Biomedical subjects

J Costentin

Publications and source records attributed to J Costentin.

At least 19 recordsLinked to original sources

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↗

PubMed1998

The octadecaneuropeptide ODN induces anxiety in rodents: possible involvement of a shorter biologically active fragment.

The octadecaneuropeptide ODN has been originally characterized as an endogenous ligand of central-type benzodiazepine receptors, on its ability to displace the anxiogenic compound beta-[3H]carboline-3-carboxylate methyl ester from its binding sites. The aim of the present study was to investigate the anxiogenic effects of intracerebroventricular administration of ODN in mice and rats. At doses ranging from 10 to 100 ng, ODN increased in mice the latency to explore a white compartment when the animals were placed in a black one. ODN also reduced the first stay duration in the white compartment. These effects were antagonized by diazepam (0.075 mg/kg, s.c.) as well as flumazenil (1 mg/kg, s.c.), indicating that ODN acts as an inverse agonist on central-type benzodiazepine receptors. In rats, ODN reduced the latency to enter a black compartment when the animals were placed in the white one. In the plus-maze elevated test, ODN reduced, in both mice and rats, the number of entries and the time spent in the open arm. In mice, ODN (100 ng) increased the thigmotaxis index, i.e. the distance traveled in the peripheral zone of the open field. Time-course studies revealed that a significant effect of ODN (100 ng) in the black/white compartment test was only observed 40 min after the injection and lasted between 3 and 6 h. The effect of a 1000-ng dose of ODN appeared more tardily than that of a 10-ng dose. In addition, a 1000-ng dose of ODN occluded the early effect of a 100-ng dose on the white compartment first stay duration. The COOH-terminal octapeptide of ODN was more rapidly effective than ODN in the black/white compartment test, suggesting that the anxiogenic effect of the peptide requires the formation of biologically active proteolytic fragment.

Amino Acid Sequence↗

PubMed1997

Aggressiveness, hypoalgesia and high blood pressure in mice lacking the adenosine A2a receptor.

Adenosine is released from metabolically active cells by facilitated diffusion, and is generated extracellularly by degradation of released ATP. It is a potent biological mediator that modulates the activity of numerous cell types, including various neuronal populations, platelets, neutrophils and mast cells, and smooth muscle cells in bronchi and vasculature. Most of these effects help to protect cells and tissues during stress conditions such as ischaemia. Adenosine mediates its effects through four receptor subtypes: the A1, A2a, A2b and A3 receptors. The A2a receptor (A2aR) is abundant in basal ganglia, vasculature and platelets, and stimulates adenylyl cyclase. It is a major target of caffeine, the most widely used psychoactive drug. Here we investigate the role of the A2a receptor by disrupting the gene in mice. We found that A2aR-knockout (A2aR-/-) mice were viable and bred normally. Their exploratory activity was reduced, whereas caffeine, which normally stimulates exploratory behaviour, became a depressant of exploratory activity. Knockout animals scored higher in anxiety tests, and male mice were much more aggressive towards intruders. The response of A2aR-/- mice to acute pain stimuli was slower. Blood pressure and heart rate were increased, as well as platelet aggregation. The specific A2a agonist CGS 21680 lost its biological activity in all systems tested.

Adenosine↗

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↗

PubMed1997

Involvement of cholinergic neurons in the release of dopamine elicited by stimulation of mu-opioid receptors in striatum.

The involvement of striatal cholinergic neurons in the release of dopamine (DA) elicited by the mu-opioid receptor agonist DAGO ([D-Ala2, NMePhe4-Gly5(ol)]enkephalin) was explored. The striatal release of DA was measured by microdialysis in rats anesthetized with chloral hydrate. When infused in the striatum, through the microdialysis probe, DAGO increased the extracellular levels of DA. The previous injection in striatum of AF 64-A, a toxin for cholinergic neurons, or the concomitant infusion of the M2-muscarinic antagonist methoctramine abolished the effect of DAGO on the DA release. It is concluded that stimulation of mu-opioid receptors, by inhibiting the acetylcholine release which stimulates tonically M2-muscarinic receptors likely associated with dopaminergic nerve endings, indirectly increases the striatal DA release.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1997

Orphan neuropeptide NocII, a putative pronociceptin maturation product, stimulates locomotion in mice.

NocII is a heptadecapeptide whose sequence lies immediately downstream of nociceptin, the newly discovered natural agonist of the ORL1 receptor, in pronociceptin, nociceptin's precursor polypeptide. Since the sequence of NocII is framed by putative convertase excision sites and it totally conserved across murine and human species, we have sought to determine whether this orphan neuropeptide might by physiologically significant, i.e. endowed with central biological activity in vivo. Intracerebroventricular administration of 10 and 100 ng of NocII increased locomotion in mice. However, unlike nociceptin, which stimulates both the horizontal and vertical (rearing) components of locomotion, NocII affected only the horizontal component. The motor stimulant action of NocII appears to depend largely on dopamine transmission since it is totally reversed by the D1 or the D2 dopamine receptor antagonists SCH 23390 and haloperidol. NocII does not modify the number of explored holes in the hole board test, indicating that, unlike nociceptin, the orphan peptide does not affect exploratory behavior in mice.

Amino Acid Sequence↗

PubMed1997

Individual differences in response to imipramine in the mouse tail suspension test.

The tail suspension test is a behavioural primary screen for detecting potential antidepressant drugs. In this test, a reduction of duration of immobility after treatment with imipramine is obtained in mice of the NMRI strain but not of the CD1 strain. The present experiments evidence important differences between individuals of the latter strain in both the amount of immobility observed in naive mice and the effects of three antidepressants. The reproducibility of the tail suspension-induced behavioural despair was high in individual CD1 male mice and allowed a preselection of spontaneous high and low immobility scorers. Only the high immobility scorers were responsive to imipramine (30 mg/kg), desipramine (30 mg/kg) and paroxetine (10 mg/kg). The percentage of spontaneous high immobility scorers was higher in NMRI (50%) than in CD1 (20%) mice, justifying the use of the former strain for screening potential antidepressants. However, controlling for individual differences in the spontaneous performance in this animal model of depression may provide a useful tool to study behavioural, neurochemical and neuroendocrine correlates of antidepressant action.

Animals↗

PubMed1997

Mechanism of the hypothermic effect of MPP+ administered centrally in mice.

The neurotoxin methyl phenyl pyridinium (MPP+) was administered intracerebroventricularly (i.c.v.) to mice. From the 1.25 microg dose per mouse, MPP+ elicited a dose-dependent hypothermic effect from doses as low as 1.25 microg per mouse. The minimal lethal dose was determined to be between 17.5 and 20 microg per mouse. The hypothermia induced by 2.5 microg MPP+ was unaffected by pretreatment with propranolol (8 mg/kg, i.p.), scopolamine (5 mg/kg, s.c.) and haloperidol (250 microg/kg, i.p.). It was decreased by yohimbine (4 mg/kg, s.c.), idazoxan (5 mg/kg, s.c.) and desipramine (20 mg/kg, i.p.). In mice injected i.c.v. with 6 hydroxydopamine (50 microg, 8 days before testing with MPP+ 2.5 microg), a significant reduction in the hypothermic effect of MPP+ was observed. A similar 6 OHDA injection has been shown previously to reduce by about 40% the DA striatal content of DA and by about 70% the hypothalamic content of NE. On the contrary, in mice injected with MPP+ (17.5 microg, 8 days before testing with 50 microg 6 OHDA) there was no modification in the hypothermic effect of 6 OHDA (50 microg). This injection of MPP+ reduced by about 40% the striatal content of DA but did not affect the hypothalamic content of NE. It is concluded that MPP+ decreases body temperature, at least in part, by acting as an indirect NE agonist, which stimulates alpha2 adrenoreceptors. In contrast, this agent in the present experimental conditions, does not destroy NE neurons in opposition to its action on DA neurons.

1-Methyl-4-phenylpyridinium↗

PubMed1996

Nociceptin stimulates locomotion and exploratory behaviour in mice.

The recently characterized heptadecapeptide nociceptin, the endogenous agonist of the orphan opioid receptor-like 1 (ORL1 receptor), has been tested for its effects on locomotion and exploratory behaviour in mice. I.c.v. administration of as little as 10 ng of nociceptin/animal stimulated locomotor activity. This effect was dose-dependent, increasing in intensity up to 100 ng and in duration for doses in the range of 1000-10000 ng. The stimulation of horizontal locomotion elicited by 100 ng nociceptin was accompanied by a stimulation of the vertical component of locomotion. These effects were not reversed by high doses (1.5 and 4.5 mg/kg s.c.) of the opioid receptor antagonist naloxone. Increasing doses of the dopamine D2 receptor antagonist haloperidol (0.1-0.5 mg/kg i.p.) as well as of the dopamine D1 receptor antagonist SCH 23390 [R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1 H-3-benzazepine hydrochloride] (0.0075-0.03 mg/kg s.c.) reversed this effect, suggesting that nociceptin exerts its motor-stimulant actions by increasing central dopaminergic transmission. Nociceptin was also found to increase the number of head dips in the hole-board test, indicating that the peptide stimulates exploratory behaviour.

Animals↗

PubMed1996

A genetic mouse model of helplessness sensitive to imipramine.

Lines of mice were selectively bred to diverge in their spontaneous helplessness in the tail suspension test. By the second generation of selection, only mice of the helpless line were sensitive to the antidepressant imipramine. Genetic factors substantially contribute to the susceptibility to helplessness in this mouse model. These selectively bred lines may represent potentially useful animal models to investigate behavioural, neurochemical and neuroendocrine correlates of antidepressant action.

Animals↗

PubMed1996

Place conditioning with cocaine and the dopamine uptake inhibitor GBR12783.

The rewarding and locomotor effects of the specific dopamine uptake inhibitor GBR12783 (2.5-20 mg kg-1, i.p.) were compared with those of cocaine. For both drugs, all doses produced a conditioned place preference (CPP), even the dose of 2.5 mg kg-1, which did not modify the locomotor activity. Despite an equivalent locomotor stimulation, the magnitude of CPP induced by cocaine (10 mg kg-1) was greater than that induced by the same dose of GBR12783. This confirms the involvement of dopamine uptake inhibition in reward, but underlines differences in relative efficacies in rewarding and motor effects of both drugs and suggests that these two properties are, at least in part, separable anatomically or functionally.

Animals↗

PubMed1996

A C-terminal cyclic 8-13 neurotensin fragment analog appears less exposed to neprilysin when it crosses the blood-brain barrier than the cerebrospinal fluid-brain barrier in mice.

A C-terminal cyclic 8-13 neurotensin fragment analog. JMV 1193, a direct agonist of central neurotensin receptors, is able to cross both the cerebrospinal fluid-brain barrier and the blood-brain barrier. When administered intracerebroventricularly (i.c.v.), its hypothermic effect was potentiated by the enkephalinase inhibition induced either by thiorphan (simultaneous intracerebroventricular administration of 10 micrograms) or by the thiorphan prodrug. acetorphan (intravenous (i.v.) administration of 10 mg/kg). Such a potentiation was not observed when both JMV 1193 and acetorphan were administered intravenously. Therefore it appears that the sensitivity of JMV 1193 to enkephalinase depends on its route of administration. It is exposed to this peptidase after i.c.v. injection (when crossing the cerebrospinal fluid-brain barrier), while it is not after i.v. administration (when crossing the blood-brain barrier).

Animals↗

PubMed1996

Complex ionic control of [3H]GBR 12783 binding to the dopamine neuronal carrier.

At 20 degrees C, [3H]GBR 12783, {1-[2-(diphenylmethoxy)ethyl]4-(3-phenyl-2-([1-3H]propenyl)-pip era zine} dissociated from the dopamine neuronal carrier present in rat striatal membranes with a t1/2 value of 27 min. At this temperature, KCI, CaCl2 and MgCl2 increased the binding dissociation, revealing that they recognize a binding site which is not mutually exclusive with that of [3H]GBR 12783. The comparison of the ability of KCl to increase the binding dissociation (by 160% at 30 mM KCl) with its potency as a binding inhibitor (Ki-2.6 +/- 0.3 mM) suggests an involvement of two recognition sites for K+ in binding inhibition, a not mutually exclusive site and another, mutually exclusive, site. Divalent cations mainly inhibited the binding via a mutually exclusive site since 3 mM Ca2+ and 10 mM Mg2+ increased the binding dissociation by 90% at 20 degrees C whereas their Ki values were 0.049 +/- 0.006 and 0.141 +/- 0.035 mM, respectively. Involvement of this mutually exclusive site was also supported by the persistence of the binding inhibition elicited by Ca2+ and Mg2+ at 0 degree C, a temperature at which they reduced the binding dissociation. At 20 degrees C, 100 mM NaCl did not modify [3H]GBR 12783 binding but it antagonized the binding dissociation elicited by inhibitory cations. Ca2+ reduced the off-rate of [3H]GBR 12783 binding at 0 degree C and in the presence of 100 mM Na+. Finally, [3H]GBR 12783-binding dissociation was increased by high 'cytosolic' K+ while 'synaptic' concentrations of Na+, K+, Ca2+, Mg2+ and Cl- were ineffective. A reduction of H2PO4-/HCO3- from 10 to 5 mM and a substitution of 5 mM H2PO4-/HCO3- by 5 mM Cl- increased the binding dissociation, suggesting that an anion-binding site could also regulate the binding.

Animals↗

PubMed1996

Locomotor sensitization to [D-Trp(11)]neurotensin after repeated injections of the dopamine uptake inhibitor GBR12783 in rats.

Rats received one daily i.p. injection of the dopamine uptake inhibitor GBR12783 (1-[2-(diphenylmethoxy)ethyl]4-(3-phenyl-2-(propenyl)-piperazine) (10mg/kg) or vehicle for 9 days. Fourteen days after discontinuing treatment, their locomotor activity was assessed after injection of GBR12783 (5 mg/kg) or vehicle, then 6 days later, after i.c.v. injection of [D-Trp(11)]neurotensin (750 ng) or saline. A sensitization to the stimulant locomotor effects of both GBR12783 and [D-Trp(11)]neurotensin occurred in rats exposed to the actimeter following the 1st, 5th and 9th injections of GBR12783. Rats without prior experience of the activity cages before the challenge tests showed no sensitization to either GBR12783 or [D-Trp(11)] neurotensin. Our data suggest that a similar mechanism may underlie the locomotor sensitization to GBR12783 and the heterosensitization to [D-Trp(11)]neurotensin.

Animals↗

PubMed1996

Pharmacological modifications of dopamine transmission do not influence the striatal in vivo binding of [3H]mazindol or [3H]cocaine in mice.

We have considered the in vivo striatal binding of two ligands of the neuronal dopamine uptake complex: [3H]cocaine and [3H]mazindol. The [3H]cocaine tracer dose labelled the dopamine uptake complex in striatum but not the noradrenaline complex in cerebellum. On the contrary, the [3H]mazindol tracer dose induced a marked labelling of the noradrenaline uptake complex in cerebellum; its prevention by desipramine (5 mg/kg) increased simultaneously the cerebral bioavailability and thereby the striatal labelling of the dopamine transporter. In mice submitted to treatments modifying dopaminergic transmission either to decrease it (gammabutyrolactone, 750 mg/kg, i.p.) or to increase it (L-DOPA, 200 mg/kg, i.p., dexamphetamine, 4 mg/kg, s.c., or their combination), only dexamphetamine pretreatment significantly reduced [3H]cocaine and [3H]mazindol binding. Thus it appears that the level of dopamine transmission would not interfere with the in vivo quantification of striatal dopamine uptake sites assessed with either ligands.

4-Butyrolactone↗

PubMed1996

Effect of low concentrations of K+ and Cl- on the Na(+)-dependent neuronal uptake of [3H] dopamine.

The specific uptake of [3H] dopamine (DA) was studied using a crude synaptosomal fraction obtained from rat striatum. In a medium containing a 10 mM NaHCO3/NaH2PO4 buffer and no added K+ ions, addition of NaCl elicited an increase in DA uptake for Na+ concentrations from 10 to 60 mM, and then a decrease of uptake for Na+ concentrations up to 130 mM. These data confirm that rather low NaCl concentrations produce a maximal DA uptake. This biphasic curve of uptake resulted from significant changes in the Vmax of the DA uptake. Except for 10 mM Na+, this curve was not significantly modified when 9 mM NaHCO3/NaH2PO4 were replaced by 9 mM NaCl. This result indicates that the Cl- dependence of the DA uptake is mainly secondary to the Na+ dependence. Addition of KCl up to 3 mM did not modify the ascending part of the NaCl-dependent uptake curve. In contrast, the reduction in uptake produced by high Na+ concentrations was prevented in a concentration-dependent manner by KCl; this effect resulted from a decrease in the Km and an increase in the Vmax for the uptake. Measurements of membrane potential, with the help of the fluorescent probe 3, 3'-diethylthiadicarbocyanine iodide [DiSC2(5)] and purified synaptosomes prepared from rat striatum and cerebral cortex, revealed that addition of 3 mM KCl to a medium containing a high Na+ concentration and no K+ ions produced a marked and stable decrease in the fluorescence level. This decrease which corresponds to an increase in membrane polarization was blocked by 0.1 mM ouabain. These data suggest that low K+ concentrations are likely to prevent the decrease in uptake elicited by high Na+ concentrations by restoration, via a Na+/K+ ATPase-mediated mechanism, of the membrane potential and/or a transmembrane electrochemical Na+ gradient more favourable to DA uptake.

Analysis of Variance↗

PubMed1996

In vivo striatal binding of the D1 antagonist SCH 23390 is not modified by changes in dopaminergic transmission.

The in vivo striatal binding of [3H]SCH 23390, an antagonist of the D1 dopamine receptors, was investigated in mice submitted to pretreatment to either decrease (gammabutyrolactone 750 mg/kg, i.p.) or, increase (3,4-dihydroxyphenylalanine (L-DOPA) 200 mg/kg i.p. plus dexamphetamine 4 mg/kg, s.c.) dopaminergic transmission. Such conditions failed to modify [3H]SCH 23390 binding. However, we observed that dopamine (at concentrations > or = 1 microM), reduced the in vitro binding of [3H]SCH 23390 in membrane fractions. These results suggest that modifications in dopamine neurotransmission do not alter the in vivo quantification of D1 receptors with [3H]SCH 23390, for example, in studies that use positron emission tomography.

4-Butyrolactone↗

PubMed1996

Indirect dopamine agonists effects on despair test: dissociation from hyperactivity.

Both dexamphetamine and the pure dopamine reuptake inhibitor GBR 12783 elicit a stimulation of locomotion and increase swimming activity in the behavioral despair test in mice. The dopamine D1 dopamine receptor antagonist SCH 23390 dose dependently (7.5-30 micrograms/kg s.c.) antagonized the stimulant locomotor effect on both drugs but did not prevent their antiimmobility effect on the behavioral despair test. The D2 dopamine receptor antagonist haloperidol dose dependently (12.5-50 micrograms/kg i.p.) antagonized the effects of dexamphetamine on both locomotor activity and behavioral despair test. By contrast, haloperidol inhibited the effects of GBR 12783 in the forced swimming test but not on locomotion. It is concluded that indirect dopamine agonists are effective on the behavioral despair test independently of a stimulation of locomotor activity. Their effects on the despair test depend on the stimulation of D2 but not D1 dopamine receptors.

Animals↗