Decrease In 5-HIAA Research Articles

Decrease of GABA in the cerebrospinal fluid of patients with progressive myoclonus epilepsy and its correlation with the decrease of 5HIAA and HVA.

The degenerative type of progressive myoclonus epilepsy (PME) is a hereditary disease with grand mal seizures, stimulus sensitive myoclonus, characteristic EEG and mental deterioration in the late stage. GABAergic antiepileptic drugs are the most effective ones in this disease, with an unknown etiology. In this study, the GABA concentration in the CSF of 15 PME patients was measured and compared with values of sex- and age-matched epileptic controls. It was correlated with the concentrations of 5HIAA and HVA in the CSF, which were determined earlier from the same patients. The GABA concentration in the PME patients was statistically significantly decreased, to about 75% of that of the epileptic controls. It correlated with HVA and 5HIAA concentrations in the PME patients, but not in the epileptic controls. It is unknown whether these findings are related to the primary cause of PME or whether they are only secondary, owing to a loss of respective neurons or synapses.

Biochemical assessment of the central 5-HT agonist activity of RU 24969 (a piperidinyl indole)

The most potent compound of a series of piperidinyl indole derivatives which decrease 5-hydroxyindole acetic acid (5-HIAA) levels in rat brain-stem was chosen for further study on the neurochemistry of serotonin (5-HT) neurons. This derivative (RU 24969: 5-methoxy 3-(1,2,3,6-tetrahydro-4-pyridinyl) 1H indole, succinate) exerted a dose-dependent reduction in 5-HIAA concentrations in rat forebrain and brain-stem, which was of rapid onset and lasted for at least 4 h. The decrease in 5-HIAA was apparently due to a decrease in 5-HT turnover since RU 24969 significantly diminished 5-HTP accumulation after RO 4-4602 administration, and 5-HIAA accumulation after probenecid treatment. Basal or 5-HT-stimulated adenylate cyclase activities in colliculi from new-born rats were unaffected by RU 24969. This compound increased serum prolactin and corticosterone levels in a dose-related manner. Together with previous behavioral observations and the potent displacement of [ 3H]-5-HT binding obtained with this series, the present data indicate that these new piperidinyl indole derivatives are likely potent 5-HT receptor agonists in rat brain.

Brain serotonin and 5-hydroxyindoleacetic acid concentrations and serotonin synthesis following tetrahydro-beta-carboline administration in mice.

The effects of various tetrahydro-β-carboline (THβC) compounds on serotonin (5-hydroxytryptamine, 5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) concentrations and serotonin synthesis in mouse brain were investigated. 6-Methoxy-THβC (6-MeO-THβC) (100 mg/kg i.p.) significantly increased 5-HT concentrations from 15 min until 4 h after administration, and decreased 5-HIAA concentrations from 15 min until 10 h. The lowest dose of 6-MeO-THβC which produced a significant 5-HT increase was 25 mg/kg whereas 12.5 mg/kg produced a significant decrease of 5-HIAA. Comparisons among the THβC's in their ability to decrease 5-HIAA concentrations showed the following order of potency: THβC>6-MeO-THβC>6-MeO-tetrahydroharman>6-OH-THβC, In order to determine the mechanism for the increase in 5-HT and decrease in 5-HIAA produced by 6-MeO-THβC, its effect was compared to that of reference drugs known to inhibit monoamine oxidase (e. g. clorgyline, deprenyl, pargyline) and synaptosomal 5-HT uptake (chlorimipramine, fluoxetine). These comparisons suggested that the increased 5-HT concentration produced by 6-MeO-THβC was primarily the result of its monoamine oxidase-A inhibiting properties, whereas the decrease in 5-HIAA was the result of a combination of monoamine oxidase-A inhibition and 5-HT uptake inhibition. Serotonin synthesis in mouse brain following treatment with various tetrahydro-β-carboline compounds and other drugs affecting serotonin metabolism was determined using the so-called in vivo tryptophan hydroxylase method. This involved administering either saline or test drug followed at various times later by an injection of the decarboxylase inhibitor RO4-4602 (800 mg/kg), killing the mouse 30 min later, and measuring 5-hydroxytryptophan (5-HTP) in brain. 6-MeO-THβC at 100 mg/kg decreased the formation of 5-HTP with respect to saline controls from 1 to 4 h after administration, and this decrease was shown to be dose-dependent as measured at 2 h. The other THβC's including THβC, 6-OH-THβC and 6-MeO-tetrahydroharman also decreased 5-HTP formation at 2 h. In order to determine the mechanism for this decreased 5-HTP formation produced by the THβC's, their effects were compared to those of reference drugs known to inhibit monoamine oxidase-A (clorgyline, Lilly 51641), to inhibit synaptosomal serotonin uptake (fluoxetine, chlorimipramine), or to be a serotonin receptor agonist (quipazine). These comparisons suggested that the decrease in 5-HTP formation produced by the THβC's was most likely the result of a combination of monoamine oxidase inhibition plus serotonin uptake inhibition with the latter effect somewhat more potent.

Alterations in brain dopamine and serotonin metabolism during the development of tolerance to human beta-endorphin in rats.

Repeated intracisternal injections of human beta-endorphin lead to development of tolerance with respect to the catalepsy, analgesia, and hypothermia which are seen following a single injection. The initial injection of beta-endorphin results in increases in the dopamine metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in neostriatum, as well as increases in the serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA), in hypothalamus and brainstem and a decrease in 5-HIAA in hippocampus. In the present study, we report changes in metabolism of dopamine and serotonin in specific brain areas during the development of tolerance to beta-endorphin. Thus, the development of tolerance to beta-endorphin with respect to catalepsy, analgesia, and hypothermia may be mediated by development of tolerance to the effects of beta-endorphin on brain dopamine and serotonin release.

Effect of 1-(m-trifluoromethylphenyl)-piperazine on 3H-serotonin binding to membranes from rat brain in vitro and on serotonin turnover in rat brain in vivo

1-(m-Trifluoromethylphenyl)-piperazine inhibited the specific binding of tritiated serotonin to membranes from rat brain in vitro at lower concentrations than did quipazine or MK-212 (6-chloro-2-[1-piperazinyk]-pyrazine). In rats 1-(m-trifluoromethylphenyl)-piperazine decreased the concentration of 5-hydroxyindoleacetic acid (5-HIAA) without altering the concentration of serotonin in whole brain. The decrease in 5-HIAA was apparently due to a decrease in serotonin turnover, since 1-(m-trifluoromethylphenyl)-piperazine caused a slower decline in serotonin concentration after synthesis inhibition by α-propyldopacetamide and a slower accumulation of 5-HIAA after probenecid injection to block its efflux from brain. The decrease in serotonin turnover is an expected result of stimulating serotonin receptors in brain and has earlier been reported to occur with quipazine. Thus all of the results are compatible with the idea that 1-(m-trifluoromethylphenyl)-piperazine acts as a serotonin receptor agonist in rat brain.

Neurochemistry of withdrawal emergent symptoms in children.

The probenecid procedure was used to study the metabolite accumulations of dopamine (DA) and serotonin (5-HT) in the cerebrospinal fluid (CSF) of 11 children receiving chronic neuroleptic therapy. Specimens were obtained while the children were being given chronically prescribed medication (Condition 1) and again 3–4 weeks later, following the discontinuation of drugs (Condition 2). At that time, five children showed typical dyskinetic withdrawal emergent symptoms (WES) and six were free of symptoms. CSF specimens were also obtained from eight drug-free children, diagnosed as having ‘chronic organic brain disease,’ who served as a contrast population against which the findings were evaluated. CSF accumulations of 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) did not differentiate the drug-treated children who showed WES from those who did not manifest these symptoms. A significant decrease in 5-HIAA was found in Condition 2, suggesting that chronic treatment with neuroleptics may effect 5-HT metabolism in children. The contrast population was found to have lower CSF concentrations of probenecid and were consequently of little help in clarifying the nature of the 5-HIAA decrement. A number of serious deficiences were noted regarding the use of the probenecid procedure, and it is felt that the use of spinal taps for studying neuroleptic effects on brain metabolism in children is unlikely to provide important information with regard to either CNS drug actions or toxicity.

Effect of a Selective 5‐HT Uptake Inhibitor — Lu 10–171 *— on Rat Brain 5‐HT Turnover

Changes in endogenous concentrations of 5-HT and 5-HIAA as well as the turnover rate of 5-HT was studied in rat brain after treatment with a new potent and selective inhibitor of the neuronal 5-HT reuptake mechanism, Lu 10-171(1-(3-dimethylamino)propyl)-1-(p-fluorophenyl)-5-phthalancarbonitrile). After a single dose of Lu 10-171 the concentration of 5-HIAA was reduced from 1 to 24 hours after treatment, whereas that of 5-HT was practically unchanged, indicating decreased turnover of 5-HT in the brain. This was confirmed using three different methods for measuring 5-HT turnover. Thus the rate of 5-HIAA accumulation in the brain after probenecid was reduced after Lu 10-171. Likewise treatment with Lu 10-171 led to a decreased fall in 5-HT and an increased fall in 5-HIAA after inhibition of 5-HT synthesis with parachlorophenylalanine (PCPA). Unexpectedly Lu 10-171 did not change either the accumulation of 5-HT or the decrease in 5-HIAA after inhibition of MAO with pargyline. By and large the results are consistent with the proposed negative feed-back regulation of 5-HT neuronal firing rate due to the abundance of 5-HT at postsynaptic receptors after inhibition of the reuptake mechanism.

Effects of harmine and brain lesions on apomorphine induced motor activity

Application of harmine (10 mg/kg IP) 30 min before apomorphine decreased the motoric effects of the latter. Following harmine an increase in 5-HT and a decrease in 5-HIAA in different brain regions have been found. Injection of 5,6-DHT into nucleus medians raphe 7 days before the experiment caused a significant increase of the apomorphine effect. Harmine pretreatment reduced this excessive motility as well additional lesion of the substantia nigra with 6-OH-DA. Lesion induced by 76-OH-DA alone was without significant effect on the hypermotility following apomorphine. Application of PCPA 3 days before testing elicited an increase of apomorphine-induced hypermotolity which could be abolished by preceding harmine application. The experiments demonstrate the inhibitory effect of the central serotoninergic system on the apomorphine syndrom as well as the serotoninergic-dopaminergic interaction in hypermotility.

Determination of monoamine and monoamine metabolites in the human brain: post mortem studies in a group of suicides and in a control group.

Different nuclei and regions of the brain from patients who had committed suicide and from controls were analysed for their content of monoamine and monoamine metabolites. There was a post mortem breakdown of 5-hydroxyindoleacetic acid (5-HIAA) which could be correlated to the time elapsed between the occurrence of death and autopsy. Homovanillic acid (HVA) and the monoamines did not decrease post mortem during the time observed (6-148 hours). There was no significant correlation between age and chemical variables in this investigation. There were no significant group differences between suicides and controls concerning dopamine, noradrenaline, 5-hydroxytryptamine, and HVA, 5-HIAA levels were significantly lower in the suicide group in six out of eight parts of the brain investigated. It was, however, also demonstrated that there was a longer time elapse between the occurrence of death and autopsy in the suicide group. The suicides came on average 48 hours later to autopsy than the controls. As there was a post mortem decrease of 5-HIAA, this time variable had to be kept constant when group differences were analysed. When the influence of this time variable was eliminated there were no longer any differences between suicides and controls. According to this investigation, there seem to be no differences in levels of monoamines and their metabolites between suicides and controls.

Antinociceptive action of oxotremorine and regional turnover of rat brain noradrenaline, dopamine and 5-HT

In the rat, oxotremorine increases the threshold for vocalisation after-discharge (affective component of pain reactions) dose dependently at subtremor doses (30-67 mug/kg s.c.). Doses of 225-506 mug/kg were needed to elevate the thresholds for vocalisation and motor response. 1-Tryptophan, PCPA, alpha-methyl-p-tyrosine, 1-Dopa, pimozide and LSD-25 did not affect the antinociceptive activity of oxotremorine, while phenocybenzamine slightly increased the threshold for vocalisation. Oxotremorine did not change the endogenous brain concentrations of noradrenaline and dopamine or 5-HT but decreased that of 5-HIAA in all brain regions at the time of maximal analgesia. The decrease of 5-HIAA was still present after pretreatment with probenecid. After inhibition of tyrosine hydroxylase, oxotremorine accelerated the depletion of dopamine in telencephalic cortex during maximal antinociceptive activity and of noradrenaline in all brain regions at a time when this activity had vanished. Atropine significantly antagonized the analgesic activity of oxotremorine. It is concluded that oxotremorine antinociceptive activity in the rat is related to a cholinergic compoent, while a monoaminergic component is not directly involved.

Studies of various amphetamines, apomorphine and clonidine on body temperature and brain 5-hydroxytryptamine metabolism in rats.

Amphetamine and various amphetamine derivatives, phenmetrazinc, pipradrol, methylphenidate and HCA can increase the concentration of 5-HIAA in the rat brain without changing that of 5-HT. Metamphetamine produced a de- crease in 5-HT and no effect on 5-HIAA whereas 10-hydroxyamphetamine produced no effects on 5-HT and 5-ttIAA. The experiments performed at different environ- mental temperatures (12--14~ 21--22~ and 21--28~ with simultaneous measurements of the body temperature indicate that no simple correlation exists between the drug induced hyperthermia and the effect on 5-HIAA. The amphet- amine and phenmetrazine effect on 5-HIAA seems to be related to hyperthermia whereas the pipradrol and methylphenidate effect on 5-HI_AA appears independent of hyperthermia. Apomorphine (2  2.5 mg/kg) which activates central dopamine receptors produced a significant increase in 5-H~AA whereas clonidine (0.5 mg/kg) which activates central noradrenaline receptors produced a significant decrease in 5-HIAA. In conclusion, the effect of various amphetamines on 5-HT metabolism seems very complex in mechanism of action and might be related to hyperthermia, to a direct effect on 5-tIT neurons and to the ratio between central dopamine/nor- adrenaline receptor activation of these drugs.

Further structure-activity studies on the lowering of brain 5-hydroxyindoles by 4-chloroamphetamine

A single injection of 4-chloroamphetamine lowered brain 5-hydroxytryptamine (5-HT) in rats, with the maximum effect at 16 hr. Multiple injections were no more effective than a single injection, and 20–40% of the 5-HT in brain persisted. No other 4-substituted amphetamines studied lowered 5-HT as much as did 4-chloroamphetamine, though 5-hydroxyindoleacetic acid (5-HIAA) levels were decreased as much by 4-trifluoromethylamphetamine. The addition of a β-hydroxyl to 4-chloroamphetamine diminished the lowering of 5-HT despite the presence of the β-hydroxyl compound in brain at levels comparable to those of 4-chloroamphetamine. When metabolic inactivation by para-hydroxylation was not a factor (as in guinea pigs or in desmethylimipramine-treated rats), 3-chloro but not 2-chloroamphetamine lowered brain 5-HT as 4-chloroamphetamine did. 2-Chloroamphetamine in desmethylimipramine-treated rats was present in brain at levels comparable to those of 4-chloroamphetamine, but the 2-chloro compound raised instead of lowered 5-HT levels. Addition of a 2-chloro substituent to 4-chloroamphetamine reduced the effect on 5-HT, whereas the decrease in 5-HIAA was at least as great with 2,4-dichloroamphetamine as with 4-chloroamphetamine. The dichloro compound was present in brain at slightly lower levels than 4-chloroamphetamine and caused slightly less CNS stimulation and hyperthermia; both compounds were found primarily in the paniculate fraction after high speed centrifugation of brain homogenates. The ability of some 4-chloroamphetamine derivatives to lower 5-HIAA more than 5-HT suggests that inhibition of tryptophan hydroxylation cannot completely account for their effects on brain 5-hydroxyindole levels.

Influences of intraventricularly administered 5-hydroxytryptamine on normal and amine-depleted rabbit: subcellular distribution of 5-hydroxytryptamine in the brain stem, and animal behaviour

Normal and p-chlorophenylalanine (PCP) pretreated rabbits were subjected to intraventricular injection of 5-hydroxytryptamine (5-HT), and subcellular distribution of 5-HT in the brain stem, drug effects and behavioural changes were investigated. 5-HT in cytoplasmic S 3-fraction was remarkably elevated by intraventricular 5-HT while those of mitochondrial P 2−, microsomal P 3− and synaptic vesicular P 2V-fractions were not increased significantly unless animals were pretreated with PCP. In PCP-treated rabbits, intraventricular 5-HT produced characteristic sedation in animals. Intraperitoneal injection of imipramine (IM) prevented 5-HT-induced increase of 5-HT in P 2-fraction whereas desmethylimipramine (DMI) had no effect. DMI was found to elevate endogenous 5-HT in P 2-fraction and 5-hydroxyindole acetic acid (5-HIAA) in the brain stem while IM caused a significant decrease of 5-HIAA in the brain stem. Reserpine (Re) clearly blocked the increase of 5-HT in P 2V-fraction. Re-induced sedation could not be counteracted by intraventricular injection of 5-HT. The results are discussed

Evidence for inhibition of the reuptake of 5-hydroxytryptamine and noradrenaline by tetrahydronaphthylamine in rat brain.

1. The concentrations of 5-hydroxytryptamine (5-HT), 5-hydroxyindolacetic acid (5-HIAA) and noradrenaline (NA) in homogenized rat brains were determined after intraperitoneal injection of 1,2,3,4-tetrahydro-2-naphthylamine (THN).2. THN caused a decrease in the concentration of brain 5-HIAA without altering its 5-HT content, but the percentage of ;free 5-HT' in the supernatant increased. The decrease in 5-HIAA and the increase in free 5-HT were negatively correlated, suggesting inhibition of the reuptake of 5-HT.3. THN decreased brain NA content without changing free NA. The fact that no increase in free NA occurred is ascribed to the action of catechol-O-methyl-transferase.4. Inhibition of the reuptake of NA and of 5-HT was further studied by using the compounds 5-methyl-alpha-ethyl-meta-tyramine (H 75/12) and 4,alpha-dimethyl-meta-tyramine (H 77/77). The results of these studies also suggested inhibition by THN of the reuptake of 5-HT as well as of NA.5. The action of THN is explained by inhibition of the reuptake of NA and of 5-HT and by release of NA from its stores. However, the possibility is not excluded that, instead of releasing NA from its stores, THN inhibits the enzyme dopamine-beta-hydroxylase.

Relationship of monoamine metabolites in human cerebrospinal fluid to age.

HOMOVANILLIC acid (HVA) and 5-hydroxyindoleacetic acid (5HIAA), metabolites of 5-hydroxytryptamine and dopamine, have been detected and measured in animal and human cerebrospinal fluid (CSF) (refs. 1–3). Although these substances in CSF probably derive from neuronal populations in the central nervous system, their precise relationship to altered brain function remains to be determined. Nevertheless, several clinical studies have reported a decrease in 5HIAA and HVA in certain groups of patients, notably depressed psychiatric patients and individuals suffering from Parkinsonism2–4. In the course of our studies on monoamine metabolites in CSF, we have found that values for these substances vary with age, both in psychiatric and neurological groups of patients. This finding may be crucial for the interpretation of values for CSF monoamine metabolites in clinical studies.

The effect of ethanol and disulfiram on serotonin- 14C metabolism in rat liver homogenates

A study was made of serotonin- 14C metabolism in rat liver homogenates with and without exogenous NAD and NADH. Serotonin was converted to 5-hydroxy-indoleacetaldehyde by MAO; neither ethanol nor disulfiram inhibited MAO. The aldehyde was converted to 5-hydroxytryptophol by the NADH-linked alcohol dehydrogenase; neither ethanol nor disulfiram inhibited alcohol dehydrogenase. The 5-hydroxyindoleacetaldehyde was converted to 5-HIAA by the NAD-linked aldehyde dehydrogenase. Ethanol decreased 5-hydroxyindoleacetaldehyde with a concomitant increase in 5-hydroxytryptophol and decrease in 5-HIAA. Disulfiram increased 5-hydroxyindoleacetaldehyde with a concomitant increase in 5-hydroxytryptophol and decrease in 5-HIAA.