Biomedical subjects

Jean Costentin

Publications and source records attributed to Jean Costentin.

At least 19 recordsLinked to original sources

PubMed2006

Pharmacological characterization of the receptor mediating the anorexigenic action of the octadecaneuropeptide: evidence for an endozepinergic tone regulating food intake.

Peptides of the endozepine family, including diazepam-binding inhibitor, the triakontatetraneuropeptide, and the octadecaneuropeptide (ODN), act through three types of receptors, that is, central-type benzodiazepine receptors (CBR), peripheral-type (mitochondrial) benzodiazepine receptors (PBR) and a metabotropic receptor positively coupled to phospholipase C via a pertussis toxin-sensitive G protein. We have previously reported that ODN exerts a potent anorexigenic effect in rat and we have found that the action of ODN is not affected by the mixed CBR/PBR agonist diazepam. In the present report, we have tested the possible involvement of the metabotropic receptor in the anorexigenic activity of ODN. Intracerebroventricular administration of the C-terminal octapeptide (OP) and its head-to-tail cyclic analog cyclo(1-8)OP (cOP) at a dose of 100 ng mimicked the inhibitory effect of ODN on food intake in food-deprived mice. The specific CBR antagonist flumazenil and the PBR antagonist PK11195 did not prevent the effect of ODN, OP, and cOP on food consumption. In contrast, the selective metabotropic endozepine receptor antagonist cyclo(1-8)[DLeu(5)]OP (100-1000 ng; cDLOP) suppressed the anorexigenic effect of ODN, OP, and cOP. At the highest concentration tested (1000 ng), cDLOP provoked by itself a significant increase in food intake. Taken together, the present results indicate that the anorexigenic effect of ODN and OP is mediated through activation of the metabotropic receptor recently characterized in astrocytes. The data also suggest that endogenous ODN, acting via this receptor, exerts an inhibitory tone on feeding behavior.

Animals↗

PubMed2006

Interactions between NTS2 neurotensin and opioid receptors on two nociceptive responses assessed on the hot plate test in mice.

The intracerebroventricular administration of the tridecapeptide neurotensin (NT) produces strong analgesic effects in tests evaluating acute pain. We investigated whether these effects are mediated by the opioid receptors. In the hot plate test, the NT receptors agonist NT1 (N(alpha)Me-Arg-Lys-Pro-Trp-Tle-Leu), s.c. injected (0.3-3 mg/kg), increased paw licking and jump latencies. These effects were inhibited by the NTS2 antagonist levocabastine (2.5 mg/kg, i.p.) but not by the selective NTS1 antagonist SR48692 (3 mg/kg, i.p.). The opioid receptor antagonist naloxone did not modify (up to the dose of 4.5 mg/kg, s.c.) the NT1 effect on licking, but abolished the increase in the jump latency (from the dose of 1.5 mg/kg). In mice made tolerant to the analgesic effect of morphine (2 mg/kg, s.c.) by previous morphine injections (32 mg/kg, s.c., twice a day, 4 days), NT1 maintained its effect on licking, but its effect on jump latency was suppressed. Levocabastine (up to the dose of 4.5 mg/kg) failed to antagonize the effects of morphine (2 mg/kg, s.c.) on both licking and jump latencies. In mice made tolerant to the analgesic effect of NT1 (0.3 mg/kg, s.c.) by previous NT1 injections (3 mg/kg, s.c., twice a day, 4 days) morphine maintained its analgesic effects both on licking and jumping latencies. We can conclude that neurotensinergic and opioidergic transmissions are functionally independent as regards the licking response. However, in the jump response, neurotensinergic transmission seems to regulate opioidergic transmission, inducing its stimulation.

Analgesia↗

PubMed2006

Coupling of ORL1 (NOP) receptor to G proteins is decreased in the nucleus accumbens of anxious relative to non-anxious mice.

We studied the involvement of endogenous ORL1 (NOP) receptors in the anxiety state. In mice selected as "anxious" and "non-anxious", ORL1 (NOP) receptor has been analysed by means of two autoradiographic approaches: [3H]nociceptin binding and nociceptin-stimulated [35S]GTPgammaS binding. We show that differences in anxiety state are associated with differences in G protein coupling efficiency of ORL1 (NOP) receptor in the nucleus accumbens, without any change in the density of the receptors.

Animals↗

PubMed2006

Antidepressant-like effect of endomorphin-1 and endomorphin-2 in mice.

Endomorphin-1 (Tyr-Pro-Trp-Phe-NH(2)) and endomorphin-2 (Tyr-Pro-Phe-Phe-NH(2)) are two recently isolated mu-opioid selective peptides with a potent antinociceptive activity, involved in a number of physiological processes, including food intake, vasomotricity, sexual behavior, as well as neuroendocrine and cardiorespiratory functions. The neuroanatomical distribution of endomorphins prompted us to study their antidepressant activity in two animal behavioral models of depression: forced-swimming and tail-suspension tests. In both tests, the intracerebroventricular (i.c.v.) injection of either endomorphin-1 or endomorphin-2 significantly decreased the duration of immobility, interpreted as an expression of 'behavioral despair', which could be related to the depression syndrome. These effects of endomorphins did not result from the stimulation of the animal motor activity. We have also demonstrated that the antidepressant-like effect of endomorphins was antagonized by the universal opioid antagonist, naloxone and the mu-opioid receptor selective antagonist, beta-funaltrexamine. In contrast, this effect was not antagonized by delta- and kappa-opioid receptor selective antagonists, naltrindole and nor-binaltorphimine, respectively. The results of the present study demonstrate that endomorphin-1 and endomorphin-2 produce potent antidepressant-like effects after i.c.v. injection in mice. We may suggest that endomorphins and the mu-opioid receptors might be involved in the physiopathology of depressive disorders, and that the endomorphinergic system could serve as a novel target for the development of antidepressant drugs.

Analysis of Variance↗

PubMed2006

Novelty preference predicts place preference conditioning to morphine and its oral consumption in rats.

Sensation seeking is frequently observed among drug addicts. This behaviour has been modelled in non-primate animals as novelty seeking. We previously determined that novelty preference did not predict amphetamine-induced place conditioning but was positively correlated with the consumption of a low concentrated amphetamine solution. Here, we studied the relationship between novelty seeking and the vulnerability to rewarding and reinforcing effects of morphine. Wistar rats were selected according to their novelty preference. In this model, animals have free choice between a new compartment and a "familiar" compartment to which they were previously exposed during two 30-min sessions, 24 h apart. We measured oral morphine consumption when this drug was presented in tap water (25 or 50 mg/l) in free choice with water or when it was presented (50 mg/l) in a 5% (w/v) sucrose solution in free choice with a sucrose solution. The oral consumption of quinine was also measured. The rewarding effect of morphine (1.25 and 5 mg/kg; i.p.) was determined in a conditioned place preference paradigm. Whereas high and low novelty seekers did not differ in reactivity to the aversive taste of quinine, preference for novelty was associated with a greater oral morphine consumption as well as an increased conditioned place preference induced by the 5 mg/kg dose of morphine. The present results support the hypothesis that novelty preference predisposes to drug abuse.

Administration, Oral↗

PubMed2006

Behavioral effects of 26RFamide and related peptides.

A novel 26-amino acid peptide possessing the Arg-Phe-NH(2) motif at its C-terminal extremity has been recently characterized and named 26RFamide (26RFa). The 26RFa precursor encompasses several potential cleavage sites and thus may generate various mature peptides including an N-terminally extended form of 26RFa (termed 43RFa), two fragments of 26RFa (26RFa(1-16) and 26RFa(20-26)), and a 9-amino acid peptide (9RFa) located in tandem in the human 26RFa precursor. In the present study, we have investigated the central effects of 26RFa and related peptides on food intake and locomotor activity in mice. We observed that i.c.v. injection of 26RFa, 43RFa, 26RFa(20-26) and 9RFa stimulated food consumption while 26RFa(1-16) and 26RFa(8-16) had no effect. A dose-dependent stimulation of locomotor activity was observed after i.c.v. administration of 26RFa, 43RFa and 26RFa(1-16), but not 26RFa(20-26), 26RFa(8-16) or 9RFa. These data indicate that the novel neuropeptides 26RFa and 43RFa act centrally to stimulate feeding and locomotor activities but the domains of the peptide involved in each of these responses are different suggesting that the two behavioral effects may be mediated through distinct receptors.

Amides↗

PubMed2006

Behavioral characterization of CD26 deficient mice in animal tests of anxiety and antidepressant-like activity.

CD26 exhibits a dipeptidylpeptidase-IV function (DPPIV) which regulates neuropeptide activity by N-terminal processing. Because abnormal plasma DPPIV was associated in mammals with behavioral changes, we examined the behavior of CD26-/- mice resulting from targeted inactivation of the gene. These animals had a decreased immobility in the forced swim and tail suspension tests, indicating a reduced depression-like behavior. We addressed some factors that could affect these results. No major differences between mutants and controls were observed in the black/white box test that investigates anxiety. In the hole-board apparatus that explores both curiosity and anxiety, CD26-/- mice of both genders made significantly more head dips than controls. In a motor activity test, mutants displayed higher horizontal and vertical activities i.e. increased novelty-induced behavioral activation. We conclude that DPPIV inactivation in mice broadly leads to an antidepressant-like and hyperactive phenotype.

Analysis of Variance↗

PubMed2006

[(35)S]GTPgammaS binding stimulated by endomorphin-2 and morphiceptin analogs.

The ability of several mu-selective opioid peptides to activate G-proteins was measured in rat thalamus membrane preparations. The mu-selective ligands used in this study were three structurally related peptides, endomorphin-1, endomorphin-2 and morphiceptin, and their analogs modified in position 3 or 4 by introducing 3-(1-naphthyl)-d-alanine (d-1-Nal) or 3-(2-naphthyl)-d-alanine (d-2-Nal). The results obtained for these peptides in [(35)S]GTPgammaS binding assay were compared with those obtained for a standard mu-opioid agonist DAMGO. [d-1-Nal(3)]Morphiceptin was more potent in G-protein activation (EC(50) value of 82.5+/-4.5 nM) than DAMGO (EC(50)=105+/-9 nM). [d-2-Nal(3)]Morphiceptin, as well as endomorphin-2 analogs substituted in position 4 by either d-1-Nal or d-2-Nal failed to stimulate [(35)S]GTPgammaS binding and were shown to be potent antagonists against DAMGO. It seems that the topographical location of the aromatic ring of position 3 and 4 amino acid residues can result in a completely different mode of action, producing either agonists or antagonists.

Animals↗

PubMed2006

Structure and functions of the novel hypothalamic RFamide neuropeptides R-RFa and 26RFa in vertebrates.

A number of RFamide peptides have been characterized in invertebrate species and these peptides have been found to exert a broad spectrum of biological activities. In contrast, in vertebrates, our knowledge on RFamide peptides is far more limited and only a few members of the RFamide peptide family have been identified in various vertebrate classes during the last years. The present review focuses on two novel RFamide peptides, Rana RFamide (R-RFa) and 26RFa, that have been recently isolated from the amphibian brain. R-RFa shares the C-terminal LPLRFamide motif with other RFamide peptides previously identified in mammals, birds and fish. The distribution of R-RFa in the frog brain exhibits strong similarities with those of other LPLRFamide peptides, notably in the periventricular region of the hypothalamus. There is also evidence that the physiological functions of R-RFa and other LPLRFamide peptides have been conserved from fish to mammals; in particular, all these peptides appear to be involved in the control of pituitary hormone secretion. 26RFa does not exhibit any significant structural identity with other RFamide peptides and this peptide is the only member of the family that possesses an FRFamide motif at its C-terminus. The strong conservation of the primary structure of 26RFa from amphibians to mammals suggests that this RFamide peptide is involved in important biological functions in vertebrates. As for several other RFamide peptides, 26RFa-containing neurons are present in the hypothalamus, notably in two nuclei involved in the control of feeding behavior. Indeed, 26RFa is a potent stimulator of appetite in mammals. Concurrently, recent data suggest that 26RFa exerts various neuroendocrine regulatory activities at the pituitary and adrenal level.

Animals↗

PubMed2006

Comparisons between anxiety tests for selection of anxious and non anxious mice.

Male Swiss albinos mice were submitted to two behavioural tests intended to determine their anxiety level: the elevated plus-maze test as well as the black and white compartments test. In addition they were submitted to the hole-board test. It was observed: (i) that the correlation between scores in the two first tests was weak, suggesting that they explore different components of anxiety; (ii) that the score on the latter test was better correlated with the response in the elevated plus-maze test than in the black and white compartments test. From these data three groups of animals were constituted, considered, respectively, as anxious, non anxious and intermediates. It was observed that both horizontal and vertical locomotion in an unfamiliar environment differed between groups, with higher activity in non anxious than in anxious. In the hole-board test, only animals classified as anxious displayed an obvious response to the anxiolytic drug diazepam (0.5mg/kg). Finally in the forced-swimming test, the three groups demonstrated a similar immobility time, suggesting that the operated segregation was not depending on a helpless component. It is proposed that the selection of mice from a combination of either elevated plus-maze and black and white compartments tests or a combination of hole-board test and black and white compartments test, allows to distinguish high or low anxiety animals among a population of mice.

Analysis of Variance↗

PubMed2006

Hypericum caprifoliatum (Guttiferae) Cham. & Schltdl.: a species native to South Brazil with antidepressant-like activity.

In this work, previously published and unpublished results on biological activity of Hypericum caprifoliatum, a native species to South Brazil, are presented. Lipophilic extracts obtained from this species showed an antidepressant-like activity in mice and rat forced swimming test. Results from in vivo experiments suggest an effect on the dopaminergic transmission. Besides that, in vitro experiments demonstrated that the extract and its main component (a phloroglucinol derivative) inhibit monoamine uptake in a concentration-dependent manner, more potently to dopamine, but this effect is not related to direct binding at the uptake sites. It was also observed that a 3-day treatment with lipophilic extract prevents stress-induced corticosterone rise in mice frontal cortex but not in plasma. The lipophilic and methanolic H. caprifoliatum extracts also demonstrated antinociceptive effect, which seems to be indirectly mediated by the opioid system. These results indicate that H. caprifoliatum presents a promising antidepressant-like effect in rodents which seems to be related to a mechanism different from that of other classes of antidepressants.

Animals↗

PubMed2006

In vitro characterization of novel peptide inhibitors of endomorphin-degrading enzymes in the rat brain.

Endomorphins, endogenous mu-opioid receptor ligands, have been shown to exert antinociceptive, antidepressant, anxiolytic, and neuromodulatory effects, as well as to influence cardiovascular, respiratory, and gastrointestinal systems. In the present study, we designed and synthesized a series of tetrapeptides and tripeptides (amides and peptide acids) of similar to endomorphins structure, but with low mu-opioid receptor affinity, and tested them as possible inhibitors of endomorphin-degrading enzymes. The obtained results indicate that the tripeptides Tyr-Pro-Ala-NH2 and Tyr-Pro-Ala-OH, which do not bind to the mu-opioid receptors, are potent inhibitors of endomorphin-degrading enzymes in the rat brain. We suggest that the in vivo administration of these novel analogs may enhance physiological effects of endogenous endomorphins by decreasing the rate of their enzymatic cleavage.

Amino Acid Sequence↗

PubMed2005

Synthesis and antinociceptive activity of cyclic endomorphin-2 and morphiceptin analogs.

Cyclic analogs of the opioid peptides endomorphin-2 and morphiceptin of the type Tyr-X-Phe-Phe-Y-NH2 and Tyr-X-Phe-D-Pro-Y-NH2 (X = Lys or Asp and Y = Lys or Asp), respectively, were synthesized in order to test their structure-activity relationships. Antinociceptive activity of the new analogs was assessed in the hot-plate test after intracerebroventricular administration in mice. The strong analgesic effect was observed for the analogs with Asp in position 2, while the analogs with Lys in the second position were inactive. Antinociception caused by Asp2 analogs was dose-dependent and reversed by the concomitant administration of the universal opioid antagonist naloxone and by the selective kappa antagonist, nor-BNI. However, receptor binding studies revealed poor affinity of all cyclic analogs at the mu-opioid receptor and no affinity at delta- and kappa-opioid receptors. It is most likely that the new cyclic analogs produced their antinociception by the release of dynorphin A, which subsequently acted on the kappa-opioid receptor.

Analgesics, Opioid↗

PubMed2005

Behavioral effects of urotensin-II centrally administered in mice.

Urotensin-II (U-II) receptors are widely distributed in the central nervous system. Intracerebroventricular (i.c.v.) injection of U-II causes hypertension and bradycardia and stimulates prolactin and thyrotropin secretion. However, the behavioral effects of centrally administered U-II have received little attention. In the present study, we tested the effects of i.c.v. injections of U-II on behavioral, metabolic, and endocrine responses in mice. Administration of graded doses of U-II (1-10,000 ng/mouse) provoked: (1) a dose-dependent reduction in the number of head dips in the hole-board test; (2) a dose-dependent reduction in the number of entries in the white chamber in the black-and-white compartment test, and in the number of entries in the central platform and open arms in the plus-maze test; and (3) a dose-dependent increase in the duration of immobility in the forced-swimming test and tail suspension test. Intracerebroventricular injection of U-II also caused an increase in: food intake at doses of 100 and 1,000 ng/mouse, water intake at doses of 100-10,000 ng/mouse, and horizontal locomotion activity at a dose of 10,000 ng/mouse. Whatever was the dose, the central administration of U-II had no effect on body temperature, nociception, apomorphine-induced penile erection and climbing behavior, and stress-induced plasma corticosterone level. Taken together, the present study demonstrates that the central injection of U-II at doses of 1-10,000 ng/mouse induces anxiogenic- and depressant-like effects in mouse. These data suggest that U-II may be involved in some aspects of psychiatric disorders.

Amino Acid Sequence↗

PubMed2005

Preference for caffeine appears earlier in non-anxious than in anxious mice.

Caffeine has reinforcing and anxiogenic properties. We have investigated whether the anxiety level of mice may influence their caffeine consumption. In a population of CD1 mice, animals were selected as anxious and non-anxious, using the elevated plus maze and the light/dark box tests. After a period during which we made mice able to associate the central effect of caffeine with the pipette delivering this substance, animals had free access to solvent (solution of sodium benzoate) and one of caffeine (0.3g/l) dissolved in this solvent. A progressive preference for the caffeine solution developed in both groups, but this occurred later in anxious than in non-anxious mice. Thus, it appears that the preference for caffeine is delayed in the anxious animals.

Administration, Oral↗

PubMed2005

Reduced appetite for caffeine in adenosine A(2A) receptor knockout mice.

Adenosine A(2A) receptor knockout mice (A(2A)R KO) were compared to wild-type controls (A(2A)R WT) in a caffeine intake paradigm. When mice had ad libitum access to caffeine (0.3 g/l) and water in a two-bottle paradigm for 12 consecutive days, adenosine A(2A)R KO mice drank less caffeinated solution, demonstrating a reduced appetite for caffeine as compared to adenosine A(2A)R WT mice. These data reveal an important role for the adenosine A(2A) receptor in the appetitive properties of caffeine.

Adenosine A2 Receptor Antagonists↗

PubMed2005

Synthesis and biological activity of N-methylated analogs of endomorphin-2.

In this paper, we describe the synthesis of a series of endomorphin-2 analogs containing N-methylated amino acids, consecutively in each position. The mu-opioid receptor binding affinities of the new analogs were determined in the displacement experiments. Their in vivo antinociceptive activity was assessed in the hot-plate test in mice after central (icv) and peripheral (ip) administration. [Sar2]endomorphin-2, which had the highest mu-receptor affinity, also showed the strongest analgesic effect when administered centrally and was the only analog that retained activity after peripheral injection.

Animals↗

PubMed2005

Opioid receptor-like 1 (NOP) receptors in the rat dorsal raphe nucleus: evidence for localization on serotoninergic neurons and functional adaptation after 5,7-dihydroxytryptamine lesion.

A high density of opioid receptor-like 1 (ORL1) receptor (also referred to as NOP receptor) is found in limbic areas and in regions containing monoamines, which are implicated in emotional activity and physiopathology of depression and anxiety. We aimed at defining precisely the localization of ORL1 receptors in dorsal raphe nucleus, by means of a lesion strategy and autoradiographic studies. In control rats, [3H]nociceptin and nociceptin-stimulated [35S]GTPgammaS bindings were found to be correlated in several brain regions. We performed in rats a selective destruction of serotoninergic neurons by surgical stereotaxic injection of 5,7-dihydroxytryptamine (5,7-DHT) in dorsal raphe nucleus. This led to a marked decrease in serotonin contents in striata and frontal cortices (about -60%) and in autoradiographic [3H]citalopram binding in posterior regions. In dorsal raphe nucleus, [3H]nociceptin binding was decreased to the same extent as [3H]citalopram binding, whereas it was unchanged in the other regions studied. Nevertheless, in the dorsal raphe, nociceptin-stimulated [35S]GTPgammaS binding was decreased to a lesser extent than [3H]nociceptin binding in 5,7-DHT-lesioned rats. The ratio between nociceptin-stimulated [35S]GTPgammaS binding and [3H]nociceptin binding was significantly increased in 5,7-DHT-lesioned rats compared with controls in this region. These data demonstrate 1) that ORL1 receptors are located on serotoninergic neurons in the dorsal raphe nucleus and 2) that, after a lesion, the functionality of remaining ORL1 receptors appears to be up-regulated, which could correspond to a compensatory mechanism.

5,7-Dihydroxytryptamine↗