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J Costentin

Publications and source records attributed to J Costentin.

At least 145 records · Page 8Linked to original sources
PubMed1991

Desensitization of mu-opioid receptors does not modify the analgesia induced by an enkephalinase inhibitor.

Acetorphan, an enkephalinase inhibitor, or morphine was injected in mice which had received saline or morphine (32 mg/kg s.c. twice a day on 8 consecutive days) chronically. In the hot-plate test, the analgesia (increase in jump latency) induced by morphine (2 mg/kg i.p.) or by the mu selective opioid agonist, [D-Ala2,N-Me-Phe4, Gly5-ol]enkephalin (DAGO) (1.5, 3 or 6 ng/mouse i.c.v.), was significant in the saline group but was strongly decreased in morphine-pretreated mice. In contrast the analgesic effect of acetorphan (5 mg/kg i.v.) or of the delta selective opioid agonist [D-Pen2,D-Pen5]enkephalin (DPDPE) (0.75, 1.5 or 3 micrograms/mouse i.c.v.) was similar in both groups. These results suggest that the enkephalins protected by acetorphan act on the delta receptor site to produce antinociception.

Analgesics↗
PubMed1991

Influence of oxygen availability on the neurotoxic effect of 6-hydroxydopamine on nigro-striatal dopaminergic neurons.

The neurotoxin 6-hydroxydopamine (6-OHDA) was intracerebroventricularly injected (50 micrograms per mouse) in mice submitted to various oxygenation conditions and the striatal levels of dopamine (DA) and its metabolites were determined by HPLC 7 days later. In normoxic conditions the striatal depletion in DA reached 50%. This effect was not modified by a normobaric hypoxia (10% O2) applied 30 min before and 30 min after the 6-OHDA injection. On the contrary, the neurotoxic effect was reduced when the hypoxia was prolonged up to 11 h after the drug administration. When a normobaric hyperoxia (60% O2) was applied 30 min before and 11 h after the 6-OHDA injection, the neurotoxic effects of the latter were not modified. These data, as well as other results obtained from ex vivo experiments showing that normobaric hypoxia or hyperoxia did not modify the striatal synaptosomal [3H]DA uptake, indicate that oxygen availability does not exert a critical influence on the efficiency of the neuronal dopamine uptake complex.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1991

Chronic inhibition of enkephalinase induces changes in the antinociceptive and locomotor effects of the enkephalinase inhibitor acetorphan in rats.

The enkephalinase inhibitor thiorphan was infused intracerebroventricularly in rats during 14 days (25 micrograms/5 microliters/hr), inducing an average inhibition of cerebral enkephalinase of about 65%. Animals were tested during the infusion for their response to acetorphan, a parenterally active derivative of thiorphan. When administered intravenously on day 8 of the infusion, acetorphan (5 mg/kg) significantly increased locomotion in chronic saline-infused rats but not in animals receiving thiorphan. Furthermore, when injected at the same dose on day 10, acetorphan did not modify the latency to jump, in the hot plate test, in thiorphan-treated rats, whereas it elicited a significant analgesia in chronic saline-treated controls. These data show that the effects induced by the administration of an enkephalinase inhibitor were diminished after a period of chronic inhibition of the enzyme, suggesting the development of tolerance.

Amino Acid Sequence↗
PubMed1991

Stimulation of D1 and D2 dopamine receptors produces additive anorectic effects.

In food-deprived mice the D1 dopamine agonist SKF 38393 induced dose dependent anorexia (ED50 = 2.6 mg/kg). This effect was reversed by the D1 antagonist SCH 23390. In similar conditions, the D2 dopamine agonist RU 24926 also induced dose dependent anorexia (ED50 = 0.19 mg/kg). This effect was reversed by the D2 antagonist (+/-) sulpiride. The mixed D1/D2 agonist apomorphine also induced an anorectic effect (150 micrograms/kg sc) which was completely reversed by (+/-) sulpiride (25 mg/kg, ip) but unaffected by SCH 23390 (5-30 micrograms/kg). The dose response curve obtained by associating SKF 38393 (2.5 mg/kg) with increasing doses of RU 24926 was roughly parallel to that obtained with RU 24926 alone. This indicates that effects of two drugs were additive. Although both D1 and D2 receptors regulate food consumption, the anorectic effect of apomorphine appears to involve only D2 receptors.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1991

An automated method for the assessment of spontaneous and stereotyped climbing behavior in mice. Effects of the selective D1- and D2-dopamine receptor agonists SKF-38393 and RU-24926 and their association.

A video-tracking technique has been used for the evaluation of climbing behavior in mice. An automated image analysis system, the Videotrack 512 (Electronique Lyonnaise), was adapted for this specific application. This allowed distinguishing between spontaneous climbing and stereotyped climbing. The activity duration of mice was simultaneously measured. In order to validate this method, in the present study the ability of apomorphine to induce climbing in mice, and the effects of the D1-dopamine receptor agonist SKF-38393 and the D2-dopamine agonist RU-24926 and their association were investigated.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1990

Stimulation of dopamine D2 receptors induces an analgesia involving an opioidergic but non enkephalinergic link.

In the hot plate test, the dopamine D2 receptor agonist RU 24926 as well as the mixed dopamine D1/D2 receptor agonist apomorphine dose dependently increased the nociceptive threshold of mice, as expressed by the jump latency. The dopamine D1 receptor agonist SKF 38393 was ineffective on this parameter. The effect of RU 24926 was antagonized by the dopamine D2 specific receptor antagonist sulpiride but not by the dopamine D1 specific receptor antagonist SCH 23390. It was not increased by SKF 38393. However, the effect of apomorphine was partially but significantly reduced by SCH 23390. Inhibitors of enkephalin-degrading peptidases (thiorphan and bestatin injected i.c.v. or acetorphan injected i.v.) did not potentiate the effect of apomorphine whereas the delta opioid antagonist IC 154, 129 did not reverse the apomorphine-induced analgesia. Finally, the effect of apomorphine was significantly decreased in mice rendered tolerant to morphine. It is concluded that, in mice, the antinociceptive effect induced by apomorphine results mainly from stimulation of D2 receptors. This stimulation probably involves an endogenous opioid, different from enkephalins, which acts at mu opioid receptors.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1990

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

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

Aging↗
PubMed1990

Optically active benzamides as predictive tools for mapping the dopamine D2 receptor.

Substituent variations on the pyrrolidinyl nitrogen of sulpiride, a selective D2 dopamine antagonist, showed that in vitro and in vivo activities are concentrated in the (S) optical series for N-alkyl analogs and in the (R) series for N-benzyl analogs. To account for these unusual structure-activity relationships, a pharmacophoric model was built from the crystallographic structure of (-)piquindone and extended to 14 other D2 antagonists. This model considers the lone pair orientation of the basic nitrogen rather than its spatial location. Two distinct active conformations for benzamides were defined, corresponding to the (S) and (R) series. An extended pharmacophore is then proposed involving four main anchoring areas: (i) an aromatic site Ar1, (ii) a tertiary nitrogen with its lone pair orthogonal to the Ar1 plane, (iii) a dipole delta 1 coplanar to the Ar1 ring and (iv) three sites for the N-substituent, including a small hydrophobic pocket and two different aromatic binding sites Ar2 and Ar3. To probe the predictive value of this model, structures were designed and several compounds were synthesized and tested as inhibitors of [125I]iodo-sulpiride binding to rat striatal membranes and as antagonists of apomorphine-induced stereotyped behavior in mice.

Animals↗
PubMed1990

Local enkephalins tonically modulate dopamine release in the striatum: a microdialysis study.

Kelatorphan, an inhibitor of the enkephalin-degrading enzymes, infused by microdialysis (10(-6) M) in the striatum of anaesthetized rats, significantly increased dopamine (DA) output but left dihydroxyphenylacetic acid and homovanillic acid extracellular levels unchanged. The local application of naltrexone (10(-6) M) prevented the effect of kelatorphan on DA release. These data indicate that local enkephalins tonically modulate DA release in rat striatum.

Amino Acid Sequence↗
PubMed1990

Relationship between the effects of dexamphetamine on locomotion and on striatal [3H]GBR 12783 binding in vivo.

In mice, low doses (1-2-4 mg/kg s.c.) of dexamphetamine stimulated locomotor activity in a dose-dependent manner. Over the same range of doses the drug dose dependently inhibited the in vivo striatal binding of the dopamine uptake inhibitor, [3H]GBR 12783. At 3 mg/kg dexamphetamine, the stimulant effect and the inhibition of the striatal binding of [3H]GBR 12783 displayed a similar time course. Pretreatments that either increased (L-DOPA 200 mg/kg, benserazide 50 mg/kg i.p.) or decreased (reserpine 5 mg/kg s.c., alpha-methyl-p-tyrosine 200 mg/kg) striatal dopamine levels did not modify the inhibition by dexamphetamine of [3H]GBR 12783 binding in vivo. This suggests that the inhibition is due to a direct effect of dexamphetamine, not mediated by endogenous dopamine, and further that a unique site is responsible for the neuronal uptake of dexamphetamine and for the binding of pure dopamine uptake inhibitors.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1990

Effects of various direct or indirect dopamine agonists on the latency of the acoustic startle response in rats.

The effects of dopamine agonists were investigated on the latency of the acoustic startle response in male Wistar rats. Four indirect dopamine agonist were tested: GBR 12783 (5-20 mg/kg), BTCP (5-20 mg/kg), dexamphetamine (3-6 mg/kg) and L-DOPA 100 mg/kg associated with benserazide 25 mg/kg; they induced an increase in startle latency. Apomorphine at a dose (50 micrograms/kg) known to decrease dopaminergic transmissions, was ineffective on the startle response. On the contrary, at 0.6 or 2 mg/kg, apomorphine induced an increase in the startle latency. A similar effect was observed with bromocriptine at 10 mg/kg from the 10th min up to at least the 9th hour after treatment. The specific agonist of D2 receptors Ru 24926 (0.45 mg/kg) enhanced the startle latency as well as the specific agonist of D1 receptors SKF 38393 (10 mg/kg). The association of these drugs resulted in an apparent additivity of their individual effects. The effect of apomorphine (0.6 mg/kg) was only partially reduced by a high dose of the specific D2 antagonist amisulpride (80 mg/kg) and more clearly antagonized by the specific D1 antagonist SCH 23390 (50 micrograms/kg). It is concluded that D2 and D1 receptors contribute to the increase in startle latency elicited by direct or indirect dopamine agonists.

Acoustic Stimulation↗
PubMed1990

Comparison of the effects of three indirect dopamine agonists, GK 13, GBR 12783 and dexamphetamine on behavioural tests involving central catecholaminergic transmissions.

GK 13 (N-[1-(2-benzo (b) thiophenyl)-cyclohexyl] piperidine), GBR 12783 (1-[2-(diphenylmethoxy)-ethyl] 4-(3-phenyl propenyl)-piperazine and dexamphetamine are three indirect catecholaminergic agonists, acting via different neurochemical mechanisms. We have compared their effects in rodents, in several behavioral tests. All three drugs increased locomotion. The stimulant locomotor effect of dexamphetamine was more easily antagonized by haloperidol than that of GBR 12783 and GK 13. Only dexamphetamine reversed reserpine-induced akinesia. This reversal was prevented by pretreatment with either GK 13 or GBR 12783. The three drugs reduced pentobarbital sleeping time in mice. They induced rotation ipsilateral to a unilateral 6-OHDA lesion of the nigrostriatal dopaminergic pathway. The stereotypies induced by GK 13 and GBR 12783 were essentially limited to sniffing. Haloperidol-induced catalepsy was apparently more easily antagonized by dexamphetamine than by GK 13 or GBR 12783. GK 13 and GBR 12783 had no significant effects on body temperature. The three drugs displayed an anti-immobility effect in the "despair test". Dexamphetamine and GK 13 reversed the hypothermia induced by apomorphine (16 mg/kg), as well as reserpine-induced hypothermia and reserpine-induced ptosis. Dexamphetamine induced a dose-dependent anorectic effect, whereas GK 13 and GBR 12783 induced only a brief and partial anorexia. Similar observations were made on water intake. Pretreatment with either GBR 12783 or GK 13 did not affect the dexamphetamine-induced anorexia. Effects of the three drugs are discussed by reference to their known neurochemical properties on catecholaminergic transmission.

Animals↗
PubMed1990

Dopamine D1 and D2 receptors mediate opposite effects of apomorphine on the body temperature of reserpinized mice.

In mice, rendered poikilothermic by a prior (18 hr) subcutaneous administration of reserpine (3 mg/kg), the subcutaneous administration of apomorphine increased dose-dependently the body temperature. This effect was potentiated by the specific D2 dopamine antagonist sulpiride. On the contrary, it was reduced by the specific D1 dopamine antagonist SCH 23390. A desensitization of D2 receptors was produced by the repeated administration of the specific D2 agonist RU 24926. This pretreatment led to an increased efficacy of apomorphine in antagonizing reserpine-induced hypothermia. Similarly, a desensitization of D1 receptors was created by the repeated administration of the specific D1 agonist CY 208-243. This pretreatment significantly diminished the efficacy of apomorphine in antagonizing reserpine-induced hypothermia. The repeated administration of the D1 agonist CY 208-243, in non-reserpinized mice, significantly increased the hypothermic effect of apomorphine (1 mg/kg). Thus, it appears that, in normal mice, but especially in reserpinized mice, the stimulation of D1 receptors by apomorphine induces an increase in body temperature that is masked, especially in normal mice, by the hypothermic effect, resulting from the simultaneous stimulation of D2 receptors.

Animals↗
PubMed1990

Role of delta opioid receptors in the effects of inhibitors of enkephalin-degrading peptidases on the horizontal and vertical components of locomotion in mice.

In the present study we report the effects of inhibitors of enkephalin-degrading peptidases on spontaneous locomotion in mice and the involvement of delta opioid receptors in these effects. Animals received intracerebroventricularly (i.c.v.) or intravenously (i.v.) enkephalinase inhibitors (thiorphan and acetorphan), aminopeptidase inhibitors (bestatin and carbaphethiol) or mixed peptidase inhibitors (kelatorphan). The i.c.v. co-administration of bestatin and thiorphan (50 micrograms + 50 micrograms) induced an increase in both the horizontal and vertical components of locomotion. A similar pattern was observed after the i.c.v. administration of kelatorphan (8.5-50 micrograms) or the i.v. co-administration of acetorphan and carbaphethiol (5 mg/kg + 10 mg/kg). The opiate antagonist naltrexone (1 mg/kg, s.c.) failed to reverse the excitolocomotor effects of kelatorphan or of bestatin and thiorphan and antagonized only partially the effects of acetorphan and carbaphethiol. Naloxone (2 mg/kg-10 mg/kg, s.c.) partially reversed the increase in locomotion elicited by bestatin and thiorphan. The pretreatment with the delta opioid antagonists ICI 154,129 (20 micrograms, i.c.v.) or ICI 174,864 (2-4 micrograms, i.c.v.) strongly decreased the effects of all the peptidase inhibitors we tested. These results suggest that endogenous enkephalins may control via delta opioid receptors the horizontal and vertical components of locomotor activity in mice.

Aminopeptidases↗
PubMed1990

Calcium-dependent release of neuromedin N and neurotensin from mouse hypothalamus.

Neuromedin N (NN), a hexapeptide, was isolated from porcine spinal cord. Its C-terminal tetrapeptide sequence is identical to that of neurotensin (NT) and it exhibits NT-like effects when injected in the central nervous system. Both peptides were recently shown to be encoded in the same precursor molecule. We have just developed a sensitive and specific radioimmunoassay (RIA) for NN and showed that the peptide central nervous system distribution paralleled that of NT, the highest concentrations being found in the hypothalamus. Using this assay and a specific RIA for NT, we show here that NN and NT were simultaneously released from slices of mouse hypothalamus by K(+)-induced depolarization in a Ca(++)-dependent manner. The ratio of released NN over NT was 0.3 and was identical to the ratio of endogenous NN over NT. For both NN and NT, the releasable peptide pool represented 2% of the endogenous peptide pool. HPLC characterization of the releasable and endogenous immunoreactive material reacting with the NN and NT antisera showed that it coeluted with synthetic NN and NT, respectively. The present data further support the hypothesis that NN acts as a neuromodulator in the central nervous system.

Amino Acid Sequence↗
PubMed1990

Prevention by a Ginkgo biloba extract (GBE 761) of the dopaminergic neurotoxicity of MPTP.

In mice implanted subcutaneously with osmotic minipumps releasing the neurotoxic agent N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) for 7 days (105 micrograms h-1/mouse) (approximately 100 mg kg-1 day-1) a significant reduction (approximately 25%) in the striatal dopaminergic nerve endings was observed. This neurotoxic effect was prevented by the semi-chronic ingestion of a Ginkgo biloba extract for 17 days (GBE 761, approximately 100 mg kg-1 day-1). The high concentrations (approximately 1 g L-1) at which GBE 761 in-vitro either prevented the uptake of [3H]dopamine by synaptosomes prepared from striatum, or prevented the specific binding of the pure dopamine uptake inhibitor [3H]GBR 12783 to membranes prepared from striatum suggests that the prevention of the MPTP neurotoxicity does not depend on an inhibition of the MPTP uptake by dopamine neurons. This is also suggested by the lack of prevention of the in-vitro striatal binding of [3H]GBR 12783 administered i.v. at a tracer dose, in mice pretreated for 8 days with GBE 761 (100 mg kg-1 p.o.) and receiving a supplementary gastric administration of GBE 761 (100 mg kg-1) 1 h before testing. Similar treatment with GBE 761 did not modify the toxicity for dopamine neurons of 6-hydroxydopamine (20 micrograms) directly injected into the striatum of rats.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1990

Thermodynamic analyses of the binding of substrates and uptake inhibitors on the neuronal carrier of dopamine labeled with [3H]GBR 12783 or [3H]mazindol.

We have investigated the thermodynamic properties of the binding of substrates and uptake blockers to the specific sites labeled with a tritiated dopamine uptake inhibitor (i.e., 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenyl-2-propenyl)piperazine ([3H] GBR 12783) or [3H]mazindol) using striatal membrane preparations. Raising the incubation temperature from 0 degrees C to 25 degrees C or 37 degrees C resulted in an increase in the dissociation constant of both [3H]mazindol and [3H]GBR 12783 for their specific sites of binding present in membrane suspensions obtained from either rabbit or rat striatum. However, maximal concentrations of binding sites were not affected by temperature. At all tested temperatures, both substrates and carrier blockers competed with either [3H]mazindol or [3H]GBR 12783 in a monophasic fashion, with Hill coefficients close to unity. Raising the temperature induced little or no increase in inhibition constants (Ki) for substrates (Ki ratio 37/0 degrees C less than 2.5). This is consistent with the mild increase of the Michaelis constant of dopamine for the neuronal uptake system when the incubation temperature was raised from 12.5 to 37 degrees C (from 126 to 406 nM). In contrast, increasing the temperature resulted in a more important increase in the Ki of uptake inhibitors (33 greater than Ki ratio greater than 5). Thermodynamic calculations showed that the binding of substrates is generally characterized by a mild decrease in enthalpy (range, -2- -6 kcal/mol) associated with an increase in entropy, whereas binding of uptake inhibitors led to a decrease of both parameters.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗