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J Costentin

Publications and source records attributed to J Costentin.

At least 19 recordsLinked to original sources
PubMed2006

[Neurobiology of cannabis--recent data enlightening driving disturbances].

During the last decades a new landscape of cannabis has been designed on account of: the increase in its use the greater youth of its users; the increase in the content of its main active constituent tetrahydrocannabinol (THC) and a lot of new epidemiological and neurobiological data. THC displays an exceptional lipophilicity, allowing its cerebral storage, leading to long lasting effects, by far more lasting than its presence in blood, and beyond the period throughout the intoxicated people feel a disablement. This is linked to its slow release from brain areas in which large proportion of spare receptors exists (reserve receptors). THC disturbs cognition and various skills required in driving. It may be responsible for psychiatric troubles: anxiety, depression, suicide attempt, psychotic attack, triggering of schizophrenia. It potentiates the alcohol effects and incites to alcohol drinking. It displays close relationships with dependence to heroin. This new landscape of cannabis urges to make a radical alteration in the public communication about this drug of abuse as it has yet collected so many troubles, accidents or tragedies.

Automobile Driving↗
PubMed2005

Binding of endomorphin-2 to mu-opioid receptors in experimental mouse mammary adenocarcinoma.

Endomorphin-2 (Tyr-Pro-Phe-Phe-NH2) binds with high affinity and selectivity to the mu-opioid receptor. In the present study, [125I]endomorphin-2 has been used to characterize mu-opioid-binding sites on transplantable mouse mammary adenocarcinoma cells. Cold saturation experiments performed with [125I]endomorphin-2 (1 nM) show biphasic binding curves in Scatchard coordinates. One component represents high affinity and low capacity (K(d) = 18.79 +/- 1.13 nM, B(max) = 635 +/- 24 fmol/mg protein) and the other shows low affinity and higher capacity (K(d) = 7.67 +/- 0.81 microM, B(max) = 157 +/- 13 pmol/mg protein) binding sites. The rank order of agonists competing for the [125I]endomorphin-2 binding site was [d-1-Nal3]morphiceptin > endomorphin-2 >> [d-Phe3]morphiceptin > morphiceptin > [d-1-Nal3]endomorphin-2, indicating binding of these peptides to mu-opioid receptors. The uptake of 131I-labeled peptides administered intraperitoneally to tumor-bearing mice was also investigated. The highest accumulation in the tumor was observed for [d-1-Nal3)morphiceptin, which reached the value of 8.19 +/- 1.14% dose/g tissue.

Adenocarcinoma↗
PubMed2005

Novel endomorphin-2 analogs with mu-opioid receptor antagonist activity.

A series of position 4-substituted endomorphin-2 (Tyr-Pro-Phe-Phe-NH2) analogs containing 3-(1-naphthyl)-alanine (1-Nal) or 3-(2-naphthyl)-alanine (2-Nal) in L- or D-configuration, was synthesized. The opioid activity profiles of these peptides were determined in the mu-opioid receptor representative binding assay and in the Guinea-Pig Ileum assay/Mouse Vas Deferens assay (GPI/MVD) bioassays in vitro, as well as in the mouse hot-plate test of analgesia in vivo. In the binding assay the affinity of all new analogs for the mu-opioid receptor was reduced compared with endomorphin-2. The two most potent analogs were [D-1-Nal(4)]- and [D-2-Nal4]endomorphin-2, with IC50 values 14 +/- 1.25 and 19 +/- 2.1 nM, respectively, compared with 1.9 +/- 0.21 nM for endomorphin-2. In the GPI assay these analogs were found to be weak antagonists and they were inactive in the MVD assay. The in vitro GPI assay results were in agreement with those obtained in the in vivo hot-plate test. Antinociception induced by endomorphin-2 was reversed by concomitant intracerebroventricula (i.c.v.) administration of [D-1-Nal4]- and [D-2-Nal4]-endomorphin-2, indicating that these analogs were mu-opioid antagonists. Their antagonist activity was compared with that of naloxone. At a dose 5 microg per animal naloxone almost completely inhibited antinociceptive action of endomorphin-2, while [D-1-Nal4]endomorphin-2 in about 46%.

Alanine↗
PubMed2004

[Physiological and neurobiological elements of food intake].

Many methods and techniques have accumulated a considerable mass of data about the mechanisms which control food intake and energetic loss. After a presentation of the main experimental approaches in this respect, the most relevant signals sent by peripheral organs to the central nervous system are presented: Glucose, triglycerides; from adipocytes: Leptin; from pancreas: Insulin, pancreatic polypeptide, amylin, enterostatin; from digestive tract: Ghrelin, cholecystokinin, peptide Y Y 3-36. Then are considered, especially at the hypothalamic level, their interpretation by neurones whose transmitters are either neuropeptides such as: Neuropeptide Y, Agouti Related Peptide, Cocaine/Amphetamine Regulated Transcript, Melanin Concentrating Hormone, alpha Melanocyte Stimulating Hormone, orexins/hypocretins, octadecaneuropeptide, nociceptin/orphanin FQ, opioid peptides, Interleukin 1, galanin, urocortin 2, Neurotrophic ciliary factor, or monoamines such as: Glutamate, dopamine, Norepinephrine, serotonine, GABA, histamine, acetylcholine. In a last part are considered the likely relationships existing between feeding, pleasure and addiction, centered on dopamine transmission in the nucleus accumbens. After this brief synopsis one should not be surprised that this so complex system which regulates feeding may be affected by various disorders; however one may be amazed by such a scarcity of drugs to influence it; in any case, many new pharmacological strategies can be expected in the future.

Animals↗
PubMed2004

[Assessment of the in vitro and in vivo toxicity of 3,4-dihydroxyphenylacetaldehyde (DOPAL)].

This work was carried out in order to evaluate the in vitro and in vivo toxicity of 3,4-dihydroxyphenylacetaldehyde (DOPAL). This aldehyde is formed from dopamine (DA) by monoamine oxidases (MAO) and is mainly oxidised to 3,4-dihydroxyphenylacetic acid by brain aldehyde dehydrogenases (ALDH), or eventually reduced to 3,4-dihydroxyphenylethanol by aldose/aldehyde reductases. In vitro, catecholaminergic SH-SY5Y cells were incubated with DA and disulfiram (DSF), an irreversible inhibitor of ALDH. As evidenced by MTT assays, a 24-h treatment with 10(-4) M DA and/or 10(-6) M DSF followed by a 24-h incubation in a drug-free medium evidenced that the toxicity of each of these drugs was potentiated by the second drug. HPLC measurements demonstrated that this drug association induced an early DOPAL production that could result in a delayed cell toxicity. For in vivo studies, male Sprague-Dawley rats were treated with L-DOPA-benserazide, which increases the production of DOPAL by MAO, and DSF. An acute injection of DSF (100mg/kg i.p.) and L-DOPA/benserazide (100mg/kg+25mg/kg, 24h later) significantly increased the DOPAL striatal level. However, a 30-day treatment with DSF (100mg/kg i.p., once every two days) and L-DOPA/benserazide (100mg/kg+25mg/kg, twice a day) did not affect both indexes used to assess the integrity of the nigro-striatal dopaminergic terminals (i.e. the striatal content in DA and the binding to the vesicular monoamine transporter on striatal membranes). These results do not support the hypothesis of a DOPAL toxicity and argue against the toxicity of L-DOPA therapy.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2004

[Comments on an animal model of depression].

Depression is a multifactorial illness and genetic factors play a role in its etiology. The understanding of its pathophysiology relies on the availability of experimental models potentially mimicking the disease. Here is presented a model built up by selective breeding of mice with strikingly different responses in the tail suspension test, a stress paradigm aimed at screening potential antidepressants. Indeed, "helpless" mice are essentially immobile in the tail suspension test, as well as the Porsolt forced-swim test, and they show reduced consumption of a palatable 2% sucrose solution. In addition, helpless mice exhibit sleep-wakefulness alterations resembling those classically observed in depressed patients, notably a lighter and more fragmented sleep, with an increase pressure of rapid eye movement sleep. Compared with "nonhelpless" mice, they display higher basal serum corticosterone levels and lower serotonin metabolism index in the hippocampus. Remarkably, serotonin1A autoreceptor stimulation induced greatest hypothermia and inhibition of serotoninergic neuronal firing in the nucleus raphe dorsalis in helpless than in nonhelpless mice. Thus, helpless mice exhibit a decrease in serotoninergic tone, which evokes that associated with endogenous depression in humans. Finally, both the behavioral impairments and the serotoninergic dysfunction can be improved by chronic treatment with the antidepressant fluoxetine. The helpless line of mice may provide an opportunity to approach genes influencing susceptibility to depression and to investigate neurophysiological and neurochemical substrates underlying antidepressant effects.

Animals↗
PubMed2003

Differential effects of novelty exposure on place preference conditioning to amphetamine and its oral consumption.

RATIONALE: Sensation/novelty seeking is frequently observed in drug abusers. Rats with high locomotor activity in response to inescapable novelty may be more prone to drug addiction. However, it is not clear whether this response to novelty represents reactivity to the novelty-induced stress or seeking for novelty. OBJECTIVES: We have compared the influence of the response to novelty-presented in a forced stressful or in a free choice non-stressful manner-on vulnerability to addictive properties of amphetamine. METHODS: Wistar rats were selected according to their (i) reactivity to inescapable novelty and (ii) novelty preference. For this purpose, animals were exposed during two 30-min sessions, 24 h apart, to the same compartment; their motor activity during the first session was used as an index of reactivity. On the third day, they were allowed to choose between this "familiar" environment and a novel one. Rewarding properties of amphetamine (0.2-3.2 mg/kg, s.c.) were determined by place conditioning. Amphetamine oral consumption (10-50 mg/l) in a free-choice paradigm was measured over a period of 32 days. RESULTS: Reactivity to novelty and novelty preference were not correlated. Reactivity to inescapable novelty predicted place conditioning induced by the lowest dose of amphetamine, whereas preference for novelty did not. High responders to inescapable novelty consumed less amphetamine than low responders. Novelty preference was positively correlated to amphetamine oral consumption only at the lowest concentration. CONCLUSIONS: Reactivity to inescapable novelty and novelty preference represent different behavioural components, which are related differentially with amphetamine place conditioning and its oral consumption.

Administration, Oral↗
PubMed2003

Caffeine reduces hypnotic effects of alcohol through adenosine A2A receptor blockade.

The role of the adenosine A(2A) receptor in the hypnotic effects of ethanol was assessed in mice. The duration of the loss of righting reflex following acute ethanol administration was shorter for A(2A) receptor-deficient mice (A(2A)R KO) than for wild-type mice (A(2A)R WT), whereas the fall in body temperature was not different between the two phenotypes. In contrast, the duration of the loss of righting reflex was increased in A(2A)R KO mice versus controls after administration of pentobarbital. Dipyridamole, an inhibitor of adenosine uptake, increased the sleep time observed following administration of ethanol in CD1 mice and in A(2A)R WT but not in A(2A)R KO mice. SCH 58261, a selective A(2A) receptor antagonist, unlike DPCPX, a selective A(1) receptor antagonist, shortened the duration of the loss of righting reflex induced by ethanol, thus mimicking the lack of receptor in deficient mice. Finally, the non-selective adenosine receptor antagonist caffeine (25 mg/kg) reduced ethanol-induced hypnotic effects. These results indicate that the activation of A(2A) receptors that follows an increase in extracellular adenosine levels caused by the administration of high doses of ethanol plays a role in its hypnotic effects. Thus, A(2A) receptor antagonists may be useful therapeutic agents for alleviating ethylic coma.

Adenosine A1 Receptor Antagonists↗
PubMed2003

Adenosine A2A receptor gene disruption provokes marked changes in melanocortin content and pro-opiomelanocortin gene expression.

A2A receptor knockout (A2AR-/-) mice are more anxious and aggressive, and exhibit reduced exploratory activity than their wild-type littermates (A2AR+/+). Because alpha-melanocyte-stimulating hormone (alpha-MSH) influences anxiety, aggressiveness and motor activity, we investigated the effect of A2AR gene disruption on alpha-MSH content in discrete brain regions and pro-opiomelanocortin (POMC) expression in the hypothalamus and pituitary. No modification in alpha-MSH content was observed in the hypothalamus and medulla oblongata where POMC-expressing perikarya are located. In the arcuate nucleus of the hypothalamus, POMC mRNA levels were not affected by A2AR disruption. Conversely, in A2AR-/- mice, a significant increase in alpha-MSH content was observed in the amygdala and cerebral cortex, two regions that are innervated by POMC terminals. In the pars intermedia of the pituitary, A2AR disruption provoked a significant reduction of POMC mRNA expression associated with a decrease in alpha-MSH content. By contrast, in the anterior lobe of the pituitary, a substantial increase in POMC mRNA and adrenocorticotropin hormone concentrations was observed, and plasma corticosterone concentration was significantly higher in A2AR-/- mice, revealing hyperactivity of their pituitary-adrenocortical axis. Together, these results suggest that adenosine, acting through A2A receptors, may modulate the release of alpha-MSH in the cerebral cortex and amygdala. The data also indicate that A2A receptors are involved in the control of POMC gene expression and biosynthesis of POMC-derived peptides in pituitary melanotrophs and corticotrophs.

Animals↗
PubMed2002

Nociceptin/orphanin FQ and related peptides reduce the increase in plasma corticosterone elicited in mice by an intracerebroventricular injection.

Nociceptin/orphanin FQ (=N/OFQ), the endogenous ligand of ORL1 receptor (=NOP), has been reported to induce, in rodents, after intracerebroventricular (i.c.v.) administration, anti-stress and anxiolytic effects. We have observed that the handling of mice followed by an i.c.v. injection of saline, induced a marked increase in the plasma corticosterone level (+250%) measured 30 minutes later. When N/OFQ was injected intracerebroventricularly, using a 1 microg dose, the increase in plasma corticosterone was significantly lower than in saline injected mice. N/OFQ(1-13)NH(2), known as a NOP receptor agonist, at the same 1 microg dose, also induced a lesser increase in plasma corticosterone level than a saline i.c.v. injection. The pseudopeptide [Phe(1)-psi(CH(2)-NH)Gly(2)]N/OFQ(1-13)NH(2), defined either as an agonist or an antagonist of NOP receptor, at the 0.1 microg dose, behaved in a similar manner as N/OFQ, by decreasing the plasma corticosterone level. Finally, [Nphe(1)]N/OFQ(1-13)NH(2), although presumed to be a selective NOP receptor antagonist, also decreased the corticosterone level at the 0.1 microg dose. These observations suggest the implication of N/OFQ in the regulation of response to stress, through an action on the hypothalamo-pituitary-adrenocortical axis. Moreover, they evidence a similar effect of N/OFQ and N/OFQ(1-13)NH(2), but also of two other related peptides displaying antagonist properties on NOP receptors. These data suggest that several subtypes of N/OFQ receptors could exist.

Animals↗
PubMed2002

Evidence for a localization of [(3)H]nociceptin binding sites on medullar primary afferent fibers.

The ORL1 receptor (opioid receptor-like 1) and its endogenous ligand, nociceptin, are involved in nociperception. We have studied, in a deafferented animal model, the modification of medullar [(3)H]nociceptin binding site density. A rhizotomy was carried out in rats at the cervicothoracic level, and the dorsal afferent fibers from C5 to T1 were lesioned. Seven days after surgery, animals were sacrificed, and the binding of [(3)H]nociceptin (2 nM) was then performed on spinal cord sections. An autoradiographic analysis revealed a significant reduction (-18%) of [(3)H]nociceptin binding site density in the dorsal horn ipsilateral to the deafferentation compared with the contralateral side of the lesion. In the ventral horn, no significant difference (-5%) of binding was observed in the ipsilateral side of the deafferentation compared with the contralateral side. Thus, [(3)H]nociceptin binding sites appear to be located mainly on either interneurons or deutoneurons of the spinal cord, because the bulk of the labeling is spared by the lesion. However, the significant reduction of labeling that occurs on the dorsal part of the ipsilateral side to the lesion indicates that [(3)H]nociceptin binding sites are also present on these dorsal afferent fibers.

Afferent Pathways↗
PubMed2002

[Protection of synaptosomal polyunsaturated fatty acids from by extract of Ginkgo biloba-EGb 761].

Previous studies have demonstrated that ascorbic acid associated with ferrous ions induced deleterious effects on several targets or functions of striatal dopaminergic nerve endings, which were prevented by the Ginkgo biloba extract EGb 761. The present study attempted to assess whether a peroxidation of polyunsaturated fatty acids of their membranes could be associated with (or even responsible for) these alterations. Synaptosomes were prepared from mice striata. Their 1 h incubation with ascorbic acid (0.1 mM) resulted in a marked increase (+300%) of thiobarbituric acid reactive substances, that roughly are considered to correspond to the malondialydehyde level. Under these conditions the level of polyunsaturated fatty acids, measured by gas chromatography, decreased by -23% whereas the level of saturated fatty acids was not modified. Both the increase in thiobarbituric acid reactive substances and the decrease in polyunsaturated fatty acids were prevented by EGb 761 (10 micro g/ml). Similarly, the increase of TBARS was prevented by the vitamin E analogue trolox C (0.1mM) as well as by the ferrous ions chelating agent desferrioxamine (0.1mM). These data suggest that the polyunsaturated fatty acids peroxidation could be the origin of previously reported synaptosomal alterations induced by ascorbic acid/Fe(2 +).

Animals↗
PubMed2001

Adenosine A2A receptor knockout mice are partially protected against drug-induced catalepsy.

Catalepsy assessed using the bar test was measured in both adenosine A2A receptor knockout (A2AR KO) and wild-type (A2AR WT) mice submitted to acute administration of the dopamine D2 receptor antagonist haloperidol (0.5, 2, 4, 6 mg/kg i.p.), the dopamine D1 antagonist SCH 23390 (0.3-3 mg/kg, s.c.), the vesicular monoamine transporter blocker reserpine (3-5 mg/kg, s.c.) or the acetylcholine muscarinic receptor agonist pilocarpine (25-50 mg/kg, i.p.). Except for reserpine, catalepsy scores were significantly lower in A2AR KO mice than in A2AR WT mice following low doses of these cataleptogenic agents. These results suggest that adenosine A2A receptors influence not only dopamine D2 and D1 receptor-mediated neurotransmission but also acetylcholine muscarinic receptor-mediated neurotransmission.

Animals↗
PubMed2001

Localization of neurotensin NTS2 receptors in rat brain, using.

The brain localization of the neurotensin receptor NTS2 was studied with [3H]levocabastine, using an autoradiographic procedure. This study suggests that NTS2 receptors are mainly intracellular. High densities of binding sites were observed in the cingulate, insular, temporal, occipital, enthorhinal cortex, amygdaloid complex, septohippocampal nuclei, medial thalamus, mammillary bodies and superior colliculi; a moderate labelling was observed in the anterior and medial hippocampus, olfactory tubercle, hypothalamus, periaqueductal gray matter, caudate putamen, nucleus accumbens, septum, lateral thalamus, dorsal raphe nucleus and cerebellum; finally, a low labelling was apparent in the ventral tegmentum area and substantia nigra. Thus it appears that NTS2 receptors are particularly abundant in the cerebral cortex, the limbic areas and some areas involved in pain perception.

Animals↗
PubMed2001

The octadecaneuropeptide [diazepam-binding inhibitor (33-50)] exerts potent anorexigenic effects in rodents.

The effects of intracerebroventricular administration of the octadecaneuropeptide ODN on food intake have been investigated in rat and mouse. In rats deprived of food from 9:00 a.m. to 7:00 p.m., i.c.v. injection of ODN (30 to 100 ng) provoked a dose-dependent reduction of food consumption during the following 12-h nocturnal period. At a dose of 100 ng, ODN almost completely suppressed food intake. Treatment of rats with diazepam (2 mg/kg s.c.; 15 min before ODN administration) did not affect the anorexigenic response evoked by 100 ng ODN. Continuous i.c.v. infusion of ODN (10 ng/h during 15 days) using osmotic minipumps, significantly reduced food intake during the 2nd, 3rd and 4th days of treatment. The decrease in food consumption was associated with a significant reduction in body weight, which persisted during the 15-day duration of the experiment. In mice deprived of food for 18 h, i.c.v. administration of a low dose of ODN (5 ng) significantly reduced food intake. Treatment of mice with diazepam (1 mg/kg s.c.; 10 min before ODN administration) did not prevent the inhibitory effect of ODN (100 ng) on food intake. The C-terminal octapeptide fragment of ODN mimicked the anorexigenic effect of the intact peptide. Taken together, the present data demonstrate that i.c.v. injection of ODN causes, in both rat and mouse, a long-lasting anorexigenic effect that is not mediated through central-type benzodiazepine receptors. The biologically active region of ODN appears to be located in the C-terminal domain of the peptide.

Animals↗
PubMed2001

Developmental changes of (3)H-labelled mu-opioid receptors in brainstems of intra-uterine growth-restricted rats.

The opioid mu-system is involved in brainstem-mediated respiratory control. Infants with intra-uterine growth restriction (IUGR) have more respiratory disorders in the early postnatal period. Using [(3)H]DAGO, a mu-selective ligand, and a computer-based image analysis of autoradiography, we compared the ontogeny and distribution of mu-opioid binding sites in the brainstem of IUGR and control rats in utero (E21), at birth (P0) and on postnatal days 1 (P1), P7, P10, P14 and P21. The ontogeny pattern was found to be similar in both groups. The density of the binding sites, which was low in E21, increased at P0, slightly declined at P1 and remained relatively constant thereafter. The distribution of DAGO-binding sites, also similar in both groups, was heterogeneous and was much denser in the dorsal areas of medulla and pons. In particular, binding sites were highly concentrated in nuclei involved in the cardio-respiratory function. However, DAGO-binding density was higher at all ages (except for P0 and P1) in IUGR than in control rats. Taken together, these results give at least a partial explanation for the effects of IUGR which lowers the Apgar score at birth and raises the incidence of respiratory disorders in infants.

Aging↗
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↗