Biomedical subjects

J Costentin

Publications and source records attributed to J Costentin.

At least 19 recordsLinked to original sources

PubMed1999

Identification of the receptor subtype involved in the analgesic effect of neurotensin.

The neuropeptide neurotensin (NT) elicits hypothermic and naloxone-insensitive analgesic responses after brain injection. Recent pharmacological evidence obtained with NT agonists and antagonists suggests that these effects are mediated by a receptor distinct from the initially cloned high-affinity NT receptor (NTR1). The recent cloning of a second NT receptor (NTR2) prompted us to evaluate its role in NT-induced analgesia. Intracerebroventricular injections in mice of two different antisense oligodeoxynucleotides from the NTR2 markedly decreased NTR2 mRNA and protein and reduced NT-induced analgesia. This effect was specific, because NTR1 levels were unaffected, and sense or scramble oligodeoxynucleotides had no effect. Structure-activity studies revealed a close correlation between the analgesic potency of NT analogs and their affinity for the NTR2 and disclosed potent and selective agonists of this receptor. These data confirm that NTR1 is involved in the NT-elicited turning behavior and demonstrate that the NTR2 mediates NT-induced analgesia.

Analgesics↗

PubMed1999

Evidence for the sequential formation of two complexes between an uptake inhibitor, GBR 12783 [1-[2-(diphenylmethoxy)ethyl]-4-(3-phenyl-2-propenyl)piperazine], and the neuronal transporter of dopamine.

Incubation of a crude synaptosomal fraction from rat striatum with GBR 12783 at 37 degrees C produced an inhibition of the specific uptake of [3H]dopamine that increased with time. The inhibition increased when GBR 12783 was present during preincubation and incubation (IC50 = 1.85+/-0.1 nM) instead of incubation alone (IC50 = 25+/-3.5 nM). Time-course studies of uptake inhibition demonstrated that a first collision transporter-inhibitor complex (TI) was formed immediately after addition of GBR 12783 so that the initial uptake velocity (V0) decreased for increasing concentrations of inhibitor (Ki > or = 20 nM). TI slowly isomerized to a more stable complex TI* (Ki* < or = 5 nM) with a value of t1/2 = 20-270 s. Fits of data to model 2 in which the steady-state uptake (VS) is set to zero were generally preferred, suggesting that formation of TI* could tend to irreversibility, as a consequence of a very low reverse isomerization. As expected, k, V0, and VS tended to steady-state values in an asymptotic manner for high concentrations of GBR 12783. GBR 12783 at 2.5 nM produced a mixed inhibition of the uptake, with an increase in KM and a decrease in Vmax; these effects were improved for 10 nM GBR 12783 and at 20 degrees C. These results are discussed in relation to previous data concerning [3H]GBR 12783 binding. The present work gives the first experimental demonstration that dopamine uptake blockers can act according to a two-step mechanism of inhibition; this is of great interest, because these inhibitors can oppose the effects of cocaine or amphetamine on the transporter according to a reaction that is partly nondependent on the concentration of the abused agent.

Animals↗

PubMed1998

The octadecaneuropeptide ODN inhibits apomorphine-induced yawning in rats.

High concentrations of diazepam-binding inhibitor (DBI) have been detected in brain areas containing dopaminergic cell bodies and nerve terminals. In the present study, we have investigated the effect of a proteolytic fragment of DBI, the octadecaneuropeptide ODN, on apomorphine-induced yawning in Sprague-Dawley rats. Injection of graded doses of ODN (12.5 to 100 ng i.c.v.) caused a dose-dependent inhibition of apomorphine-induced yawning and penile erections. At a dose of 100 ng, intracerebroventricularly administered ODN was able to inhibit, during more than 3 h, the apomorphine-evoked yawning. ODN also inhibited pilocarpine-induced yawning. Apomorphine induces a bell-shaped dose-dependent effect on yawning with a maximum response at the dose of 100 microg/kg and a much lower effect at a dose of 200 microg/kg. Injection (i.c.v.) of 100 ng ODN markedly attenuated the number of yawns induced by 100 microg/kg apomorphine but partially restored the yawning behavior in rats treated with a 200 microg/kg dose of apomorphine. At doses of 0.5 or 5 mg/kg s.c., diazepam did not modify the inhibitory effect of ODN on the apomorphine-induced yawning. Taken together, the present data suggest that ODN inhibits yawning downstream dopaminergic as well as cholinergic synapses involved in yawning. In addition, the effect of ODN cannot be ascribed to an inverse agonistic activity on central-type benzodiazepine receptors.

Animals↗

PubMed1998

Pre-exposure to alcohol does not sensitize to the rewarding effects of cocaine.

The conditioned place preference (CPP) induced by cocaine 2.5 mg/kg was measured in rats pre-exposed to ethanol (14 days with only 10% v/v ethanol followed by a free choice between ethanol solution and water for 14 days). Rats were divided according to their alcohol intake during the free choice period into low-drinking (<3 g/kg per day), intermediate-drinking and high-drinking (> 4 g/kg per day) rats. Cocaine-induced CPP was not modified in high-drinking rats relative to controls. Low-drinking rats had a lower CPP than high-drinking rats and controls. We conclude that pre-exposure to alcohol did not sensitize to the cocaine rewarding effects, and that alcohol low-drinking rats showed the lowest preference for cocaine.

Alcohol Drinking↗

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↗

PubMed1998

Behavioural and neurochemical evidence that the antimicrobial agent oxolinic acid is a dopamine uptake inhibitor.

The antimicrobial agent oxolinic acid, injected i.p. in mice, induced a dose dependent increase in locomotor activity. This stimulation culminated at the 32 mg/kg dose and became smaller for higher doses (64-128 mg/kg). When opposed to increasing doses (50-100-200 microg/kg i.p.) of haloperidol (D2 dopamine receptor antagonist), the stimulant locomotor effect of 32 mg/kg oxolinic acid was not significantly reversed. On the contrary increasing doses (7.5-15-30 microg/kg s.c.) of SCH 23390 (D1 dopamine receptor antagonist) inhibited the stimulant locomotor effect. In mice made completely akinetic by a pretreatment with reserpine (4 mg/kg s.c., 18 h before testing), dexamphetamine (2 mg/kg s.c.) reversed this akinesia and even displayed a stimulant activity, similar to that observed in mice not treated by reserpine. On the contrary, oxolinic acid (32 mg/kg) did not reverse the reserpine induced akinesia and even opposed the reversion induced by dexamphetamine. In a synaptosomal fraction prepared from striatum of rats, oxolinic acid inhibited the 3H dopamine uptake with an IC50 = 4.3+/-0.6 x 10(-6) M. Finally, in mice injected i.v. with a tracer dose of 3H WIN 35428 (1 microCi) (a dopamine uptake blocker), 32 mg/kg oxolinic acid, i.p. administered, reduced by about 50% the specific binding of the radioligand to striatal dopamine carriers. It is concluded that the stimulant locomotor effect of oxolinic acid depends on the blockade of the neuronal dopamine uptake complex.

Animals↗

PubMed1998

The specific dopamine uptake inhibitor GBR 12783 improves learning of inhibitory avoidance and increases hippocampal acetylcholine release.

The specific dopamine uptake inhibitor, GBR 12783 was tested on the retention performance of a one-trial passive avoidance test. For a moderate electric shock intensity, GBR 12783 (10 mg/kg), injected before acquisition session, improved retention performance. Scopolamine (0.125-0.5 mg/kg) completely blocked the promnesic effect of GBR 12783. Moreover, GBR 12783 increased hippocampal acetylcholine release in vivo. These data suggest that the promnesic effect of GBR 12783 is mediated by an increase in the septo-hippocampal cholinergic transmission.

Acetylcholine↗

PubMed1998

Nociceptin-induced apparent hyperalgesia in mice as a result of the prevention of opioid autoanalgesic mechanisms triggered by the stress of an intracerebroventricular injection.

The effects on nociperception of nociceptin/Orphanin FQ (noc/OFQ), the endogenous ligand of the ORL1 (opioid receptor like 1) receptor, have been evaluated in mice upon intracerebroventricular injection of 10 to 10,000 ng doses of the peptide. In the hot plate test (55 degrees C) the licking, rearing and jump latencies were significantly reduced by noc/OFQ (100-250 ng). Noc/OFQ (100-1000 ng) also reduced the latency to tail withdrawal in the tail flick test. In the formalin test (injection in a hind paw of a formalin solution), noc/OFQ (100 ng) increased significantly the duration of paw licking and/or biting at the earliest period of observation. In the writhing test, the number of writhes evoked by intraperitoneal administration of dilute acetic acid was not modified by noc/OFQ at doses in the range of 10-1000 ng, but was decreased by 10,000 ng. The reduction in jump latency in the hot plate test was observed even when mice were pretreated with morphine (2 mg/kg, s.c.). The analgesic effect of acetorphan (5 mg/kg, i.v.) was also reduced by nociceptin (100 ng); on the other hand the hyperalgesic effect of naloxone (4.5 mg/kg, s.c.) was not additive with that of nociceptin (100 ng). Comparing in various tests the nociceptive thresholds of uninjected mice to that of saline i.c.v. injected mice, it appeared that the latter injection induced an increase in these thresholds which was prevented by nociceptin. It is suggested that nociceptin displays hyperalgesic effects by preventing autoanalgesic (opioidergic) mechanisms triggered by the stress elicited by intracerebroventricular injection.

Analgesia↗

PubMed1998

[Cloning of prepronociceptin has led to the discovery of other biologically active peptides].

Among the opioid receptors family, the cloning of the mu, kappa and delta receptors was followed by that of another member, named ORL1 (Opiate Receptor Like 1). In spite of obvious homologies with the mu, kappa and delta receptors, ORL1 does not display a relevant affinity for the endogenous ligands of these former receptors (beta endorphin, enkephalins, dynorphin A...). This observation has prompted to search for an endogenous ligand of ORL1. A heptadecapeptide which fulfils this function, with a nanomolar affinity, has been found. It was named either nociceptin or orphanin FQ. It demonstrates, according either to the dose or to the route of administration, hyperalgesic, allodynic, antiopioidergic or even analgesic effects. It displays also many behavioural effects, modifying especially locomotion, exploratory behaviour, motivation, anxiety, memory, food intake. Nociceptin results from the cleavage of a large precursor protein, prepronociceptin (PPNOC). In this latter, nociceptin is flanked on its C-terminal region by another peptide which may be regarded either as a heptadecapeptide (NocII), or a bidecapeptide (NocIII) according to the inclusion or not of a fragment constituted by 3 arginine residues. Investigating the functions modulated by NocII, we observed that it stimulates locomotor activity of mice and shortens the forepaws licking latency in the hot plate test (55 degrees C); these effects are not shared by NocIII. The simultaneous administration of NocII and nociceptin resulted in animals put on the hot plate to the appearance of their respective effects, not modified by the presence of the other. A 41 amino acid peptide flanks nociceptin on its N-terminal region in PPNOC. It may be cleaved to generate a heptadecapeptide, named nocistatin on account of its antagonist effect on the hyperalgesia/allodynia induced by nociceptin. Thus, the discovery of ORL1 has led to that of nociceptin, that of its precursor PPNOC, and thereby to that of NocII/NocIII and nocistatin. The functions modulated by these peptides are being investigated whereas their receptors are yet unknown. These multiple targets allow to expect new strategies to modulate their functions.

Animals↗

PubMed1998

[Creation of a line of "depressed" mice from a selection of breeders exhibiting a behavioral helplessness].

Antidepressants are used since 40 years. All presently used antidepressants have a slow onset of action and do not improve all patients; thus, there is an absolute need for new antidepressants. A variety of animal models, often based upon the monoaminergic theory of depressive disorders, has been used to screen the current antidepressants. In fact, the main focus of most of these animal models has been to predict the antidepressant potential i.e. to establish predictive validity. However, the evaluation of such animal models should also consider face validity, i.e. how closely the model resembles the human condition, and this should help to identify innovating medicines. Antidepressants, when taken by a healthy person, induce nothing more than side effects, unrelated to an action on mood, whereas they alleviate depressive symptomatology in depressed patients. We have speculated that genetically selected animal models would be closer to the human clinical situation than models based on standard laboratory strains. We have depicted here that marked differences exist between strains of mice in the amount of immobility i.e. "spontaneous helplessness" observed in the tail suspension test, a method used to screen potential antidepressants. We have studied the behavioural characteristics of mice selectively bred for spontaneous high or low immobility scores in the tail suspension test. Hopefully, these selectively bred lines will provide a novel approach to investigate behavioural, neurochemical and neuroendocrine correlates of antidepressant action.

Animals↗

PubMed1998

Sensitization to the rewarding effects of the specific dopamine uptake inhibitor GBR12783.

The conditioned place preference (CPP) induced by increasing doses (1.25-40 mg/kg) of cocaine or the specific dopamine uptake inhibitor GBR12783 was investigated in rats previously treated with cocaine (10 or 20 mg/kg), GBR12783 (10 mg/kg) or morphine (10 mg/kg) for 15 days. In solvent-pretreated rats, cocaine- and GBR12783-induced CPPs were biphasic, with the highest scores observed at 20 mg/kg. Prior exposure to GBR12783 sensitized the rats to the rewarding effects of low doses of either GBR12783 or cocaine. Pretreatment with cocaine 20 mg/kg, but not 10 mg/kg, sensitized the rats to its own rewarding effects. Furthermore, it was less efficient than GBR12783 in sensitizing the animals to the rewarding effects of both drugs. These data confirm the major role of dopamine uptake inhibition in the sensitization process. On the other hand, the magnitude of CPP induced by a high dose of both drugs (20 mg/kg) was decreased after pretreatment with either GBR12783 or cocaine, reaching the lower scores observed at 40 mg/kg. This decrease was unrelated to altered anxiety level but was associated with sensitization to stereotypies. Morphine pretreatment modified neither the CPP induced by high doses of cocaine or GBR12783 nor cocaine- or GBR12783-induced stereotypies. However, prior exposure to morphine sensitized the rats to the rewarding effects of cocaine (2.5 mg/kg) but not to those of GBR12783, suggesting that other mechanisms working in concert with dopamine may facilitate the rewarding effect of cocaine without affecting that of GBR12783.

Animals↗

PubMed1998

[From gene to behavior, a new method for elaboration of new psychotropic agents].

Traditionally, the screening of new neuropsychotropic agents started from the observation of behavioural effects resulting from the administration of a new chemical. Then, one tried to determine its mechanism of action. Since about a decade the way for discovering psychotropic agents tends to be inverse. It starts from the characterization of genes and investigates on their expression products which are new biological targets. Ligands for these targets are developed and then the effects resulting from their administration are considered. In this new strategy, we will consider the cloning of genes and their expression in cultured cells; the knock out of these genes by homologous recombinaison; the extinction of gene expression by antisense oligodeoxynucleotides; the concentration of behavioural phenotypes by selective breeding.

Animals↗

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↗