[Effect of fluoxetine treatment on serotonin and MHPG in 32 patients with major depressive disorder]. / Effet d'un traitement à la fluoxétine sur la sérotonine et le MHPG chez 32 patients atteints de dépression majeure.

Considering the concept that depressive disorders were not only resulting from activity of one neurotransmitter, possible interactions between the noradrenergic system and a selective serotonin uptake inhibitor, fluoxetine, were investigated in order to test the hypothesis of noradrenergic or serotonergic involvement in depression. So the biological parameters (plasma and urinary MHPG, platelet serotonin) were evaluated by HPLC. The aim of this study was to evaluate the correlations between the concentrations of MHPG and serotonin in 32 melancholic patients treated by fluoxetine (20 mg/day) during a minimum of three weeks. The clinical examination with evaluation of the antidepressant effect carried out using the HDS/MES rating scale, allowed to divide the patients into three groups: responders to treatment, partial responders and non responders. In the same time, a control group of healthy subjects was investigated. ANOVA applied to platelet serotonin at day 0 showed a tendency toward heterogeneity between the three patient groups and the control group. The concentrations of serotonin in the three patients groups were highly reduced after 21 days of treatment. Concerning plasma and urinary MHPG there was non significant difference among the three patients groups at day 0 and the control groups. After treatment by fluoxetine, the results suggest that the urinary sulfate MHPG is an indicator of the metabolism of brain norepinephrine and seems to be a better turnover indicator than the plasma sulfate MHPG. The selective evaluation of sulfate and glucuronide MHPG could give a better survey of the psychobiological state of the patients than the total MHPG evaluation.

[Fluoxetine: relations between plasma concentration and therapeutic effects in 32 patients with major depression and treated with 20 mg/day]. / Fluoxétine: relations entre concentrations plasmatiques et effets thérapeutiques chez 32 patients atteints de dépression majeure et traités à 20 mg/j.

The aim of this clinical study was to investigate 32 melancholic patients treated by fluoxetine (20 mg/day). The clinical examination to evaluate the antidepressant effect of fluoxetine was realized by using the HDS/MES criteria. The patients were divided into three groups (responders, partial responders with or without a relapse, non responders) according to their clinical evolution during treatment. Fluoxetine and norfluoxetine were evaluated by HPLC after 3 weeks of treatment. In the present study, 53% of the patients have a positively reaction to the 21 day's treatment. Our results showed no correlation between the psychiatric scores and the plasma concentrations of fluoxetine and norfluoxetine.

Effects of fluoxetine and norfluoxetine on 5-hydroxytryptamine metabolism in blood platelets and brain after administration to rats.

The effects of intraperitoneal administration of fluoxetine (2.5, 5, 10 or 20 mg kg(-1)) and norfluoxetine (10 mg kg(-1)) on 5-hydroxytryptamine (5-HT) and 5-hydroxyindole-3-acetic acid (5-HIAA) metabolism were examined in the blood platelets and brain of rats killed 3 h after a single dose. Several experiments were performed to evaluate the effect of norfluoxetine. Plasma 5-HT concentrations decreased significantly (48%) compared with control group results 3 h after administration of a single dose of fluoxetine (10 or 20 mg kg(-1)). Similar plasma 5-HT levels, 0.54+/-0.04 and 0.56+/-0.09 mg L(-1), respectively, were observed after administration of 10 mg kg(-1) fluoxetine or norfluoxetine. In the same way 5-HIAA levels in whole brain were similar, 0.36+/-0.03 and 0.34+/-0.01 microg(-1), respectively, after administration of fluoxetine or norfluoxetine. There was a good correlation between plasma and brain levels of fluoxetine (0.962) and norfluoxetine (0.957). The results suggest that fluoxetine and norfluoxetine lead to reduced levels of 5-HT in platelets and of 5-HIAA in the brain. Like the parent drug, norfluoxetine is a potent and selective inhibitor of 5-HT uptake.

Effects of aluminum chloride on normal and uremic adult male rats. Tissue distribution, brain choline acetyltransferase activity, and some biological variables.

Normal and uremic adult male rats were given a daily ip injection of 20 mg Al (Al chloride)/kg for 14 d. The results indicate that Al induces a significant decrease in food ingestion, weight gain, and total protein concentration in the plasma. Compared with control animals, very high increases in Al levels were found in plasma and hepatic homogenates (about 36 and 19 times, respectively). In the brain homogenates, the Al increases were lower (about 23%). The brain cholineacetyltransferase activity was reduced: 10.6 and 14.9% in normal and uremic rats, respectively. The nephrectomy and the food restriction did not affect the total protein concentrations in plasma and the cerebral cholineacetyltransferase activity. Both were only found to be reduced in the rats treated by Al chloride.

Effects of postnatal aluminum exposure on biological parameters in the rat plasma.

Young rats were treated by gastric intubation with aluminum chloride (100 mg Al/kg/day) and aluminum lactate (100 and 200 mg Al/kg/day) from postnatal days 5 to 14. This treatment lead to a reduction in body weight. The plasma concentrations of total proteins and albumin decreased whereas the alpha 1 globulins increased in the treated rats. The aluminum concentrations in plasma and hepatic homogenates increased particularly at 200 mg Al lactate. The reduction in average body weight could be attributed to various causes: a decreased food consumption, a transient undernutrition, a reduction of the protein synthesis in the liver. The increase of the plasma concentration of the alpha 1 globulins revealed an inflammation process.

Assay of urinary free and conjugated 3-methoxy-4-hydroxyphenylethyleneglycol by high-performance liquid chromatography with amperometric detection.

The aim of this study was to develop an analytical method for free and conjugated 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) in urine. After hydrolysis of the conjugated forms, the urinary MHPG was purified by solid-phase extraction on anion exchanger and eluted with a water-methanol (1:1, v/v) mixture. After addition of ethyl acetate to the eluate and back-extraction into acetic acid, the aqueous phase was separated on a C18 column by HPLC and detected amperometrically. The results obtained from forty healthy human subjects were compared with the literature values. The precision and accuracy of the assay were studied using 4-methoxy-3-hydroxyphenylethyleneglycol (iso-MHPG) as internal standard.

In vitro effect of aluminum chloride on choline acetyltransferase activity of the rat brain during postnatal growth.

A decrease in the activity of choline acetyltransferase (ChAT) has been well documented in brains from individuals with Alzheimer's disease (AD) (Bird et al., 1983; McGeer, 1984). Decreased ChAT activity was also found in dialysis encephalopathy victims, but this reduction was less marked than that observed in AD (Yates et al., 1980). The involvement of aluminum in the etiology of AD has been proposed by some authors on the basis of abnormal concentration of aluminum in autopsied brain samples from AD patients (Krishnan et al., 1987), in the neurofibrillary tangles (Perl and Pendlebury, 1986) and the neuritic plaques (Candy et al., 1986). King (1984) hypothesized that elevated levels of aluminum contribute to the cholinergic deficits in AD. Aluminum is considered to be the causal factor in dialysis encephalopathy (Alfrey et al., 1976), particularly in young children with azotemia (Andreoli et al., 1984). Several animal studies demonstrate in vivo an aluminum effect on ChAT (Yates et al., 1980; Hofstetter et al., 1987). The distribution of the cholinergic perikarya in the rat CNS has been established immunohistochemically using antisera to ChAT (Sofroniev et al., 1982). From the basal forebrain, ChAT positive fiber bundles could be followed to the olfactory bulb, neocortex and hippocampus (Ichikawa and Hirata, 1986). This paper examines the influence of aluminum chloride at different concentrations on the activity of ChAT in homogenates from basal forebrain and neostriatum of rats during postnatal growth.

Element variations in pregnant and nonpregnant female rats orally intoxicated by aluminum lactate.

Pregnant or nonpregnant female rats were orally intoxicated by aluminum lactate (400 mg Al/kg/d) from d 0-19 of gestation to determine the treatment's influence on element variations in the females and their fetuses. The aluminum levels of plasma, liver, spleen, and kidneys were significantly higher in treated pregnant rats than non-pregnant female rats. Differences of P, Ca, Cu, Zn, or Mg levels were observed among the four groups of female rats in the tissues and plasma. The aluminum content of the 20-d-old fetuses did not significantly differ between the treated and control groups. On the contrary, calcium and magnesium levels in the whole fetuses from treated or nontreated dams are significantly different.

Effects of postnatal aluminum exposure on choline acetyltransferase activity and learning abilities in the rat.

Young rats were treated by gastric intubation with aluminum lactate (0, 100, and 200 mg Al/kg/day) from postnatal days 5 to 14 to determine the treatment's influence on brain choline acetyltransferase activity and learning abilities. The results indicated that aluminum concentrations in the cerebral areas increased in parallel to plasma aluminum at the dose of 200 mg. In the same case, choline acetyltransferase activity was reduced. At postnatal days 50 and 100, the treated rats did not show alterations in their learning abilities in the 2 tests which are based on different motivations (avoidance of an aversive light or alimentary motivation) and different ways of achievement (pressing on a lever or running in a maze). A low reduction in the general activity, particularly in the radial maze test, was only observed in rats treated with 200 mg Al/kg/day.

Aluminum transfer through milk in female rats intoxicated by aluminum chloride.

Female rats received an ip injection of aluminum chloride (10 mg Al/kg/d) during the first 12 d after parturition; this treatment led to a reduction in food intake associated with a reduction in body wt. Pups of the intoxicated dams showed a growth retardation after postnatal day 7. One day after treatment, the female rats intoxicated with aluminum had a considerably higher level of aluminum in milk than controls. The aluminum levels of plasma, liver, spleen, and kidneys were also significantly higher in treated female rats than controls. On the contrary, in the same tissues of pups from treated or not treated dams, no differences in aluminum levels were observed. No effect of aluminum treatment was detected on plasma silicon levels in dams and pups.

Developmental alterations in offspring of female rats orally intoxicated by aluminum lactate at different gestation periods.

Pregnant rats were treated orally with aluminum lactate (400 mg Al/kg/day) during three periods of gestation to determine the treatment's influence on mortality, weight gain, neuromotor maturation, and learning abilities of their pups. No effect of treatment on litter size, mortality rate, and weight gain of pups was detected. In the negative geotaxis test, the scores of pups from females treated during the second and third weeks of gestation were diminished. In the locomotor coordination and the operant conditioning tests, significant differences in the comparison of controls vs. the three treated groups were found, indicating long-term effects of early intoxication upon the central nervous system.

Developmental alternations in offspring of female rats orally intoxicated by aluminum chloride or lactate during gestation.

The oral treatment of pregnant rats by aluminum chloride or lactate at various doses was applied from day 1 to day 21 of gestation to determine its influence on mortality, weight evolution, and neuromotor maturation of their pups. No effect of treatment on litter size was detected, but an increased mortality appeared during the first week: treatment by aluminum lactate was less active than was an equivalent treatment by aluminum chloride. Weight was transitorily delayed, but the reversal of this effect could be attributed to the decrease of litter size. The neuromotor maturation of surviving pups treated with the two aluminum salts showed an important impairment during the first 2 weeks of postnatal life.

Choleretic and hepatoprotective properties of Eupatorium cannabinum in the rat.

According to our results, the traditional therapeutic indications of Eupatorium cannabinum L., choleretic and hepatoprotective effects, have been widely demonstrated. An aqueous extract induces hypercholeresis in the rat, the site of bile formation is canalicular in origin and both bile acid-dependent and bile acid-independent flows could be stimulated; the extract possesses anti-necrotic properties against carbon tetrachloride-induced hepatotoxicity, reducing widely the plasma GPT level in pretreated rats.

Glucose and amino acid metabolism in chick telencephalon slices: changes with incubation conditions and animals' development.

Glucose and amino acid metabolism in 1- and 30-day-old chick telencephalon slices was studied in two incubation media in the presence or in the absence of a continuous oxygenation. Medium 1 has a composition and a tonicity similar to cerebrospinal fluid, medium 2 is hypertonic and does not contain any K+ ions. The incorporation of glucose carbon into amino acids and the distribution of radioactivity between the different amino acids are close to the ones observed in the chick brain in vivo only when the slices are incubated in medium 1, with oxygen at 30 days and without oxygen for the 1-day-old chick. It also appears that if oxygenation is necessary for incubation of mature brain tissue in vitro, the absence of the medium oxygenation is more suitable for the study of glucose metabolism in 1-day-old chick brain slices.

Influence of Anisotes trisulcus and Crepis rueppellii extracts on sites of bile formation in the rat.

Anisotes trisulcus and Crepis rueppellii, two medicinal plants from Yemen, have been investigated for their hepatobiliary properties. A study of their choleretic effect and of sites of bile formation was carried out in the rat, by evaluation of bile flow, bile acids output and 14C-erythritol clearance. The data suggest that both extracts of these plants induce hypercholeresis, but Anisotes would stimulate the bile acid-dependent fraction and Crepis the bile acid-independent fraction.

Effects of prenatal aluminum exposure on neuromotor maturation in the rat.

The oral treatment of pregnant rats with AlCl3 was realized from 8th day of gestation to parturition to determine its influence on the neuromotor development of the young rats with a bank of assessment tests. As the quality of the maternal care has an influence on young rat development, the maternal behavior had also been quantified with different parameters. The results indicated that aluminum, at the two doses (160 and 200 mg/kg), had no effect on food intake, the weight of females and their maternal behavior. On the other hand, pre-weaning mortality was significantly increased in the treated dams' young. Surviving pups showed a delay in their neuromotor development as well as a weight delay during the first postnatal week. Different explicative hypotheses have been considered.

Activity of acetoacetyl--CoA thiolase and regulation of ketone body metabolism in the brain of the developing chick.

The acetoacetyl-CoA thiolase activity was estimated in subcellular fractions isolated from the cerebral hemispheres, the optic lobes and the cerebellum of the chick between the 20th day of embryonic life and the 30th day of postnatal maturation. Acetoacetyl-CoA thiolase is located both in mitochondria and microsomes of the chick brain. Mitochondrial enzyme activity remains high between the 20th day of embryonic life and the 2nd or the 4th day after hatching, depending on the considered brain area. It then decreases until 30 days after hatching. Cytoplasmic thiolase activity remains unchanged during pre- and postnatal development in the cerebral hemispheres; it increases during the same time in the optic lobes. In the cerebellum, cytoplasmic thiolase activity develops in the same way as in mitochondria. The regulation of ketone body utilization by the developing chick brain widely differs from that by the mammalian brain. In the chick, 3-hydroxybutyrate is nearly the single ketone body utilized by the brain. It is converted into acetyl-CoA in the mitochondria and cytoplasm of the chick brain through two exactly parallel pathways involving the participation of the same enzymes.

Activities of 3-oxo acid-CoA transferase and acetoacetyl-CoA synthetase in brain and liver of the developing chick.

The 3-oxo acid-CoA transferase and acetoacetyl-CoA synthetase activities were estimated in subcellular fractions isolated from the cerebral hemispheres, the optic lobes, the cerebellum and the liver of the chick between the twentieth day of embryonic life and the thirtieth day of postnatal development. In the 3 areas of chick brain, the transferase activity increases during the whole postnatal development. Transferase is located both in mitochondria and microsomes unlike in the rat brain where this enzyme is specifically mitochondrial. There is no detectable activity of synthetase in the chick brain. These differences in enzyme localization imply that acetoacetate is converted into acetoacetyl-CoA only by 3-oxo acid-CoA transferase in the mitochondria and cytoplasm of the chick brain, whereas, in the rat brain, this reaction is performed by 3-oxo acid-CoA transferase in mitochondria and by acetoacetyl-CoA synthetase in the cytosol. There is no detectable activity either for transferase or for synthetase in the chick liver.