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Biomedical subjects

C Suñol

Publications and source records attributed to C Suñol.

At least 37 records · Page 2Linked to original sources

Regional effects on the cerebral concentration of noradrenaline, serotonin and dopamine in suckling rats after a single dose of lindane.

The effect of a low single dose of lindane (gamma-hexachlorocyclohexane) on monoaminergic neurotransmission during brain postnatal development was studied in 8-, 15-, 22- and 29-day-old suckling rats. Concentrations of noradrenaline, serotonin, dopamine and their metabolites were determined in eight cerebral regions 1 h after dosing (20 mg/kg lindane per os). All these aminergic systems were altered in a regional- and age-related pattern. Decreases of noradrenaline in regions rich with noradrenergic terminals together with increases of the ratio 5-HIAA/serotonin and DOPAC/dopamine suggest, as a whole, an enhanced release of the monoamines. This increased neuronal activity does not exclude an initial action of lindane on the inhibitory GABAergic system that would activate the neurotransmitter release in other systems shortly after a single administration of the neurotoxic agent.

Aging↗

Evidence for acute tolerance to the behavioral effects of lindane: concomitant changes in regional monoamine status.

The effects of the organochlorine insecticide lindane on plus-maze ((+)-maze) behavior of rats and on regional monoamine status were studied at two time points, 30 min and 24 hr post-dosing. Animals were given lindane, 20 mg/kg, 30 min before (L1/2 group), or 40 mg/kg, 24 hr before (L24 group), experimental time; these schedules allowed the study of animals with equivalent brain concentration of lindane at two different time points after administration. The (+)-maze results indicated a reduction in the number of entries into the arms of the maze 30 min after administration of lindane that was not present 24 hr later, suggesting the development of an acute tolerance to the behavioral effects of the chemical. In a parallel group of animals, concentrations of noradrenaline (NA), serotonin (5HT), 5-hydroxyindoleacetic acid (5HIAA), dopamine (DA), dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) were determined by HPLC in seven brain regions. Significant decreases in NA concentrations were found in L1/2 animals in hippocampus and cerebral cortex and also in the L24 group in the latter region. 5HT/5HIAA ratios increased in several brain regions in the L24 rats but not in the L1/2 rats, thus showing an inverse relationship with behavioral effects. DOPAC/DA and HVA/DA ratios in hypothalamus and cerebral cortex were, by contrast, increased in both groups of treated animals. In conclusion, it appears that an acute tolerance can develop to the behavioral effects of lindane, and that there are modifications produced in central monoaminergic systems by lindane that show brain region and and treatment schedule specificity.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗

Microcomputer adaptation of the wheel-shaped activity monitor: effects of lindane.

The development of microcomputers with increased power and memory capacity may allow for the spreading of the techniques of microanalysis of animal behavior in neurotoxicology. The present work describes the adaptation of the wheel-shaped activity monitor to a personal computer system (IBM-PC/XT/AT-compatible). The system has been used to study the effects elicited by a single 30 mg/kg dose of the organochlorine insecticide gamma-hexachlorocyclohexane (lindane) on the spontaneous behavior of rats. Lindane induced complex changes in behavior, the most prominent being a disruption of the temporal pattern of activity and changes in the local activity/locomotor activity ratios and in place preferences in the monitor. Effects on body weight and number of fecal boluses were also observed.

Animals↗

GABAergic modulation of lindane (gamma-hexachlorocyclohexane)-induced seizures.

The main objective of this work was to study the role of the GABAergic system on the convulsions elicited by the organochlorine insecticide lindane. The concentration of lindane in rat brain at the onset of the first tonic convulsion was taken as the endpoint for the neurotoxic action of the insecticide administered by intravenous infusion. Pretreatment with the GABA agonists muscimol and progabide, the GABA uptake blocker SK&F 89976-A, the GABA transaminase inhibitor gamma-acetylenic GABA, and the GABA indirect agonist phenobarbital significantly increased the threshold concentration of lindane in brain required to induce convulsions. The GABA agonist THIP, the GABA competitive antagonist bicuculline, and the prodrug cetyl-GABA had no effect on the brain level of lindane required to induce seizures. The noncompetitive GABA antagonists, picrotoxinin and pentylenetetrazol, significantly decreased the brain concentration of lindane needed to elicit convulsions. The concentration of GABA in the brain of lindane-treated rats was only modified by the significant increase produced after gamma-acetylenic GABA pretreatment. These results show that the convulsions elicited by lindane can be facilitated by some GABA antagonists and antagonized by GABA mimetics, especially those that enhance GABA functionality. The present data are consistent with the proposed in vitro competition of lindane for the picrotoxinin binding site associated with the Cl- ionophore of the GABAA receptor, and suggest that lindane may also interact in vivo with this site.

Animals↗

Regional concentrations of GABA, serotonin and noradrenaline in brain at onset of seizures induced by lindane (gamma-hexachlorocyclohexane).

The main objective of this study was to determine the modifications induced by the pesticide lindane (gamma-hexachlorocyclohexane) in the regional concentration of neurotransmitters in brain, taking the tonic-clonic seizure as the main sign of its neurotoxic action. The animals were given lindane (150 mg/kg p.o. in olive oil) and killed at the onset of the first seizure (mean latency time: 18.3 +/- 5.5 min, n = 16). The inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and the biogenic amines noradrenaline (NA) and serotonin (5-HT), as well as its corresponding acidic metabolite, were determined by high performance liquid chromatography with fluorimetric or electrochemical detection in different areas of the brain: hippocampus, mesencephalon, colliculi, frontal cortex, parietal cortex, striatum and thalamus. The concentration of GABA in whole tissue was only significantly decreased in the colliculi. The concentration of serotonin (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) were decreased in the colliculi, striatum and frontal cortex, suggesting a decreased synthesis and release of 5-HT, but increased in the parietal cortex. The concentration of NA was significantly decreased in the parietal cortex. Thus, the results indicate that lindane induces some modifications of the concentration of neurotransmitters in cortical structures, basal nuclei, midbrain and colliculi. These changes may be consequent upon the proposed interaction of lindane with the GABAergic system, although a direct action of lindane on other neurotransmitter systems cannot be excluded.

Animals↗

Convulsant effect of lindane and regional brain concentration of GABA and dopamine.

Lindane (gamma-hexachlorocyclohexane) is an organochlorine insecticide with known neurotoxic effects. Its mechanism of action is not well understood although it has been proposed that lindane acts as a non-competitive antagonist at the gamma-aminobutyric acid (GABA)-A receptor. We studied the effect of lindane (150 mg/kg) on the GABAergic and dopaminergic systems by measuring the concentration of GABA, dopamine and its metabolites in 7 brain areas at the onset of seizures. All animals suffered tonic convulsions at 18.3 +/- 1.4 min after lindane administration. The concentration of GABA was only slightly but significantly decreased in the colliculi without modifications in the other areas. The concentration of dopamine was increased in the mesencephalon and that of its metabolite DOPAC was also increased in the mesencephalon and the striatum.

3,4-Dihydroxyphenylacetic Acid↗

Effect of lindane at repeated low doses.

The relationship between brain concentration of lindane and its convulsant effect have been studied in rats after repeated low doses of lindane. The mean brain plateau concentration was achieved in 5-8 days. The doses administered (5, 12 and 20 mg/kg) and the brain concentration of lindane at the plateau were highly correlated. The incidence rate of response (percentage of rats with tonic convulsions) was also highly correlated with the log of concentration of lindane in brain for all doses and days studied. A decrease in brain concentration of lindane was observed after 12 days of daily administration at doses of 5 and 12 mg/kg but not at the highest dose (20 mg/kg).

Animals↗

Relationship between lindane concentration in blood and brain and convulsant response in rats after oral or intraperitoneal administration.

The relationships between brain and blood concentrations of lindane and its convulsant effects have been studied in rats after different po and ip doses. A good correlation was observed between dose and the frequency and time to onset of tonic seizures, the intensity of the response and lethality. An oral ED50 (84 mg/kg) and an ip ED50 (131 mg/kg) for the half-maximal incidence rate of lindane-induced tonic seizures was determined. The incidence of response was directly proportional to the log of lindane concentration in brain and blood, with an EC50 of 5.3 micrograms/g and 1.5 micrograms/ml, respectively. The threshold concentration of lindane eliciting tonic seizures was estimated to be approximately 5 micrograms/g in brain and approximately 1.5 micrograms/ml in blood. The kinetics of lindane in brain and blood were examined after a single 60 mg/kg po or ip dose over a period from 5 min to 1 week. Concentrations of lindane in brain and blood were found to be highly correlated.

Adipose Tissue↗

Comparative ontogenesis of brain tryptamine, serotonin, and tryptophan.

The pattern of ontogenetic development of tryptophan (TP), tryptamine (T), indole-3-acetic acid (IAA), 5-hydroxytryptamine (5-HT; serotonin), and 5-hydroxyindole-3-acetic acid (5-HIAA) in the brains of rats aged 1-45 days is presented. Analysis of the five components in each brain allows the calculation of the acid/amine and amine/amino acid ratios. These metabolic indexes are a useful tool to study and compare the metabolic origins and fates of both amines. The ontogenetic patterns of TP, T, and IAA are very similar, especially during the first week postpartum. The highest and lowest levels found for T were 2.2 ng/g and 0.1 ng/g at the 1st and 5th day, respectively. The temporal relationship between the T/TP and IAA/T ratios suggests the existence of mechanisms protecting T against monoamine oxidase (MAO) which develop in parallel to synaptogenesis. Significant correlations were found between TP and IAA during the whole period studied and between TP and T during the first week after birth. The 5-HT peak found during the first postpartum week could be due to a non-neuronal pool of 5-HT protected against MAO and possibly contained in mast cells. Preliminary determinations on leptomeningeal membranes suggest the existence of such a pool.

Animals↗

Determination of tryptamine in brain tissue by capillary gas chromatography mass spectrometry (selected ion monitoring).

The development of an analytical method for the determination of brain tryptamine using capillary gas chromatography mass spectrometry (selected ion monitoring) is presented. The method involves solvent extraction of brain homogenates and further derivatization (pentafluoropropionyl derivatives) of the dried extracts. Gas chromatographic analysis is performed using a bonded phase silica fused capillary column. Selected monitoring of m/z 289 and 292 (isotope dilution technique) allows the determination of tryptamine in adult rat brain (450 +/- 73 pg g-1) (means +/- SEM), n = 6.

Animals↗

Liquid-chromatographic determination of indole-3-acetic acid and 5-hydroxyindole-3-acetic acid in human plasma.

We describe a "high-performance" reversed-phase liquid-chromatographic method for determination of indole-3-acetic acid (I) and 5-hydroxyindole-3-acetic acid (II) in human plasma. I is eluted at 1.0 mL/min with a mixture of 1-pentanesulfonic acid (pH 3.1), methanol, and water. It is detected by fluorometry. A mixture of citric acid/sodium phosphate solution (pH 4.8) and methanol, at 1.5 mL/min, is used to elute II, which is detected with an electrochemical cell. Platelet-poor plasma samples were pretreated with HCl, perchloric acid, and trichloroacetic acid for protein precipitation. Best results were obtained with the last (protein precipitation is incomplete with HCl, while recoveries of I are concentration dependent with perchloric acid). Analytical recoveries were 58% (SD 3.1%, CV 5.3%, n = 12) and 79% (SD 3.3%, CV 5.3%, n = 9) for I and II, respectively. Concentrations of I and II in plasma ranged from 0.61 to 3.32 (mean 1.54, SD 0.59, n = 15) mumol/L and from 33.0 to 102.6 (mean 51.8, SD 20.1, n = 16) nmol/L, respectively.

Adult↗

Direct gas chromatograph-mass spectrometer connection of glass capillary columns for the analysis of serotonin and metabolites by selective ion monitoring.

A direct connection system that requires no modifications to either the gas chromatograph or the mass spectrometer is described for the coupling of glass capillary columns to a commercial mass spectrometer. Vacuum-tight connections can be readily achieved with standard 1/16-in. fittings and septum discs. The system can be operated with column outlet helium flow-rates of 1.5-2 ml/min at ion source pressures of 2-5 - 10(-5) mmHg. Although an injector splitter of our own design has been used, the initial test results obtained with a splitless injection method based on the use of a solids injection syringe together with a packed column injector assembly indicate the feasibility of developing a totally splitless and connection system that is simple to use. The system has been applied to the detection of the pentafluoropropionyl derivatives of serotonin, methoxytryptamine, methoxytryptophol and 5-hydroxytryptophol by selective ion monitoring techniques. Column performances under both sets of conditions (gas-liquid chromatography alone and combined with mass spectrometry) are compared and the evaluation of direct versus indirect coupling showed yields of the order of 50% through the molecular separator.

Chromatography, Gas↗

Mass spectrometric determination of new prostaglandin derivatives (series A and E).

The reaction of prostaglandins E1, E2, A1 and A2 with a 1:1 mixture of N,O-bis-trimethylsilyltrifluoroacetamide and piperidine favours the quantitative enolization of the 9-keto group of prostaglandins E, thus giving the corresponding tetrakis-TMS derivatives with molecular ions at m/e 642 and m/e 640 for prostaglandins E1 and E2, respectively, and also gives a new type of prostaglandin A-piperidyl-TMS derivative characterized by very strong base peaks at m/e 464 and 462, with molecular ions at m/e 637 and 635 for prostaglandins A1 and A2, respectively. The probable reaction mechanisms prevailing in both cases are discussed in accordance with the low and high resolution mass spectral data presented.

Chemical Phenomena↗

Effects of lindane on spontaneous behavior of rats analyzed by multivariate statistics.

The effects of subconvulsant doses (10, 15, 30 mg/kg) of the organochlorine insecticide gamma-hexachlorocyclohexane (lindane) on the spontaneous activity of male Wistar rats were assessed in an automated wheel-shaped activity monitor in 4 hr sessions. Most of the activity variables defined on the raw data showed statistically significant differences among treatment groups. These data can be interpreted as a lindane-induced change in the temporal distribution of the activity. The multivariate statistical technique principal component analysis was used to obtain a composite variable that measured this change. The variable obtained was found to be well correlated with dose levels and brain concentration of lindane and was used to estimate a minimal effective dose (MED) of 1.85 mg/kg and a upper limit for a minimal effective concentration (MEC) in brain of 0.84 micrograms/g by a log-linear regression approach. The results obtained with this approach further support the conclusion that the behavioral effects of lindane can be significant at exposure levels far below its LD50.

Analysis of Variance↗