis was not a result of changes in the neuronal uptake of transmitter. The observed change might be the result of a compensatory increase in the activity of the serotoninergic neurons at high pressure. Among the three monoamine transmitter systems, that mediated by 5-HT may be most important in the pathogenesis of the high pressure neurologic syndrome.

Animals↗

PubMed1989

3,4-Methylenedioxymethamphetamine ("ecstasy") selectively destroys brain serotonin terminals in rhesus monkeys.

3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy"), an amphetamine analog, is a "designer drug" which is being increasingly abused. The potential neurotoxic hazard of MDMA in humans was assessed by examining the effects of repeated systemic administration of MDMA on selected neurochemical and behavioral measures in rhesus monkeys. In the first study, MDMA (2.5 or 10 mg/kg twice daily for 4 days) produced selective and significant neurochemical decreases in cerebrospinal fluid (CSF) concentrations of 5-hydroxyindoleacetic acid (5-HIAA) and brain concentrations of serotonin and 5-HIAA. At the high dose of MDMA, a selective decrease in serotonin uptake sites (reflecting destruction of brain serotonin terminals) was observed. To determine if these changes after high dose MDMA were pharmacologic or truly neurotoxic, in a subsequent study monkeys were treated with MDMA (10 mg/kg twice daily for 4 days) and then monitored for 14 weeks. Throughout this period, CSF 5-HIAA was decreased in MDMA-treated animals but not in saline-injected controls. At the end of this period, significant decreases in the concentration of serotonin, 5-HIAA and serotonin uptake sites were observed in cerebral cortex and striatum but not in hypothalamus or spinal cord. In contrast to these widespread alterations in serotonin markers, comparable noradrenergic and dopaminergic measures in CSF and brain appeared generally unaffected. These data demonstrating potent and selective effects of MDMA on various brain serotonin parameters in rhesus monkeys suggest that the drug may produce similar effects in humans.

3,4-Methylenedioxyamphetamine↗

PubMed1989

Acute and chronic effects of corticotropin-releasing factor on schedule-controlled responding and neurochemistry of pigeons.

Key pecking by pigeons was maintained under various schedules of food presentation. Acute i.c.v. administration of corticotropin-releasing factor (CRF) (3.0-30.0 micrograms/kg) decreased responding in both components of a multiple 3-min fixed-interval, 30-response fixed-ratio schedule and under a multiple fixed-ratio schedule in which responding during one component was punished by shock delivery. The rate-decreasing effects of intermediate doses of CRF were blocked by the CRF antagonist alpha-helical CRF9-41 under the multiple fixed-internal fixed-ratio schedule, with 10.0 micrograms/kg of the antagonist producing a more complete reversal than 30.0 micrograms/kg. The rate-reducing effects of 10.0 and 30.0 micrograms/kg of CRF disappeared rapidly when CRF was administered daily, with complete restoration of responding occurring by the 4th day of chronic administration. Acute effects were recovered when CRF administration was discontinued for 7 to 14 days. Analyses of cerebrospinal fluid revealed that behaviorally active doses of CRF produced large, dose-dependent increases in levels of the serotonin metabolite 5-hydroxyindoleacetic acid and in the dopamine metabolites dihydroxyphenylacetic acid and homovanillic acid; smaller increases also occurred in the levels of 3-methoxy-4-hydroxyphenylethylene glycol, the metabolite of norepinephrine. Chronic administration of 30 micrograms/kg of CRF for a 4-day period did not reveal any change in metabolite levels when compared to those obtained after acute administration, with the exception of 3-methoxy-4-hydroxyphenylethylene glycol which approached control levels after chronic CRF. These results indicate that, as is the case with mammals, CRF has potent behavioral and neurochemical activity in avian species and that tolerance occurs rapidly to the behavioral effects.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1983

[Interactions of cerebral serotonin and catecholamines].

It has been demonstrated that the administration of large doses of dopa or 5-hydroxytryptophan (5-HTP) affected not only dopamine (DA) or serotonin (5-HT) neurons but also other neurons. This report concerns the effects of tryptophan, 5-HTP or dopa on concentrations of 5-HT, DA, norepinephrine, and their metabolites in p-chlorophenylalanine-, 5,7-dihydroxytryptamine (5,7-DHT)- or non-treated rat brain. The results were as follows: 1) When the brain DA levels increased more than six-fold after the i.p. administration of l-dopa, the brain 5-HT levels significantly decreased, and 5-hydroxyindoleacetic acid (5-HIAA) levels significantly increased. 2) In the nerve ending fraction of rat brain, the administration of l-dopa induced the largest increase of DA levels in the striatum, while administration of dl-5-HTP produced the largest increase of 5-HT levels in the hypothalamus. These results suggest that the distribution of newly synthesized 5-HT or DA after the administration of 5-HTP or dopa, respectively, depends not only on that of aromatic l-amino acid decarboxylase, but also on that of nerve cells which selectively take up 5-HTP or dopa or that of synaptic vesicles which selectively take up 5-HT or DA. 3) The large doses of 5-HTP administration to 5,7-DHT pretreated rats induced the largest increase of 5-HT levels in the striatum. Thus, results in the present study indicate that the distribution of DA or 5-HT after the administration of dopa or 5-HTP, respectively, depends on the doses of dopa or 5-HTP given as well as the presence or absence of the lesioned 5-HT or DA neurons.

5,7-Dihydroxytryptamine↗