Biomedical subjects

J Costentin

Publications and source records attributed to J Costentin.

At least 109 records · Page 6Linked to original sources

PubMed1994

Cocaine and GBR 12783 recognize nonidentical, overlapping binding domains on the dopamine neuronal carrier.

In incubation medium containing Na+ as the only cation, the specific binding of [3H]cocaine to a membrane preparation obtained from rat striatum reached a maximal level for 10 mM Na+, whereas higher concentrations decreased its affinity. The specific binding of [3H]cocaine was inhibited monophasically by GBR 12783, mazindol, nomifensine and substrates of the transporter; in saturation experiments, GBR 12783 competitively blocked the [3H]cocaine specific binding and vice versa. Treatment of the striatal membranes with N-ethylmaleimide resulted in a concentration-dependent reduction of the specific binding of [3H]GBR 12783 (1-[2-(diphenylmethoxy)ethyl]4-(3-phenyl-2-[1-3H]propenyl)-piperaz ine) which was significantly more marked than that of the specific binding of [3H]cocaine, the nonspecific binding of [3H]cocaine being measured with either cocaine or dopamine. Addition of substrates or pure uptake inhibitors to the treatment medium afforded protection against the N-ethylmaleimide-induced reduction in both bindings. In particular, cocaine offered protection for [3H]GBR 12783 binding and vice versa. All results are consistent with a model in which pure uptake blockers and substrates recognize nonidentical but overlapping binding domains on the neuronal carrier of dopamine.

Animals↗

PubMed1994

Short-term treatments with haloperidol or bromocriptine do not alter the density of the monoamine vesicular transporter in the substantia nigra.

[3H]dihydrotetrabenazine ([3H]TBZOH) was used to label the monoamine vesicular transporter in the rat substantia nigra. An accumulation of neuronal vesicles in the substantia nigra pars compacta was observed after blockade of the fast axonal transport by a microinjection of colchicine (10 micrograms/2 microliters) into the medial forebrain bundle. This accumulation was measured after sustained 2-day pharmacological modifications of the central dopaminergic transmission. It was not modified after s.c. administration of either the direct dopamine (DA) receptor agonist bromocriptine (four injections of 4 or 6 mg/kg) or the DA receptor antagonist haloperidol (four injections of 0.5-1-1.5-2 mg/kg). Thus, it appears that these pharmacological modifications, imposed to the activity of the nigro-striatal dopaminergic system during 2 days, have no consequence on the rate of synthesis of its vesicles.

Animals↗

PubMed1994

Ascorbic acid increases synaptosomal potassium-induced dopamine release.

On synaptosomes prepared from striata of mice, increasing concentrations of ascorbic acid (from 0.01 mM to 0.5 mM) did not modify the 3H-dopamine uptake. However, at the 0.1 mM concentration, ascorbic acid increased the potassium-induced release of 3H-dopamine by synaptosomes previously loaded with the amine. This effect was dependent on the presence of Ca2+ in the superfusion medium and was not shared by dehydroascorbic acid (from 1 mM to 0.01 mM). This effect of ascorbic acid, which occurs in the range of its endogenous concentrations, suggests that it is a putative modulator of dopaminergic transmission.

Animals↗

PubMed1994

Thigmotaxis as an index of anxiety in mice. Influence of dopaminergic transmissions.

When mice are introduced into an open-field, they are inclined to explore mainly the peripheral zone of this open-field. This tendency to remain close the walls, called thigmotaxis, decreases gradually during the first minutes of exploration. We have considered the degree of thigmotaxis during this period of decrease as an index of anxiety in mice. This hypothesis has been validated with several reference anxiogenic drugs (dexamphetamine, pentylenetetrazole, yohimbine, idazoxan) which increased thigmotaxis; and with anxiolytic drugs (buspirone, phenobarbital), which reduced it. On this test the selective or non-selective indirect dopamine agonists GBR 12783, dexamphetamine and cocaine induced an increase of thigmotaxis. Finally, the simultaneous involvement of D1 and D2 dopamine receptors has been evidenced in the anxiogenic-like effect associated with an increase of dopaminergic transmissions.

Adrenergic alpha-Antagonists↗

PubMed1994

Locomotor effects of [D-Trp11]neurotensin and dopamine transmission in rats.

Intracerebroventricular (i.c.v.) administration of [D-Trp11]neurotensin to rats decreased locomotor activity at a low dose (30 ng) and increased it at a high dose (750 ng). Only this high dose increased the dopamine turnover in the nucleus accumbens. The locomotor stimulant effect elicited by this high dose was potentiated by the dopamine uptake inhibitor, GBR 12783 (1-[2-(diphenyl-methoxy)ethyl]4-(3-phenyl-2-propenyl) piperazine) (5 mg/kg, i.p.), and reduced by the dopamine releaser, dexamphetamine (1.5 mg/kg). It was suppressed by the bilateral injection of 6-hydroxydopamine (8 micrograms/2 microliters) into the nucleus accumbens when rats were tested 4 days after the lesion. Fifteen days after the lesion, the i.c.v. administration of 750 ng of [D-Trp11]neurotensin induced hypolocomotion during the first hour of the test, and hyperlocomotion during the second hour. This latter locomotor stimulant effect was suppressed by the dopamine antagonist, haloperidol (50 micrograms/kg, i.p.). Thus, the hypokinetic effect of 30 ng [D-Trp11]neurotensin is independent of dopamine transmission, whereas the hyperkinesia elicited by 750 ng proceeds via an increase in dopamine transmission in the nucleus accumbens.

Amphetamine↗

PubMed1994

Involvement of glutamate receptors in the striatal enkephalin-induced dopamine release.

In anesthetized rats, the intrastriatal infusion of the delta-opioid receptor agonist, [D-Pen2,D-Pen5]enkephalin, increased the extracellular concentration of dopamine. This effect was abolished by the NMDA receptor antagonist, 3-[(+/-)-2-carboxypiperazine-4-yl]propyl-1-phosphonate, but was unchanged by the AMPA (D,L-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate) and kainate receptor antagonist, 6,7-dinitroquinoxaline-2,3-dione. This suggests that the dopamine release induced by the delta-opioid agonist depends critically on the involvement of glutamatergic transmission via NMDA receptors.

Analgesics↗

PubMed1994

Effect of CH3HgCl and several transition metals on the dopamine neuronal carrier; peculiar behaviour of Zn2+.

CH3Hg+ and metal ions inhibited the specific binding of (1-[2-(diphenylmethoxy)ethyl]-4-(3-phenyl-2-[1-3H]propenyl) piperazine) ([3H]GBR 12783) to the dopamine neuronal carrier present in membranes from rat striatum with a general rank order of potency CH3Hg+ > Cu2+ > Cd2+ > Zn2+ > Ni2+ = Mn2+ = Co2+, suggesting that -SH groups are chiefly involved in this inhibition. Five millimolar dithiothreitol reversed the rather stable block of the specific binding produced by Cd2+ or Zn2+. An increase in the concentration of Na+, or addition of either K+ or Ca2+ reduced the inhibitory effects of metal cations, except Cu2+. Zn2+ (3 microM) reduced the inhibitory potency of Cd2+ on the binding but was ineffective against CH3Hg+ and Cu2+. Zn2+ at 0.3 to 10 microM significantly enhanced the specific binding of [3H]GBR 12783 and [3H]cocaine by 42 to 146%. Zn2+ (3 microM) increased the affinity of all pure uptake inhibitors tested and of the majority of the substrates for the [3H]GBR 12783 binding site. Dissociation experiments revealed that Zn2+ both inhibited and enhanced the [3H]GBR 12783 binding by recognizing amino acids located close to or in the radioligand binding site. Micromolar concentrations of Zn2+ noncompetitively blocked the [3H]dopamine uptake but they did not modify the block of the transport provoked by pure uptake inhibitors. These findings suggest that Na+, K+, Ca2+ and metal ions could recognize some -SH groups located in the [3H]GBR 12783 binding site; low concentrations of Zn2+ could allow a protection of these -SH groups.

Animals↗

PubMed1994

Invariance of the density of dopamine uptake sites and dopamine metabolism in the rat brain after a chronic treatment with the dopamine uptake inhibitor GBR 12783.

A chronic treatment (10 mg/kg, twice daily during 9 days) with the dopamine uptake inhibitor GBR 12783 was performed in rats at a dose increasing their locomotor activity. Forty-eight hours after the last administration, animals were sacrificed and 3H mazindol binding was performed on brain slices. Autoradiographic analysis revealed no change in this binding relatively to control animals in regions with high dopamine contents: striatum, nucleus accumbens, olfactory tubercle, substantia nigra and ventral tegmentum area. The treatment did not either modify the levels of dopamine (DA) and metabolites (HVA, DOPAC) both in the striatum and the nucleus accumbens. Thus, early after the end of the treatment, the chronic blockade of the dopamine uptake complex regulates neither the dopamine uptake complex nor the dopamine metabolism.

Afferent Pathways↗

PubMed1994

6-Fluoro-serotonin as a substrate for the neuronal serotonin transporter.

6-Fluoro-serotonin (6F-5-HT) was previously identified in the rat brain after peripheral administration of 6-fluoro-DL-tryptophan, a serotonin (5-HT) synthesis inhibitor. These present studies, performed with rat brain synaptosomes show that: i-neuronal 6F-5-HT uptake partly involved the 5-HT transporter since it was inhibited by clomipramine, a 5-HT uptake inhibitor, ii-6F-5-HT blocked the synaptosomal uptake of 3H-5-HT, with an IC50 value of 98 +/- 13 nM, and iii- 6F-5-HT induced 3H-5-HT release from preloaded synaptosomes, with an EC50 value of 95 +/- 6 nM; this release was decreased in the presence of clomipramine, suggesting the involvement of the 5-HT transporter. This release was also reduced when using synaptosomes from reserpinized rats, suggesting that the vesicular pool also participates to the 3H-5-HT release induced by 6F-5-HT. So, 6F-5-HT behaved as a substrate for the 5-HT neuronal transporter.

Animals↗

PubMed1994

Comparison of the subregional distributions of the monoamine vesicular transporter and dopamine uptake complex in the rat striatum and changes during aging.

We have studied the heterogeneous distribution of the vesicular monoamine transporter, labelled with 3H dihydrotetrabenazine (3H TBZOH) and the dopamine uptake complex, labelled with 3H GBR12783 in the rat striatum. The ratio TBZOH/GBR12783 was higher in the anterior part of the striatum than in the caudal part. This discrepancy could not be explained by the contribution of serotoninergic innervation to 3H TBZOH binding, since the ratio TBZOH/citalopram was also higher in the anterior striatum than in the caudal striatum. The monoamine vesicular transporter and the dopamine uptake complex were more abundant in the lateral regions than in the regions situated near the midline. In the caudal striatum, the ventral part was richer in vesicular transporter than the dorsal part. In aged rats (30 months), a significant decrease in the density of both transporters was noticed in the middle part of the striatum. In the anterior part of the striatum, the ratio TBZOH/GBR12783 was elevated in aged rats compared to adult ones. This could participate in a functional adaptation of the partially diminished population of dopaminergic neurons during aging.

Aging↗

PubMed1994

The stimulant effect of modafinil on wakefulness is not associated with an increase in anxiety in mice. A comparison with dexamphetamine.

Modafinil is a new drug used in the treatment of narcolepsy. Its administration in mice induced a dose-dependent increase in locomotor activity. The effects of modafinil were compared with those of dexamphetamine on three tests that assessed the anxiety level (drugs were used at doses which induced a roughly similar stimulation of locomotor activity). Dexamphetamine increased the latency of exploration of a white compartment, increased thigmotaxis in an open-field and decreased the time spent in the open arms of an elevated plus-maze. None of these responses was significantly modified by modafinil. We conclude that modafinil does not share the anxiogenic effects of dexamphetamine.

Animals↗

PubMed1994

Tolerance to the hypothermic but not to the analgesic effect of [D-Trp11]neurotensin during the semichronic intracerebroventricular infusion of the peptide in rats.

The peptidase-resistant derivative of neurotensin, [D-Trp11]neurotensin, has been continuously infused intracerebroventricularly (75 ng/h) with an osmotic minipump for 10 days. On several days during this infusion the locomotor activity, the body temperature, the food intake, the body weight, and the nociceptive response in the plantar test were measured. A nonsignificant decrease of body temperature and a sustained analgesic effect were observed at each time considered. The response to a test dose of [D-Trp11]neurotensin (75 ng per rat) injected intracerebroventricularly at the 10th day of the chronic infusion revealed a complete tolerance to its hypothermic effect. Thus, it appears that the analgesic effect of [D-Trp11]neurotensin is independent of a hypothermic or an incapacitating effect of the peptide and does not give rise to tolerance after a 10-day continuous administration, in contrast to the hypothermic effect.

Analgesics↗

PubMed1994

Locomotor and analgesic effects of morphine and acetorphan in rats chronically treated with morphine or thiorphan.

A continuous 8-day s.c. administration of morphine (450 microgram/kg/h) sensitized rats to the morphine-induced stimulation of locomotion (morphine test dose = 3 mg/kg, s.c.) but not to the acetorphan (5 mg/kg, i.v.)-induced stimulation of locomotion. On the other hand, a continuous 10-day intracerebroventricular infusion of the enkephalinase inhibitor, thiorphan (25 micrograms/rat/h), known to desensitize the acetorphan-induced stimulation of locomotion, also desensitized the morphine (3 mg/kg, s.c.)-induced stimulation of locomotion. The continuous 10-day, s.c. administration of morphine desensitized to the morphine (3 mg/kg, s.c.)-but not acetorphan (5 mg/kg, i.v.)-induced analgesia, as measured by the latency to jump from a hot plate (55 degrees C). On the other hand, the continuous 10-day intracerebroventricular infusion of thiorphan did not desensitize to morphine (3 mg/kg, s.c.)-induced analgesia. Thus, the chronic actions of morphine and thiorphan, according to the tested function, did not result in cross-sensitization (locomotion) or cross-tolerance (nociception). These differences could depend on the involvement of different opioid receptors (mu vs. delta) and/or on different functional organizations.

Analgesics↗

PubMed1994

The nonpeptide neurotensin antagonist, SR 48692, used as a tool to reveal putative neurotensin receptor subtypes.

The nonpeptide neurotensin (NT) antagonist, SR 48692, was recently shown to inhibit NT binding to the cloned rat and human NT receptor and to antagonize NT effects in a variety of in vitro and in vivo assays. Here, we show that, in contrast to its antagonistic action on NT-induced hypomotility in the rat, SR 48692 failed to antagonize NT-induced hypothermia and analgesia in the mouse and rat. We suggest that these effects might be mediated through a subtype of SR 48692-insensitive NT receptor.

Analgesics↗

PubMed1994

In vivo and in vitro structure-activity studies with peptide and pseudopeptide neurotensin analogs suggest the existence of distinct central neurotensin receptor subtypes.

The present study was designed to compare, with respect to structure-activity relationships, the receptors that subserve the hypothermic and analgesic effects of neurotensin (NT) to the receptor that mediates the effects of NT in mesencephalic dopamine (DA) neurons, and to compare these receptors to the cloned adult rat brain NT receptor and to newborn mouse and rat brain NT receptors. The results show that NT receptors in homogenates from newborn mouse and rat brain and from COS 7 cells transfected with the cloned high-affinity NT receptor from the adult rat brain displayed virtually identical structure-activity relationships toward a series of 12 peptide and pseudopeptide NT analogs, as assessed by the ability of the compounds to inhibit the binding of [125I]NT binding in these systems. Furthermore, when eight of these analogs were tested for their ability to inhibit [125I]NT binding and to potentiate K(+)-evoked DA release in primary cultures of rat mesencephalic neurons, it was found that they all behaved as agonists with binding and biological potencies quite similar to those observed in the other binding assays. Finally and strikingly, when seven of these analogs with checked metabolic stability were tested in vivo for their hypothermic and analgesic (tail-flick test) effects after i.c.v. injection in the mouse, they exhibited relative potencies that were completely different from those obtained in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗

PubMed1993

5-HT1A receptor blockade increases penile erections induced by indirect serotonin agonists.

Indirect serotonergic agonists, whether promoters of 5-HT release such as fenfluramine (5 mg kg-1) or inhibitors of 5-HT uptake such as fluoxetine (10 mg kg-1), elicited in rats penile erections at a modest but significant level. Their effects were markedly potentiated by the beta-blocker tertatolol, (0.6-5 mg kg-1) which displays 5-HT1A receptor blocking activity, but not by the beta-blocker labetalol (6.25 and 25 mg kg-1), which lacks such activity. In addition, tertatolol, but not labetalol, potentiated penile erections induced by meta-chloro-phenylpiperazine (1 mg kg-1). Thus, it appears that increasing serotonergic transmission increases only moderately penile erections because of the functional opposition exerted by 5-HT1A (inhibition) and 5-HT1C (activation) serotonin receptors on this response.

Adrenergic beta-Antagonists↗

PubMed1993

Specific binding of [3H]GBR 12783 to the dopamine neuronal carrier included in polarized membranes.

We have compared the properties of the binding to the neuronal dopamine carrier located either in polarized membranes of synaptosomes or in non polarized, classical membranes. Non-polarized membranes were prepared by sonication of the partially purified synaptosomal fraction obtained from rat striatum which was used as the source of polarized membranes. Binding experiments were carried out at 37 degrees C in Krebs Ringer related media. [3H]GBR 12783 (1-[2-(diphenylmethoxy)ethyl]4-(3-phenyl-2-[1- 3H]propenyl)piperazine) specifically bound with a nanomolar affinity to a homogeneous population of site (maximal binding site concentration: 8-10 pmol/mg protein). Pure uptake inhibitors, but not substrates, competed for the [3H]GBR 12783 binding site located in polarized membranes of synaptosomes at concentrations effective against dopamine neuronal transport. Except for [3H]GBR 12783, the replacement of Cl- by isethionate- did not result in significant change in the ability of pure uptake inhibitors to compete for the specific binding site. A reduction in the Na+ concentration from 135 to 10 mM induced a significant decrease in the inhibitory potency of GBR 12783, mazindol, nomifensine and methylphenidate. This decrease was likely to result from the presence of K+, Mg2+ and Ca2+, whose inhibitory effects were modified and/or increased by decreasing the Na+ concentration. These data indicate that the membrane polarity is not clearly involved in the binding of pure uptake inhibitors to the dopamine neuronal carrier; furthermore they underline the critical role of Na+ and K+ transmembrane gradients in both the recognition of the carrier by dopamine and its inward transport.

Animals↗

PubMed1993

In vivo occupancy of the striatal dopamine uptake complex by various inhibitors does not predict their effects on locomotion.

We compared the ability of various dopamine (DA) uptake inhibitors to displace the in vivo striatal [3H]GBR 12783 (1-[2(diphenylmethoxy) ethyl)-4-(3-phenyl-1[3H]-2-propenyl)-piperazine) binding with their stimulant effect on locomotor activity on mice. GBR 12783 (8 mg/kg), GBR 13069 (10 mg/kg), cocaine (20 mg/kg), mazindol (3 mg/kg) or pyrovalerone (2 mg/kg) stimulated locomotion as long as they occupied the DA uptake complex. In contrast, nomifensine (3 mg/kg) did not stimulate locomotion although it competed with [3H]GBR 12783 for the occupancy of the DA uptake complex at a significant level (> 50%). Administered at their ED50 doses, GBR 12783, BTCP (N-[1-(2-benzo(b)thiophenyl)cyclohexyl]piperidine, GBR 13069, amineptine and dexamphetamine significantly increased locomotor activity whereas the other inhibitors tested did not. The locomotor response elicited by GBR 12783 (10 mg/kg) was not decreased by desipramine (20 mg/kg) nor by oxaprotiline (10 mg/kg). The increase in locomotion elicited by GBR 12783 was positively correlated with the basal locomotor activity of the mice. The stimulant effect of GBR 12783 was potentiated by SKF 525A and by budipine. Additional pharmacological properties might conceal the relationship between the effects of some DA uptake inhibitors on locomotion, and on in vivo occupancy of DA uptake sites.

Animals↗