SEARCH · PubMed Health

Results for “HYDROXYINDOLEACETIC ACID”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 775 records · Page 43Linked to original sources

PubMed1998

Fumonisin B1-induced increases in neurotransmitter metabolite levels in different brain regions of BALB/c mice.

Fumonisin B1, a toxin produced by Fusarium moniliforme, causes a variety of diseases in animals, including those involving the central nervous system, such as equine leukoencephalomalacia (ELEM). The changes of biogenic amines may reflect fumonisin B1 neurotoxicity. It was previously reported that consumption of feed contaminated with Fusarium moniliforme cultures produced an elevation of 5-hydroxyindoleacetic acid (5-HIAA), the major metabolite of 5-hydroxytryptamine (5-HT), in whole rat brains. In a subsequent study from the same laboratory, rats given fumonisin B1 orally for 4 weeks showed no changes in neurotransmitter levels of the whole brain. In the current study, groups of five male BALB/c mice were injected with fumonisin B1 subcutaneously at doses of 0, 0.25, 0.75, 2.25, 6.75 mg kg-1 body weight daily for 5 days. One day after the last treatment, their brains were dissected into cerebrum, cerebellum, medulla oblongata, midbrain, corpus striatum and hypothalamus. Levels of norepinephrine (NE), dopamine (DA), DA metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and 5-HT and 5-HIAA were determined. A significant elevation of HVA was observed in mice treated with high doses of fumonisin B1 in most brain regions. In striatum, a decrease of 5-HT was observed by the fumonisin B1 treatment. Ratios of neurotransmitters to metabolites such as HVA/DA and 5-HIAA/5-HT were elevated in several brain regions of the treated groups. An accumulation of neurotransmitter metabolites is suggestive of increased neuronal activity or interference with their efflux from cells.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2001

Social impulsivity inversely associated with CSF 5-HIAA and fluoxetine exposure in vervet monkeys.

Animal and human research suggests that the central serotonin system is involved in the inhibition of impulsive behavior. Two studies were designed to assess this relationship in male vervet monkeys (Cercopithecus aethiops sabaeus) using a standardized test of impulsivity in a social context: the Intruder Challenge. In the first study, an index of impulsivity in response to an unfamiliar adult male intruder (including latency to approach and aggressive and assertive interactions) was inversely correlated with levels of the serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA) in cisternal cerebrospinal fluid (r = -0.33, p <.01, n = 138). The approach, but not aggressive, component of the Impulsivity Index was the primary contributor to this relationship (partial r = -0.27, p <.01). The second experiment compared responses to the Intruder Challenge after 9 weeks of daily treatment with fluoxetine (2 mg/kg, i.m.) or vehicle. Fluoxetine-treated subjects (n = 6) had significantly lower Impulsivity Index scores than controls (n = 12). The results from these two investigations provide evidence for serotonergic influences on social impulsivity.

Age Factors↗

PubMed1998

Effect of tryptophan treatment on self-biting and central nervous system serotonin metabolism in rhesus monkeys (Macaca mulatta).

UNLABELLED: Two studies were conducted to examine the effects of oral L-tryptophan (TRP) supplementation as a treatment for self-injurious behavior (SIB) and to investigate behavior and central serotonin turnover of male rhesus monkeys. In Study One, TRP was administered to seven individually housed rhesus monkeys with a recent history of spontaneous SIB. While the monkeys were on TRP treatment (100 mg/kg twice a day), cisternal cerebrospinal fluid (CSF) concentrations of 5-hydroxyindoleacetic acid increased markedly (p = .0013) above baseline (baseline mean = 207.6 pmol/ml +/- 39; TRP mean = 320.3 pmol/ml +/- 83.4), and the duration of self-biting behavior decreased below baseline (p = .03). In Study Two, 14 individually housed rhesus monkeys without a history of SIB were placed on three different doses of TRP in random order (50, 100, and 200 mg/kg twice a day). TRP had no effect on any behavioral or biochemical variables in the normal monkeys. CONCLUSIONS: Supplemental tryptophan in well-tolerated doses reduced self-biting and increases serotonin turnover rate in male monkeys with a recent history of SIB. The same doses of TRP do not affect behavior or serotonin metabolism in male monkeys without a history of SIB.

Animals↗

PubMed2000

CSF 5-HIAA and nighttime activity in free-ranging primates.

Men with low CNS serotonin turnover, as measured by cerebrospinal fluid 5-hydroxyindoleacetic acid (CSF 5-HIAA) concentrations, exhibit aberrant circadian activity patterns characterized by disrupted sleep rhythms and daytime hyperactivity. To assess whether similar patterns are found in nonhuman primates we examined the relationships between CSF 5-HIAA and nighttime activity in free-ranging monkeys. CSF samples were obtained from 16 adult male rhesus macaques living on a 475 acre, heavily forested sea island. Each subject was captured, fitted with a radio-telemetry motion-detector collar, and then released back into its group. A receiver placed near the sleeping trees of the study subjects recorded activity between 2100 hrs and 0600 hrs. Trained observers recorded behavioral data during the day. The animals followed a typical diurnal activity pattern, as they were active 74% of the sampled time during the day and 37% of the sampled time during the night. CSF 5-HIAA concentrations were inversely correlated with total duration of nighttime activity as well as mean duration of all active events. Nighttime activity was inversely correlated with daytime activity. CSF 3-methoxy-hydroxyphenylglycol (MHPG) concentrations were positively correlated with total nighttime activity, and inversely correlated with daytime sleep frequency. We conclude that male rhesus with low CSF 5-HIAA concentrations have higher total nighttime activity, longer mean periods of nighttime activity, and sleep more during the day than do males with high CSF 5-HIAA concentrations. This suggests that low serotonergic neurotransmission is associated with aberrant diurnal activity, as evidenced by a disruption of nighttime sleep patterns and a compensatory higher rate of inactivity during the day.

Animals↗

PubMed2000

Effect of single intracerebroventricular injection of alpha-interferon on monoamine concentrations in the rat brain.

The effect of a single intracerebroventricular (i.c.v.) injection of alpha-IFN on levels of central monoamines and their metabolites in six brain regions (frontal cortex, striatum, hypothalamus, hippocampus, mid brain and medulla) of the rat was investigated. Wistar rats (n=10) were decapitated 2 h after i.c.v. injection of alpha-IFN. The brain tissues were homogenized, and monoamine concentrations were measured by high-performance liquid chromatography with an electrochemical detector. The levels of 5-hydroxytryptamine (5-HT) were significantly reduced in the frontal cortex in a dose-dependent manner, and the levels of both 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) were reduced in the mid brain and the striatum. The levels of noradrenaline (NA) were also significantly reduced in a dose-dependent manner in the frontal cortex. Some neurophysiological changes that affect activity of the noradrenergic or/and the serotonergic neuron system may occur during IFN therapy.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2001

Role of monoamine oxidase inhibition and monoamine depletion in fenfluramine-induced neurotoxicity and serotonin release.

The role of both monoamine synthesis and monoamine oxidase inhibition in mediating the fenfluramine-induced damage to serotonin neurones was examined; as pretreatment agents, both alpha-methyl-para-tyrosine (AMPT) and parachlorophenylalanine (PCPA) were used to deplete dopamine and serotonin, respectively, while clorgyline and deprenyl were used to inhibit monoamine oxidase types A and B. While both AMPT and deprenyl did not alter fenfluramine induced serotonin or 5-hydroxyindoleacetic acid (5-HIAA) depletion in any area, PCPA did partially reduce the serotonin depletion in the hippocampus and hypothalamus. Although pretreatment with clorgyline did not significantly alter fenfluramine-induced serotonin depletion, it did produce a 65% mortality rate in animals treated with both drugs. Both PCPA and clorgyline significantly increased the depletion of striatal 5-HIAA concentration consequent to fenfluramine; however, these drugs also produced a long-term depletion of striatal 5-HIAA when administered alone, therefore, the changes seen after the coadministration with fenfluramine may be viewed as additive. Finally, acute PCPA pretreatment attenuated the rapid rise in 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (homovanillic acid) induced by fenfluramine, and acute clorgyline reversed the drop in serotonin and rise in 5-HIAA induced by fenfluramine. These results indicate that the rapid increase in dopamine activity induced by fenfluramine is partially dependent on serotonin concentration and release and that the mechanism of fenfluramine-induced toxicity is unlike that of the other substituted amphetamines.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2006

Early maternal rejection affects the development of monoaminergic systems and adult abusive parenting in rhesus macaques (Macaca mulatta).

This study investigated the effects of early exposure to variable parenting style and infant abuse on cerebrospinal fluid (CSF) concentrations of monoamine metabolites and examined the role of monoaminergic function in the intergenerational transmission of infant abuse in rhesus monkeys (Macaca mulatta). Forty-three infants reared by their biological mothers and 15 infants that were cross-fostered at birth and reared by unrelated mothers were followed longitudinally through their first 3 years of life or longer. Approximately half of the infants were reared by abusive mothers and half by nonabusive controls. Abused infants did not differ from controls in CSF concentrations of 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), or 3-methoxy-4-hydroxyphenylgycol (MHPG). Abused infants, however, were exposed to higher rates of maternal rejection, and highly rejected infants had lower CSF 5-HIAA and HVA than low-rejection infants. The abused females who became abusive mothers in adulthood had lower CSF 5-HIAA than the abused females who did not. A similar trend was also observed among the cross-fostered females, suggesting that low serotonergic function resulting from early exposure to high rates of maternal rejection plays a role in the intergenerational transmission of infant abuse.

Age Factors↗

PubMed1987

Effect of probenecid on cerebral and cisternal cerebrospinal fluid lactate content.

In this study, the cisternal CSF contents of lactate and glucose were sequentially measured in free-moving rats that had been administered probenecid, 200 mg/kg-1, drug diluent, or no injections. In animals receiving either no injections or injections of drug diluent, CSF lactate and glucose were constant over a 6-h period (93-106% of control), whereas rats receiving probenecid showed increased lactate at 1 and 2 h (170 and 125% control, respectively) and increased glucose at 1, 2, and 3 h (169, 141 and 129% control, respectively). Cerebral cortex content of energy metabolites and lactate and blood lactate levels were statistically unaltered at 0.5-6 h exposure to probenecid, whereas cerebral and blood glucose contents were increased after 1 and 2 h exposure to probenecid. Rats exposed to 5% O2 and probenecid for 0.5 h showed a statistically higher CSF lactate at 0.5 and 1.5 h reoxygenation (169 and 168% control, respectively). A similar effect was also seen in rats exposed to 5% O2 and the 5-hydroxyindoleacetic acid (5-HIAA) transport inhibitor Na divalproate. The results suggested that the increase in CSF glucose was secondary to a probenecid-induced elevation of blood glucose, whereas the increase in CSF lactate seemed to be secondary to a reduced rate of efflux of lactate from the CSF. It is suggested that it may be possible to increase the CSF lactate content by mechanisms that are independent of direct effects on the processes of cerebral energy metabolism.

Animals↗

PubMed1999

Increased dopaminergic and 5-hydroxytryptaminergic activities in male rat brain following long-term treatment with anabolic androgenic steroids.

1. The effects of treating groups of rats with four different anabolic androgenic steroids (AAS) (testosterone, nandrolone, methandrostenolone, and oxymetholone) on 5-hydroxytryptamine (5-HT) and dopamine (DA) neurones in different brain regions were examined. The AAS was injected six times with 1 week's interval and the rats were sacrificed 2 days after the final injection. 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA), DA and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were measured. The effect on DA and 5-HT synthesis rate was analysed as the accumulation of 3,4-dihydroxyphenyl-alanine (DOPA) and 5-hydroxytryptophan (5-HTP), respectively, after inhibition of the amino acid decarboxylase with NSD-1015 (3-hydroxy-benzylhydrazine dihydrochloride). Additionally, the monoamine oxidase (MAO) activity was analysed in the hypothalamus. 2. The DOPAC + HVA/DA ratio was increased in the striatum in all treatment groups. However, the synthesis rate of DA was significantly increased only in the methandrostenolone treated group. 3. The 5-HIAA/5-HT ratio was increased in all treatment groups in the hippocampus, in the frontal cortex in the methandrostenolone-treated animals and in the hypothalamus in the testosterone- and oxymetholone-treated rats, while the 5-HT synthesis rate was not affected by the AAS-treatments. 4. The MAO-A activity was increased in the oxymetholone-treated rats while the other treatment groups were unaffected. The MAO-B activity was not changed. 5. The results indicate that relatively high doses of AAS increase dopaminergic and 5-hydroxytryptaminergic metabolism in male rat brain, probably due to enhanced turnover in these monaminergic systems.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1994

Selective lesions by manganese and extensive damage by iron after injection into rat striatum or hippocampus.

Regional 45Ca2+ accumulation and analysis of monoamines and metabolites in dissected tissues were used to localize, quantify, and characterize brain damage after intracerebral injections of Mn2+ into striatum and hippocampus. The specificity of Mn(2+)-induced lesions is described in relation to brain damage produced by local Fe2+ or 6-hydroxydopamine (6-OHDA) injections. In striatum, Fe2+ and Mn2+ produced dose-dependent (0.05-0.8 mumol) dopamine (DA) depletion, with Fe2+ being 3.4 times more potent than Mn2+. Studies examining the time course of changes in monoamine levels in striatum following local application of 0.4 mumol of Mn2+ revealed maximal depletion of all substances investigated (except 5-hydroxyindoleacetic acid) after 3 days. The effects on DA (87% depletion at day 3) and its major metabolites were most pronounced and lasted until at least 90 days (40% depletion), whereas serotonin and noradrenaline levels recovered within 21 and 42 days, respectively. In addition, levels of 3-methoxytyramine, which is used as an index of DA release, also recovered within 42 days, indicating a functional restoration of DA neurotransmission despite substantial loss of DA content. Intrastriatal Mn2+ (0.4 mumol) produced time-dependent 45Ca2+ accumulation in striatum, globus pallidus, entopeduncular nucleus, several thalamic nuclei, and substantia nigra pars reticulata ipsilateral to the injection site. In contrast, 6-OHDA injected at a dose equipotent in depleting DA produced significantly less 45Ca2+ accumulation in striatum and globus pallidus and no labeling of other brain areas, whereas Fe2+ (0.4 mumol) produced extensive 45Ca2+ accumulation throughout basal ganglia, accumbens, and cerebral cortex. In hippocampus, high Mn2+ (0.4 mumol) produced limited 45Ca2+ accumulation in subiculum and dentate gyrus, whereas low Fe2+ (0.1 mumol) produced widespread 45Ca2+ accumulation throughout hippocampus, thalamus, and cerebral cortex. It is concluded that (a) Mn2+ is selectively neurotoxic to pathways intrinsic to the basal ganglia, (b) intrastriatal injections can be used as a model for systemic Mn2+ intoxications, and (c) high endogenous Fe3+ and/or catecholamine levels potentiate the neurotoxicity of Mn2+.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2002

Cerebrospinal fluid concentrations of biogenic amines and corticotropin-releasing factor in adolescent non-human primates as a function of the timing of adverse early rearing.

Adolescent bonnet macaques nursed as infants by mothers facing unpredictable requirements for food procurement (variable foraging demand, VFD) display persistent neurobiological disturbances. This study examined the long-term neurochemical and behavioral effects of adverse rearing initiated later in infancy than in previous cohorts of subjects to test the hypothesis that the timing of an early adverse experience would influence patterns of biobehavioral outcome. Cisternal cerebrospinal fluid (CSF) monoamine and corticotropin-releasing factor (CRF) concentrations were obtained from 20 bonnet macaques (11 VFD-reared and 9 normally reared controls) approximately 2 years after the end of differential rearing. VFD-reared primates displayed on multiple samplings significantly lower CSF CRF concentrations and higher CSF 5-hydroxyindoleacetic acid (5-HIAA) concentration compared to controls. In the VFD-reared, significant inverse correlations between CRF and all three monoamines were found (5-HIAA, 3-methoxy-4-hydroxyphenethyleneglycol and homovanillic acid), most prominently for 5-HIAA. In controls, but not VFD-reared subjects, CSF CRF was positively correlated with changes in "gregariousness" upon presentation of a fear stimulus. VFD-reared subjects displayed greater baseline hierarchical engagement than controls. In contrast to prior findings, in which rearing under VFD conditions at an earlier age led to increased CSF CRF compared with controls, CSF CRF was lower after later exposure to VFD rearing than in controls. Thus, the timing of exposure to VFD conditions early in life evidently determines whether CSF CRF was found to be elevated or decreased, within the context of increased serotonin metabolism, during the course of primate maturation.

Animals↗

PubMed1994

Sleep deprivation in the rat: XVIII. Regional brain levels of monoamines and their metabolites.

Several theories have linked sleep with change in monoamine activity. However, the use of sleep deprivation to show that changes in sleep generate changes in monoamines (directly or through feedback) has produced inconsistent results. To explore whether longer sleep deprivation, better documented sleep loss, more complete controls or regional brain analyses would produce clear sleep loss-induced change, eight rats were subjected to total sleep deprivation (TSD) by the disk-over-water method for 11-20 days and were guillotined along with yoked control (TSC) and home-cage control (HCC) rats. Brains were removed and dissected to obtain the caudate, frontal cortex, hippocampus, hypothalamus, midbrain and hindbrain (pons-medulla). Tissue sections were analyzed for concentrations of serotonin (5HT), its metabolite 5-hydroxyindoleacetic acid (5HIAA), dopamine (DA), its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC), and either norepinephrine or, in the caudate section, the DA metabolite homovanillic acid. The ratios DOPAC/DA and 5HIAA/5HT, which under some conditions are indicators of turnover, were also calculated. Because sleep deprivation time varied across sets of TSD, TSC and HCC rats and not all eight sets were analyzed simultaneously, a repeated-measures ANOVA was performed within sets with HCC, TSC and TSD considered as successive levels of sleep deprivation treatment. In no case did TSD rats have significantly higher or lower values of amines, metabolites or ratios than both HCC and TSC rats. The most common outlying values were for TSC rats. Thus, these results failed to demonstrate sleep loss-induced regional changes in levels of major brain monoamines or their metabolites.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗

PubMedDate not supplied

Demonstration of an association among dietary cholesterol, central serotonergic activity, and social behavior in monkeys.

Epidemiologic studies link plasma cholesterol reduction to increased mortality rates as a result of suicide, violence, and accidents. Deficient central serotonergic activity is similarly associated with violence and suicidal behavior. We investigated the relationship among dietary and plasma cholesterol, social behavior, and the serotonin system as a possible explanation for these findings. Juvenile cynomolgus monkeys (eight female and nine male) were fed a diet high in fat and either high or low in cholesterol. We then evaluated their behavior over an 8-month period. Plasma lipids and cerebrospinal fluid metabolites of serotonin, norepinephrine, and dopamine were assessed on two occasions, at 4 and 5.5 months after the initiation of behavioral observations. Animals that consumed a low-cholesterol diet were more aggressive, less affiliative, and had lower cerebrospinal fluid concentrations of 5-hydroxyindoleacetic acid than did their high-cholesterol counterparts (p < .05 for each). The association among dietary cholesterol, serotonergic activity, and social behavior was consistent with data from other species and experiments and suggested that dietary lipids can influence brain neurochemistry and behavior; this phenomenon could be relevant to our understanding of the increase in suicide and violence-related death observed in cholesterol-lowering trials.

Aggression↗

PubMed1976

Effect of ketamine anaesthesia on the content of monoamines and their metabolites in the rat brain.

The effects of ketamine anaesthesia (100 mg/kg i.p.) on the content of brain 5-hydroxytryptamine (5HT), 5-hydroxyindoleacetic acid (5HIAA), noradrenaline (NA), dopamine (DA) and homovanillic acid (HVA) were studied in male Wistar rats. Fifteen min after ketamine injection, when the rats were deeply anaesthetized, the 5HT content in many brain regions tended to be increased. An opposite tendency was found in the brain 5HIAA content. In rats treated with probenecid, which markedly lengthened ketamine anaesthesia, the accumulation of 5HIAA was significantly reduced by ketamine. In addition to ketamine anaesthesia, probenecid was found to lengthen thiopental anaesthesia. One hour after the ketamine administration, when the rats were no longer anaesthetized but were excited, the brain NA concentration was increased by 17% (P less than 0.02). The brain DA content was unchanged, but at 15 min and 1 hour after ketamine administration the striatal HVA content was increased by about 55% (P less than 0.05), suggesting an increased turnover of DA. The results suggest that during recovery from ketamine anaesthesia the increased NA content and the increased DA turnover may be associated with the postanaesthetic excitement of the rat, whereas the decreasamine anaesthesia.

Anesthesia, General↗

PubMed1984

Concurrent determination of brain dopamine and 5-hydroxytryptamine turnovers in individual freely moving rats using repeated sampling of cerebrospinal fluid.

5-Hydroxytryptamine (5-HT) turnover and dopamine (DA) turnover values were obtained in individual conscious rats by measuring the rates of accumulation of 5-hydroxyindoleacetic acid (5-HIAA), 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) in cisternal CSF samples taken from each rat at 0, 30, and 60 min after probenecid (200 mg/kg i.p.) administration. In a separate experiment, 5-HT and DA turnover values were determined in CSF, striatum, and rest of brain of groups of rats killed 0, 30, or 60 min after probenecid. Whole brain turnover values were calculated from striatal and rest of brain values. Mean turnover values using CSF were comparable with both procedures. DA turnover values were greater when based on total (i.e., free + conjugated) DA metabolites than when based on free metabolites. After partial inhibition of monoamine synthesis with the decarboxylase inhibitor DL-alpha- monofluoromethyl -DOPA ( MFMD , 100 mg/kg p.o.) DA and 5-HT turnover values were comparably reduced in whole brain, rest of brain, and CSF but more markedly reduced in the striatum. Mean DA and 5-HT turnover values obtained using CSF were similar with probenecid doses over the range 150-250 mg/kg i.p. but were variable when repeatedly determined in the same rats after administration of 200 mg/kg probenecid. Results in general show that the CSF procedure may be used to determine concurrently both 5-HT and DA turnover (when estimated from the sum of total but not free metabolites) and that it provides a good index of whole brain turnover of these transmitters in the conscious individual rat.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1986

Monoamine neurotransmitter metabolism and locomotor activity during chemical hypoxia.

The effects of hypoxia on metabolism of 5-hydroxytryptamine (5-HT or serotonin) and 3,4-dihydroxyphenylethylamine (DA or dopamine) were compared with those on open-field activity in male CD-1 mice. Chemical hypoxia was induced with NaNO2. Hypoxia did not alter striatal concentrations of DA, 5HT, Trp, Tyr, 5-hydroxyindoleacetic acid, or homovanillic acid. However, NaNO2 (75 mg/kg) reduced the rates of conversion of [3H]Tyr to [3H]DA (-41%) and [3H]Trp to [3H]5-HT (-39%). Hypoxia also reduced dihydroxyphenylacetic acid (DOPAC) levels (-27%) and DOPAC/DA ratios (-20%). Open-field behavior, as measured in an automated activity monitor, decreased in a dose-dependent fashion with 75-150 mg/kg of NaNO2 (-35 to -90%). Comparison with previous studies suggests that the syntheses of dopamine, serotonin, and the amino acids are equally vulnerable to hypoxic insults but may be less sensitive than the synthesis of acetylcholine.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1994

Effect of acute administration of the 5-HT1A receptor ligand, lesopitron, on rat cortical 5-HT and dopamine turnover.

1. The involvement of presynaptic 5-hydroxytryptamine1A (5-HT1A) autoreceptors in the anxiolytic-like properties of lesopitron (E-4424) (2-(4-[4-(4-chloro-1-pyrazolyl)butyl]-1- piperazinyl)pyrimidine) was studied. Brain microdialysis was used to examine the effect of the drug on the release of 5-hydroxytryptamine (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the frontal cortex of awake, freely moving rats. Moreover, extracellular cortical 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were also studied to assess the possible participation of dopaminergic systems. 2. Lesopitron administered at a dose which induces anxiolytic behavior in rats (30 micrograms kg-1, i.p.) markedly reduced 5-HT levels (to 45% of the basal value) in cortical perfusates, having no effect on 5-HIAA, DOPAC and HVA. The effects of lesopitron were compared with those produced by the anxiolytic, and structurally related compound, buspirone. 3. Buspirone administered at a dose inducing anxiolytic-like effects in rats (5 mg kg-1, i.p.) produced a marked decrease in cortical 5-HT levels (to 20% of the basal value), but in contrast to lesopitron, buspirone produced a pronounced increase in cortical DOPAC (to 300% of the basal value) and HVA (to 400% of the basal value) levels. Buspirone administered at a low dose (30 micrograms kg-1, i.p.) was unable to affect cortical 5-HT levels. 4. To test the hypothesis that the 5-HT decreasing effect of lesopitron could be due to 5-HT1A autoreceptor (somatodendritic)-mediated inhibition of 5-HT neurotransmission, lesopitron was administered locally into the raphe nuclei. Intraraphe administration of 10 micro M lesopitron caused a decrease incortical 5-HT levels (the effect being of the same order as that obtained after systemic injection), with no effect on 5-HIAA, DOPAC and HVA. Raphe 5-HT extracellular levels were not modified afterintraraphe administration of lesopitron, indicating the absence of 5-HT reuptake blocking properties.5 We concluded that lesopitron, at an anxiolytic dose produced a marked inhibition of 5-HT release in the frontal cortex of awake, freely moving rats. This effect was observed after systemic administration as well as after intraraphe administration of the drug, suggesting an agonistic action at raphe 5-HTIA autoreceptors controlling 5-HT release in the projecting areas. In contrast to buspirone, lesopitrontreatment had no effect on cortical DOPAC or HVA levels.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1987

Monoamine metabolite levels in rat CSF: kinetic studies.

The kinetics of monoamine metabolites, 3-methoxy-4-hydroxyphenylglycol (MHPG), 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA), in cisternal CSF were determined after monoamine oxidase (MAO) inhibition (pargyline, 100 mg/kg) and tyrosine hydroxylase inhibition (alpha-methyl-p-tyrosine, alpha-MPT, 250 mg/kg) in awake rats. In addition, the possibility of a peripheral contribution to CSF MHPG levels was investigated by infusing large amounts of the metabolite into vena jugularis. Pargyline induced an exponential decrease of CSF MHPG, 5-HIAA and HVA, with respective half-lives of 51, 86 and 46 min. alpha-MPT caused a slower decline of MHPG and HVA, while 5-HIAA was unaffected. Results from the MHPG-infusion experiments indicate minor peripheral contribution to CSF MHPG levels in acute pharmacological studies. The present paper gives further support for the validity of our new animal model in detecting acute changes in central monoaminergic activity.

Animals↗