Biomedical subjects

I Leroux-Nicollet

Publications and source records attributed to I Leroux-Nicollet.

At least 19 recordsLinked to original sources

PubMed2001

Decreased densities of dopamine and serotonin transporters and of vesicular monoamine transporter 2 in severely kainic acid lesioned subregions of the striatum.

Fifteen days after a striatal kainic acid (KA) injection, we have examined presynaptic modifications of dopamine and serotonin terminals in the striatum through (i) autoradiographic labeling of dopamine, serotonin and vesicular monoamine transporters respectively with 3H-mazindol, 3H-citalopram and 3H-dihydrotetrabenazine, and (ii) determination of the contents in dopamine, serotonin and their metabolites. Acetylcholinesterase histochemical labeling enabled the definition of severely and moderately KA-lesioned subregions within the striatum. A significant decrease of the three transporters labeling density was observed only in the severely lesioned subregions. The strong decrease in serotonin transporter labeling revealed here has not been described until now. Besides, the striatal contents of homovanillic acid (dopamine metabolite) and 5-hydroxyindolacetic acid (serotonin metabolite) were significantly increased in the lesioned striatum. The whole data evidence an incomplete sparing of dopamine and serotonin terminals in the striatum 15 days after a KA injection, especially in the areas where the degeneration of postsynaptic neurons was the most extensive.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2000

Reserpine or chronic paroxetine treatments do not modify the vesicular monoamine transporter 2 expression in serotonin-containing regions of the rat brain.

To date, very little information is available about the regulation of vesicular monoamine transporter in central serotonergic regions. The expression of the vesicular monoamine transporter 2 (VMAT2) has been studied in the serotonergic system of the rat brain after an 18 day treatment with the serotonin selective-reuptake inhibitor paroxetine (10 mg/kg, i.p., once daily). This treatment, while increasing serotonergic transmission, did not modify either VMAT2 mRNA expression or (3)H-dihydrotetrabenazine binding site density in any of the studied regions. These results suggest that VMAT2 regulation in the central serotonergic system is not involved in the mechanism of action of antidepressants. In addition, a single administration of reserpine (5 mg/kg, s.c.), while blocking the vesicular monoamine uptake function, had no effect on VMAT2 immunoreactivity in the dorsal raphe nucleus 2 or 30 days after injection. It is concluded that neither a reduction (reserpine) nor an enhancement (paroxetine) of the serotonin transmission induces VMAT2 regulation in serotonergic system in the rat brain.

Animals↗

PubMed1998

Transient expression of the vesicular monoamine transporter during development in the rat thalamus and cortex.

The postnatal developmental pattern of the central vesicular monoamine transporter-2 (VMAT2) was analyzed in the rat brain by means of quantitative autoradiography with a specific and high affinity ligand [3H]dihydrotetrabenazine ([3H]TBZOH). We show a dense expression of VMAT2 in the cortex (especially area 17) and thalamus (particularly the dorsal lateral geniculate nucleus) at postnatal days 1 and 8. This pattern of VMAT2 distribution was transient since it was no longer observed at day 20 or in the adult rat brain where VMAT2 density was weak and uniform in these regions. These data suggest that monoamine vesicular storage participates in the early postnatal maturation of thalamus and cortex.

Animals↗

PubMed1997

Autoradiographic localization of [3H]nociceptin binding sites from telencephalic to mesencephalic regions of the mouse brain.

The binding sites of [3H]nociceptin (also named Orphanin FQ), the endogenous ligand of the ORL1 (opiate receptor like 1) receptor, were localized in the central nervous system of the mouse using an autoradiographic procedure. A high density of binding sites was seen in the cerebral cortex, paraventricular nucleus of the thalamus, amygdaloid complex, suprachiasmatic nucleus, medial thalamus and medial geniculate nucleus. Moderate binding was observed in the nucleus accumbens, lateral septum, lateral thalamus, hippocampus, periaqueductal grey matter and pons. Finally, low levels of binding were seen in the striatum, olfactory tubercle, hypothalamus and substantia nigra. Thus, it appears that the ORL1 receptor is particularly abundant in the cerebral cortex and limbic system of the mouse brain.

Amygdala↗

PubMed1996

Reserpine affects differentially the density of the vesicular monoamine transporter and dihydrotetrabenazine binding sites.

We have studied the effect of a single injection of reserpine (5 mg/kg, s.c.) on the synaptic vesicle monoamine transporter (VMAT) density in the rat striatum, using two labelling procedures: radioimmunolabelling with an antibody against VMAT, and binding of the specific ligand [(3)H]dihydrotetrabenazine ([(3)H]TBZOH). In the rostral and medial striatum, the distribution of VMAT immunoreactivity displayed the highest density in the lateral subregions. In the caudal part of the striatum, VMAT immunoreactivity showed increasing density from dorsal to ventral subregions. The VMAT immunoreactivity was not altered 2 and 30 days after the reserpine injection, whereas [(3)H]TBZOH binding site density, measured on adjacent slices, showed a dramatic decrease at day 2 and a moderate recovery at day 30, suggesting that despite a persistent blockade of [(3)H]TBZOH binding sites, VMAT protein density was unchanged.

Animals↗

PubMed1996

Locomotor sensitization and decrease in [3H]mazindol binding to the dopamine transporter in the nucleus accumbens are delayed after chronic treatments by GBR12783 or cocaine.

Rats were treated once daily for 15 consecutive days with either cocaine or the specific dopamine uptake inhibitor 1-[2- (diphenylmethoxy)ethyl]-4-(3-phenyl-2-(propenyl)-piperazine (GBR12783) at a dose (10 mg/kg) that given acutely increases locomotor activity. Two or 14 days after the last administration, the motor stimulant responses of rats to a challenge dose (5 mg/kg) of the drug administered previously were compared with the motor stimulant responses of rats daily injected with solvent. A sensitization to the acute stimulant locomotor effect of these drugs was only observed 14 days after cessation of chronic treatments. After this withdrawal period, autoradiographic analysis revealed a significant decrease in the desipramine-insensitive [3H]mazindol binding to the dopamine transporter in the shell of the nucleus accumbens. No change was noticed in other regions with high dopamine content: core of nucleus accumbens, striatum, olfactory tubercle, substantia nigra and ventral tegmental area. Absence of concomitant decrease in [3H]dihydrotetrabenazine labeling, which indicates lack of effect on vesicular monoamine transporters, suggests that the decrease in accumbal [3H]mazindol binding did not result from a cytotoxic effect on corresponding dopamine neurons. In addition, 14 days after the last administration of GBR12783, the levels of dopamine and metabolites (dihydroxy-phenylacetic acid, homovanillic acid) and the ability of acute GBR12783 to synergize with haloperidol-induced increase in these metabolites were not modified either in the whole nucleus accumbens or in the striatum.

Animals↗

PubMed1995

Time-course of modifications elicited by reserpine on the density and mRNA synthesis of the vesicular monoamine transporter, and on the density of the membrane dopamine uptake complex.

The long-term effects of a unique injection of reserpine (5 mg/kg s.c.) on the vesicular monoamine transporter and dopamine uptake complex have been investigated, in parallel with behavioral and neurochemical effects. Early after treatment, a dramatic decrease in locomotor activity, as well as a marked depletion in striatal dopamine (DA), associated with a prominent enhancement in dopaminergic turnover were observed in reserpine-treated rats. From 2 to 60 days after reserpine injection, a recovery in locomotor activity occurred, in parallel with an increased DA content in the striatum, reaching about 50% of controls at day 60. At this time, the dopamine turnover was quite normal. The density of the dopamine uptake sites in the striatum, studied with 3H GBR12783, was unchanged after reserpine treatment at any time studied up to 60 days. By contrast, the density of binding sites for 3H dihydrotetrabenazine (3H TBZOH), a marker for the vesicular monoamine transporter, remained dramatically decreased in the striatum all over the time of the study (> -90% of controls at day 2 and -80% at day 30 and 60). A lesser decrease (-60%) was observed in the substantia nigra pars compacta (SNc), 2 and 30 days after reserpine treatment. This suggests that at least 60% of the vesicular monoamine transporter is sensitive to reserpine in this cell bodies region, indicating that this proportion of the transporter is integrated in functional vesicles, a prerequisite for reserpine binding.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗

PubMed1994

Short-term treatments with haloperidol or bromocriptine do not alter the density of the monoamine vesicular transporter in the substantia nigra.

[3H]dihydrotetrabenazine ([3H]TBZOH) was used to label the monoamine vesicular transporter in the rat substantia nigra. An accumulation of neuronal vesicles in the substantia nigra pars compacta was observed after blockade of the fast axonal transport by a microinjection of colchicine (10 micrograms/2 microliters) into the medial forebrain bundle. This accumulation was measured after sustained 2-day pharmacological modifications of the central dopaminergic transmission. It was not modified after s.c. administration of either the direct dopamine (DA) receptor agonist bromocriptine (four injections of 4 or 6 mg/kg) or the DA receptor antagonist haloperidol (four injections of 0.5-1-1.5-2 mg/kg). Thus, it appears that these pharmacological modifications, imposed to the activity of the nigro-striatal dopaminergic system during 2 days, have no consequence on the rate of synthesis of its vesicles.

Animals↗

PubMed1994

Invariance of the density of dopamine uptake sites and dopamine metabolism in the rat brain after a chronic treatment with the dopamine uptake inhibitor GBR 12783.

A chronic treatment (10 mg/kg, twice daily during 9 days) with the dopamine uptake inhibitor GBR 12783 was performed in rats at a dose increasing their locomotor activity. Forty-eight hours after the last administration, animals were sacrificed and 3H mazindol binding was performed on brain slices. Autoradiographic analysis revealed no change in this binding relatively to control animals in regions with high dopamine contents: striatum, nucleus accumbens, olfactory tubercle, substantia nigra and ventral tegmentum area. The treatment did not either modify the levels of dopamine (DA) and metabolites (HVA, DOPAC) both in the striatum and the nucleus accumbens. Thus, early after the end of the treatment, the chronic blockade of the dopamine uptake complex regulates neither the dopamine uptake complex nor the dopamine metabolism.

Afferent Pathways↗

PubMed1994

Comparison of the subregional distributions of the monoamine vesicular transporter and dopamine uptake complex in the rat striatum and changes during aging.

We have studied the heterogeneous distribution of the vesicular monoamine transporter, labelled with 3H dihydrotetrabenazine (3H TBZOH) and the dopamine uptake complex, labelled with 3H GBR12783 in the rat striatum. The ratio TBZOH/GBR12783 was higher in the anterior part of the striatum than in the caudal part. This discrepancy could not be explained by the contribution of serotoninergic innervation to 3H TBZOH binding, since the ratio TBZOH/citalopram was also higher in the anterior striatum than in the caudal striatum. The monoamine vesicular transporter and the dopamine uptake complex were more abundant in the lateral regions than in the regions situated near the midline. In the caudal striatum, the ventral part was richer in vesicular transporter than the dorsal part. In aged rats (30 months), a significant decrease in the density of both transporters was noticed in the middle part of the striatum. In the anterior part of the striatum, the ratio TBZOH/GBR12783 was elevated in aged rats compared to adult ones. This could participate in a functional adaptation of the partially diminished population of dopaminergic neurons during aging.

Aging↗

PubMed1992

Consequences of an intrastriatal injection of kainic acid on the dopaminergic neuronal and vesicular uptake systems.

Intrastriatal kainic acid injection destroys the neurons originating from the striatum, including those on which terminals of the nigro- and meso-striatal dopaminergic neurons project. We have studied at various times the consequences of this lesion on dopamine metabolism and on the neuronal and vesicular transporters. Two and 15 days after kainic acid injection, whereas dopamine turnover was increased and the dopamine content unchanged, there was no modification in the binding of [3H]GBR 12783, a marker of the neuronal uptake complex, but the binding of [3H]dihydrotetrabenazine, a marker of the vesicular transporter, was significantly decreased. At later times (30 and 60 days) when the dopamine turnover was decreased as well as the dopamine content, the binding of [3H]dihydrotetrabenazine was more dramatically decreased (about 30% of controls) than that of [3H]GBR 12783. In addition autoradiography showed an increase in the density of [3H]dihydrotetrabenazine binding sites in the substantia nigra. Thus it appears that the long-term (60 days) repercussions of a kainic acid lesion affect simultaneously the dopamine turnover (which is decreased) and the vesicular transporter whereas the dopamine uptake complex is little affected.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1992

Kainic acid lesion of the striatum increases dopamine release but reduces 3-methoxytyramine level.

Kainic acid lesion of the striatum leads to the disruption of the striatonigral regulatory loop. Although microdialysis showed an increase in dopamine release, two days after kainic acid injection, 3-methoxytyramine levels are dramatically decreased. This suggests that the postsynaptic membrane-bound catechol-O-methyltransferase (COMT), but not the glial COMT, is responsible for the formation of measured 3-methoxytyramine.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1990

Postnatal development of the monoamine vesicular transporter in mesencephalic and telencephalic regions of the rat brain: a quantitative autoradiographic study with [3H]dihydrotetrabenazine.

[3H]Dihydrotetrabenazine [3H]TBZOH, a high affinity ligand of the monoamine vesicular transporter, has been used to study by autoradiography the development of monoaminergic synaptic vesicles from birth to adulthood, in the rat brain. The study was focused on dopaminergic areas. Binding sites for [3H]TBZOH were already detectable in 1-day-old rats, and the affinity for the ligand was identical in the striatum of 8-day-old and adult rats. The density of binding sites almost attained the adult level at day 20 postnatal in regions rich in dopaminergic cell bodies (substantia nigra pars compacta and ventral tegmental area), as well as in the lateral septum. In the striatum, nucleus accumbens, and olfactory tubercle, the increase in binding sites density was progressive from birth to adulthood. This increase was more pronounced in the olfactory tubercle.

Aging↗

PubMed1988

In vivo and in vitro autoradiographic labelling of central dopaminergic systems with [3H]GBR12783 in rodents.

Labelling of central dopaminergic systems with the dopamine uptake inhibitor [3H]GBR12783 was performed in vivo in mice by i.v. injection of a tracer dose of the ligand (40 microCi) 1 h before sacrifice. Autoradiographic pictures obtained from these experiments were quantified. The data were compared to those obtained by in vitro labelling of rat brain slices with this ligand. Significant specific labelling was observed both in vivo and in vitro in the striatum, the nucleus accumbens, the olfactory tubercle and the substantia nigra.

Animals↗

PubMed1988

Involvement of norepinephrine neurons in the hypothermia induced by intracerebroventricular administration of 6-hydroxydopamine in mice, evidenced by antidepressants.

The intracerebroventricular (i.c.v.) administration of increasing doses of 6-hydroxydopamine (6OHDA) (12.5-50 micrograms) induces in mice a dose-dependent hypothermic effect. This hypothermic effect is not affected either by serotonin uptake inhibitors (indalpine, clomipramine, trazodone, fluoxetine) or by dopamine uptake inhibitors (GBR 12783, amineptine). On the contrary, the hypothermia is partly antagonized by norepinephrine uptake inhibitors (desipramine, nomifensine, viloxazine, maprotiline, protryptiline), as well as amfonelic acid. The antagonism elicited by desipramine is observed when the drug is administered intraperitoneally (from 5 mg/kg) or intracerebroventricularly (from 5 microgram per mouse). 6-hydroxydopamine-induced hypothermia is antagonized by imipramine after a time lag of 1 hour; this antagonism lasts 6-11 hours after intraperitoneal administration of the drug (20 mg/kg). The hypothermic effect of 6-hydroxydopamine is diminished by a previous 6-hydroxydopamine i.c.v. administration (50 micrograms, 7 days before), except in mice pretreated with desipramine at the time of the first 6-hydroxydopamine injection. The hypothermic effect is completely abolished by two previous 6-hydroxydopamine i.c.v. administrations (50 micrograms, 7 days interval). It is also decreased in mice receiving DSP4 15 days before testing (50 mg/kg, i.p.). Finally, neither haloperidol (0.5 mg/kg i.p.) nor SCH23390 (100 micrograms/kg s.c.) antagonize 6-hydroxydopamine-induced hypothermia. It is concluded that this effect is largely depending on central norepinephrine neurons.

Animals↗

PubMed1985

The effects of 17 alpha-ethynyloestradiol and of acute inflammation on the plasma concentration of rat alpha 1-acid glycoprotein and on the induction of its hepatic mRNA.

We measured the serum concentration of alpha 1-acid glycoprotein (alpha 1-AGP) and we evaluated the content of its hepatic mRNA in rats after 17 alpha-ethynyloestradiol treatment or after turpentine-induced acute inflammation, or after both treatments performed simultaneously. We have also studied the affinity of serum alpha 1-AGP for concanavalin A under these conditions. Both types of stimuli induce a marked retention of the glycoprotein on free concanavalin A. The serum concentration of alpha 1-AGP is increased about 14-fold compared with that in control rats when a single pharmacological dose (50 micrograms) or multiple injections of 17 alpha-ethynyloestradiol are administered. This increase is greater in turpentine-oil-injected rats (about 21-fold) and reaches a maximum (about 32-fold) in rats injected with 17 alpha-ethynyloestradiol plus turpentine oil; this increase in alpha 1-AGP corresponds to the addition of the effects of the two inducing agents. Similar changes are also observed either in the alpha 1-AGP mRNA content as estimated by using an alpha 1-AGP-specific cDNA probe, or in the amount of translatable alpha 1-AGP mRNA. The results indicate that: after a high dose of 17 alpha-ethynyloestradiol and after acute inflammation, the increase of the alpha 1-AGP serum concentration is due to an accumulation of the alpha 1-AGP mRNA; different mechanisms and/or pathways are probably involved in regulating the synthesis of alpha 1-AGP under various stimuli; 17 alpha-ethynyloestradiol as well as acute inflammation seem to control the glycosylation process of alpha 1-AGP in an identical manner.

Animals↗

PubMed1985

Differential responsiveness of cultured suckling and adult rat hepatocytes to growth-promoting factors: entry into S phase and mitosis.

The capacity of suckling and adult rat hepatocytes in culture to enter into S phase and mitosis in response to EGF, insulin, and glucagon was measured. Both cell types were isolated in high yield and purity and cultured in the absence of serum under identical conditions. At the time of isolation, suckling rat hepatocytes were all diploid and in the G1 phase of the cell cycle. Adult rat hepatocytes constituted a population of mixed ploidy level, as shown by flow cytometry. Upon stimulation, both suckling and adult rate hepatocytes entered S phase after a minimum lag period of 24 h. For suckling rat hepatocytes EGF was required, but its stimulating action was dependent on insulin and/or glucagon. In contrast, adult rat hepatocytes entered into S phase in response to EGF alone; insulin and glucagon did not significantly potentiate its effect. Under optimal hormonal stimulation for entry into S phase a large proportion of suckling rat hepatocytes underwent mitosis, whereas only a few mitoses were observed in the case of adult rat hepatocytes. Therefore, there is a differential response of suckling and adult rat hepatocytes to growth factors which correlates with ploidy level, and this difference may be associated with the degree of maturation.

Aging↗

PubMed1985

Dexamethasone can modulate the synthesis and organization of cytokeratins in cultured differentiating rat hepatocytes.

Dexamethasone, added to suckling rat hepatocytes cultured in serum-free medium supplemented with insulin and epidermal growth factor (EGF), caused a selective dose-dependent increase in cytokeratin synthesis. The response was dependent on the initial hepatocyte density. At 5 X 10(4) hepatocytes/cm2 a concentration of 1 or 10 microM dexamethasone, in the presence of insulin, enhanced the synthesis of a 55 000 relative mass (Mr) cytokeratin and to a lesser degree a 49 000 Mr cytokeratin, whereas at 1 X 10(5) hepatocytes/cm2 10 microM dexamethasone preferentially stimulated a 51 000 Mr component. Preferential synthesis of the 51 000 Mr component also occurred when either 1 or 10 microM dexamethasone was added to cultures seeded at 2 X 10(5) hepatocytes/cm2. The inclusion of EGF along with dexamethasone and insulin in cultures at 2 X 10(5) cells/cm2 yielded a differential effect of dexamethasone concentration equivalent to that observed at the lower cell density in absence of EGF. Under conditions where increased cytokeratin synthesis was observed, the hepatocytes maintained a high production of albumin and lost their capacity to produce alpha-fetoprotein, a change in gene expression associated with the normal differentiation of suckling rat hepatocytes. In contrast, no enhancement of cytokeratin synthesis was observed in hepatocytes following addition of EGF and insulin only, a condition that promoted hepatocyte growth and the maintenance of alpha-fetoprotein production. The dexamethasone-induced enhancement of cytokeratin synthesis was still present at 3 days postseeding. At this time, morphological observations by phase-contrast and immunofluorescence microscopy using monoclonal antibodies against the 55 000 and 49 000 Mr components revealed that under growth-promoting conditions the hepatocytes were spread and the cytokeratin filaments were stretched, whereas under differentiation-promoting conditions the cultures constitute a compact monolayer of cells exhibiting highly ordered filaments. These data suggest a close relationship between synthesis and organization of cytokeratins and promotion of differentiation of suckling rat hepatocytes by glucocorticoids.

Animals↗