Biomedical subjects

J M Vaugeois

Publications and source records attributed to J M Vaugeois.

At least 19 recordsLinked to original sources

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

Adenosine A2A receptor antagonists are potential antidepressants: evidence based on pharmacology and A2A receptor knockout mice.

1. Adenosine, an ubiquitous neuromodulator, and its analogues have been shown to produce 'depressant' effects in animal models believed to be relevant to depressive disorders, while adenosine receptor antagonists have been found to reverse adenosine-mediated 'depressant' effect. 2. We have designed studies to assess whether adenosine A2A receptor antagonists, or genetic inactivation of the receptor would be effective in established screening procedures, such as tail suspension and forced swim tests, which are predictive of clinical antidepressant activity. 3. Adenosine A2A receptor knockout mice were found to be less sensitive to 'depressant' challenges than their wildtype littermates. Consistently, the adenosine A2A receptor blockers SCH 58261 (1 - 10 mg kg(-1), i.p.) and KW 6002 (0.1 - 10 mg kg(-1), p.o.) reduced the total immobility time in the tail suspension test. 4. The efficacy of adenosine A2A receptor antagonists in reducing immobility time in the tail suspension test was confirmed and extended in two groups of mice. Specifically, SCH 58261 (1 - 10 mg kg(-1)) and ZM 241385 (15 - 60 mg kg(-1)) were effective in mice previously screened for having high immobility time, while SCH 58261 at 10 mg kg(-1) reduced immobility of mice that were selectively bred for their spontaneous 'helplessness' in this assay. 5. Additional experiments were carried out using the forced swim test. SCH 58261 at 10 mg kg(-1) reduced the immobility time by 61%, while KW 6002 decreased the total immobility time at the doses of 1 and 10 mg kg(-1) by 75 and 79%, respectively. 6. Administration of the dopamine D2 receptor antagonist haloperidol (50 - 200 microg kg(-1) i.p.) prevented the antidepressant-like effects elicited by SCH 58261 (10 mg kg(-1) i.p.) in forced swim test whereas it left unaltered its stimulant motor effects. 7. In conclusion, these data support the hypothesis that A2A receptor antagonists prolong escape-directed behaviour in two screening tests for antidepressants. Altogether the results support the hypothesis that blockade of the adenosine A2A receptor might be an interesting target for the development of effective antidepressant agents.

Animals↗

PubMed2001

In vivo labelling of the adenosine A2A receptor in mouse brain using the selective antagonist [3H]SCH 58261.

The selective A2A receptor antagonist [3H]SCH 58261 was injected intravenously in mice and the radioactivity accumulating in various brain regions was determined by tissue sampling. Radioactivity levels in regions of interest such as the striatum were highest 15 min after injection and quickly declined thereafter (30 min and 1 h postinjection) in a time-dependent manner. The amount of labelling was ranked as follows: striatum (4.6 +/- 0.3 fmol/mg protein) >> cortex > hippocampus > pons = hypothalamus > cerebellum (0.5 +/- 0.05 fmol/mg protein). Specific labelling of the A2A receptor occurred in striatum and cortex because significantly less radioactivity accumulated in these areas from adenosine A2A receptor knockout mice as compared to wild-type littermates. In control outbred CD1 mice, a striatum-to-cerebellum ratio of 7.6 +/- 0.6 was found. At 30 min postinjection, the nonselective adenosine receptor antagonist caffeine reduced the radioactivity due to [3H]SCH 58261 in the striatum by 32% at 1 mg/kg i.p. and by 66% at the stimulant dose of 6.25 mg/kg i.p. Radioactivity in the striatum was lowered, respectively, by 66 and 86% 30 min after injection of 3 or 10 mg/kg i.p. doses of unlabelled SCH 58261. The present results indicate that [3H]SCH 58261 directly labels striatal A2A receptors in vivo. Thus [3H]SCH 58261 is an excellent tool for studying brain distribution and A2A receptor occupancy of various compounds ranging from xanthines, such as caffeine, to other A2A antagonists.

Adenosine↗

PubMed2000

The anxiogenic-like effect of caffeine in two experimental procedures measuring anxiety in the mouse is not shared by selective A(2A) adenosine receptor antagonists.

RATIONALE: The elevated plus-maze and the light/dark box are two established anxiety tests in rodents, which are useful to screen putative anxiogenic effects of drugs. OBJECTIVE: Caffeine is well known to promote anxious behaviour in humans and animal models, but the precise site of action of the drug is still a matter of debate. The present study investigated whether the anxiogenic effects of caffeine observed in mice depend on the blockade of A(2A) receptor. First, the effects induced by the non-selective drug caffeine were compared with those elicited by two selective A(2A) receptor antagonists over a wide range of doses in the same experimental conditions. The effects of A(2A) or A(1 )adenosine receptor agonists and of a selective A(1) adenosine receptor antagonist were also investigated. Second, wild-type and A(2A) receptor knockout mice offered another approach to delineate the role played by A(2A) receptor in caffeine's anxiogenic effects. METHODS: Mice were exposed to the elevated plus-maze or to the light/dark box for 5 min after acute or chronic administration of tested drugs. RESULTS: Caffeine acutely administered (50 or 100 mg/kg IP) induced anxiety-like effects in both procedures. Its chronic administration (50 mg/kg IP twice daily) for 1 week or consumption in the drinking water (0.3 g/l) for 8 days or 2 months were also anxiogenic in the plus-maze test. The A(2A) receptor antagonists ZM241385 (up to 60 mg/kg IP) and SCH58261 (up to 10 mg/kg IP) were devoid of acute effects in both tests. One week administration of ZM241385 (30 mg/kg IP) or SCH58261 (3 mg/kg IP) had no effects in the plus-maze test. An antagonist (DPCPX) and an agonist (CPA) at A(1) receptors had no acute effects on anxiety-related indices, whereas an A(2A) receptor agonist (CGS 21680) displayed non-specific motor effects in the plus-maze test. Acute administration of caffeine (50 mg/kg IP) induced no clear-cut anxiety-like effects in the plus-maze test in A(2A) receptor knockout mice that exhibited higher basal anxiety levels than wild-type mice. Chronic administration (50 mg/kg IP twice daily) for 1 week elicited less anxiety-like behaviour in A(2A) receptor knockout than in wild-type mice. CONCLUSIONS: Adaptative mechanisms following mutation in A(2A) receptors or their long-term blockade after chronic ingestion of caffeine may be responsible for increase proneness to anxiety. However, the short-term anxiety-like effect of caffeine in mice might not be related solely to the blockade of adenosine A(2A) receptors, since it is not shared by A(2A) selective antagonists.

Adenosine↗

PubMed2000

The stimulant effects of caffeine on locomotor behaviour in mice are mediated through its blockade of adenosine A(2A) receptors.

1. The locomotor stimulatory effects induced by caffeine (1,3, 7-trimethylxanthine) in rodents have been attributed to antagonism of adenosine A(1) and A(2A) receptors. Little is known about its locomotor depressant effects seen when acutely administered at high doses. The roles of adenosine A(1) and A(2A) receptors in these activities were investigated using a Digiscan actimeter in experiments carried out in mice. Besides caffeine, the A(2A) antagonist SCH 58261 (5-amino-7-(beta-phenylethyl)-2-(8-furyl)pyrazolo[4,3-e]-1,2, 4-triazolo[1,5-c]pyrimidine), the A(1) antagonist DPCPX (8-cyclopentyl-1,3-dipropylxanthine), the A(1) agonist CPA (N(6)-cyclopentyladenosine) and A(2A) receptor knockout mice were used. 2. Caffeine had a biphasic effect on locomotion of wild-type mice not habituated to the open field, stimulating locomotion at 6.25 - 25 mg kg(-1) i.p. doses, while depressing it at 100 mg kg(-1). In sharp contrast, caffeine dose-dependently decreased locomotion in A(2A) receptor knockout mice over the whole range of tested doses. 3. The depressant effects induced by high doses of caffeine were lost in control CD1 mice habituated to the open field. 4. The A(1) agonist CPA depressed locomotion at 0.3 - 1 mg kg(-1) i.p. doses. 5. The A(1) antagonist DPCPX decreased locomotion of A(2A) receptor knockouts and CD1 mice at 5 mg kg(-1) i.p. and 25 mg kg(-1) i.p. respectively. 6. DPCPX (0.2 - 1 mg kg(-1) i.p.) left unaltered or even reduced the stimulant effect of SCH 58261 (1 - 3 mg kg(-1) i.p.) on CD1 mice. 7. These results suggest therefore that the stimulant effect of low doses of caffeine is mediated by A(2A) receptor blockade while the depressant effect seen at higher doses under some conditions is explained by A(1) receptor blockade.

Analysis of Variance↗

PubMed1999

Although chemically related to amineptine, the antidepressant tianeptine is not a dopamine uptake inhibitor.

We investigated whether the antidepressant tianeptine shares the dopamine uptake inhibitory properties of the chemically related antidepressant amineptine. Tianeptine dose dependently (5, 10, 20, 40 mg/kg IP) increased locomotor activity in mice. This stimulant effect (20 mg/kg IP) was dose dependently prevented not only by the D1 dopamine receptor antagonist SCH 23390 (7.5. 15, 30 microg/kg SC), but also by the D2 dopamine receptor antagonist haloperidol (50, 100, 200 microg/kg IP), in contrast to that elicited by dopamine uptake inhibitors. Where the latter prevent dexamphetamine-induced (3 mg/kg SC) reversion of akinesia in mice pretreated with reserpine (4 mg/kg SC, 5 h before test), tianeptine (20 mg/kg IP, 30 min before test) did not. Tested up to a concentration of 10-4 M, tianeptine did neither inhibit the [3H]dopamine uptake into mouse striatal synaptosomes nor compete in vitro with the specific binding of [3H]WIN 35,428 at dopamine transporters from striatal membranes. Finally, in mice injected IV with a tracer dose of [3H]WIN 35,428 (1 microCi), the highest tested dose of tianeptine (40 mg/kg IP) did not reduce the specific binding of the radioligand to striatal dopamine transporters. It is concluded that the antidepressant effect of tianeptine does not depend upon a blockade of the neuronal dopamine transporter.

Animals↗

PubMed1998

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

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

Animals↗

PubMed1998

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

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

Animals↗

PubMed1997

Aggressiveness, hypoalgesia and high blood pressure in mice lacking the adenosine A2a receptor.

Adenosine is released from metabolically active cells by facilitated diffusion, and is generated extracellularly by degradation of released ATP. It is a potent biological mediator that modulates the activity of numerous cell types, including various neuronal populations, platelets, neutrophils and mast cells, and smooth muscle cells in bronchi and vasculature. Most of these effects help to protect cells and tissues during stress conditions such as ischaemia. Adenosine mediates its effects through four receptor subtypes: the A1, A2a, A2b and A3 receptors. The A2a receptor (A2aR) is abundant in basal ganglia, vasculature and platelets, and stimulates adenylyl cyclase. It is a major target of caffeine, the most widely used psychoactive drug. Here we investigate the role of the A2a receptor by disrupting the gene in mice. We found that A2aR-knockout (A2aR-/-) mice were viable and bred normally. Their exploratory activity was reduced, whereas caffeine, which normally stimulates exploratory behaviour, became a depressant of exploratory activity. Knockout animals scored higher in anxiety tests, and male mice were much more aggressive towards intruders. The response of A2aR-/- mice to acute pain stimuli was slower. Blood pressure and heart rate were increased, as well as platelet aggregation. The specific A2a agonist CGS 21680 lost its biological activity in all systems tested.

Adenosine↗

PubMed1997

Individual differences in response to imipramine in the mouse tail suspension test.

The tail suspension test is a behavioural primary screen for detecting potential antidepressant drugs. In this test, a reduction of duration of immobility after treatment with imipramine is obtained in mice of the NMRI strain but not of the CD1 strain. The present experiments evidence important differences between individuals of the latter strain in both the amount of immobility observed in naive mice and the effects of three antidepressants. The reproducibility of the tail suspension-induced behavioural despair was high in individual CD1 male mice and allowed a preselection of spontaneous high and low immobility scorers. Only the high immobility scorers were responsive to imipramine (30 mg/kg), desipramine (30 mg/kg) and paroxetine (10 mg/kg). The percentage of spontaneous high immobility scorers was higher in NMRI (50%) than in CD1 (20%) mice, justifying the use of the former strain for screening potential antidepressants. However, controlling for individual differences in the spontaneous performance in this animal model of depression may provide a useful tool to study behavioural, neurochemical and neuroendocrine correlates of antidepressant action.

Animals↗

PubMed1996

A genetic mouse model of helplessness sensitive to imipramine.

Lines of mice were selectively bred to diverge in their spontaneous helplessness in the tail suspension test. By the second generation of selection, only mice of the helpless line were sensitive to the antidepressant imipramine. Genetic factors substantially contribute to the susceptibility to helplessness in this mouse model. These selectively bred lines may represent potentially useful animal models to investigate behavioural, neurochemical and neuroendocrine correlates of antidepressant action.

Animals↗

PubMed1996

Pharmacological modifications of dopamine transmission do not influence the striatal in vivo binding of [3H]mazindol or [3H]cocaine in mice.

We have considered the in vivo striatal binding of two ligands of the neuronal dopamine uptake complex: [3H]cocaine and [3H]mazindol. The [3H]cocaine tracer dose labelled the dopamine uptake complex in striatum but not the noradrenaline complex in cerebellum. On the contrary, the [3H]mazindol tracer dose induced a marked labelling of the noradrenaline uptake complex in cerebellum; its prevention by desipramine (5 mg/kg) increased simultaneously the cerebral bioavailability and thereby the striatal labelling of the dopamine transporter. In mice submitted to treatments modifying dopaminergic transmission either to decrease it (gammabutyrolactone, 750 mg/kg, i.p.) or to increase it (L-DOPA, 200 mg/kg, i.p., dexamphetamine, 4 mg/kg, s.c., or their combination), only dexamphetamine pretreatment significantly reduced [3H]cocaine and [3H]mazindol binding. Thus it appears that the level of dopamine transmission would not interfere with the in vivo quantification of striatal dopamine uptake sites assessed with either ligands.

4-Butyrolactone↗

PubMed1996

In vivo striatal binding of the D1 antagonist SCH 23390 is not modified by changes in dopaminergic transmission.

The in vivo striatal binding of [3H]SCH 23390, an antagonist of the D1 dopamine receptors, was investigated in mice submitted to pretreatment to either decrease (gammabutyrolactone 750 mg/kg, i.p.) or, increase (3,4-dihydroxyphenylalanine (L-DOPA) 200 mg/kg i.p. plus dexamphetamine 4 mg/kg, s.c.) dopaminergic transmission. Such conditions failed to modify [3H]SCH 23390 binding. However, we observed that dopamine (at concentrations > or = 1 microM), reduced the in vitro binding of [3H]SCH 23390 in membrane fractions. These results suggest that modifications in dopamine neurotransmission do not alter the in vivo quantification of D1 receptors with [3H]SCH 23390, for example, in studies that use positron emission tomography.

4-Butyrolactone↗

PubMed1996

Indirect dopamine agonists effects on despair test: dissociation from hyperactivity.

Both dexamphetamine and the pure dopamine reuptake inhibitor GBR 12783 elicit a stimulation of locomotion and increase swimming activity in the behavioral despair test in mice. The dopamine D1 dopamine receptor antagonist SCH 23390 dose dependently (7.5-30 micrograms/kg s.c.) antagonized the stimulant locomotor effect on both drugs but did not prevent their antiimmobility effect on the behavioral despair test. The D2 dopamine receptor antagonist haloperidol dose dependently (12.5-50 micrograms/kg i.p.) antagonized the effects of dexamphetamine on both locomotor activity and behavioral despair test. By contrast, haloperidol inhibited the effects of GBR 12783 in the forced swimming test but not on locomotion. It is concluded that indirect dopamine agonists are effective on the behavioral despair test independently of a stimulation of locomotor activity. Their effects on the despair test depend on the stimulation of D2 but not D1 dopamine receptors.

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↗

PubMed1992

In vivo labelling of the neuronal dopamine uptake complex in the mouse striatum by [3H]GBR 12783.

Various characteristics of the in vivo striatal binding of [3H]GBR 12783 (1-[2-(diphenylmethoxy)-ethyl]-4-(3-phenyl-1[3H]-2-propenyl)pipera zine), a specific ligand of the neuronal dopamine uptake complex, were determined in mice. Increasing doses of the ligand revealed the saturability of the binding at a single site with half-maximal saturation at a dose of approximately 7 mumol/kg and an apparent maximal number of binding sites (Bmax) of 12.8 pmol/mg protein in striatum. Specific binding was prevented by various dopamine uptake blockers, pyrovalerone, GBR 13069, GBR 12783, N-[1-2-benzo(b)thiophenyl)cyclohexyl] piperidine, cocaine, methylphenidate and was inhibited in a stereoselective manner by the enantiomers of nomifensine. Other drugs which are not dopamine uptake blockers either did not modify [3H]GBR 12783 binding (the diphenylbutylpiperazine derivative flupenthixol) or increased it (the diphenylpiperazine derivative flunarizine or the chemically unrelated compounds fenfluramine and SKF 525A). A close correlation was found between occupancy of the striatal [3H]GBR 12783 binding site and the stimulant locomotor effect of the drug. A similar specific striatal binding of [3H]GBR 12783 was evidenced in both NMRI and CD1 strains. It was concluded that [3H]GBR 12783 administered in vivo provides a measure of the density of dopamine uptake sites in mouse striatum.

Animals↗

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↗

PubMed1988

Ionic requirements for the specific binding of [3H]GBR 12783 to a site associated with the dopamine uptake carrier.

At 0 degrees C, when Na+ was the only cation present in the incubation medium, increasing the Na+ concentration from 3 to 10 mM enhanced the affinity of [3H]1-[2-(++di-phenylmethoxy)ethyl]-4-(3-phenyl-2-propenyl)piperaz ine [( 3H]GBR 12783) for the specific binding site present in rat striatal membranes without affecting the Bmax. For higher Na+ concentrations, specific binding values plateaued and then slightly decreased at 130 mM Na+. In a 10 mM Na+ medium, the KD and the Bmax were, respectively, 0.23 nM and 12.9 pmol/mg of protein. In the presence of 0.4 nM [3H]GBR 12783, the half-maximal specific binding occurred at 5 mM Na+. A similar Na+ dependence was observed at 20 degrees C. Scatchard plots indicated that K+, Ca2+, Mg2+, and Tris+ acted like competitive inhibitors of the specific binding of [3H]GBR 12783. The inhibitory potency of various cations (K+, Ca2+, Mg2+, Tris+, Li+, and choline) was enhanced when the Na+ concentration was decreased from 130 to 10 mM. In a 10 mM Na+ medium, the rank order of inhibitory potency was Ca2+ (0.13 mM) greater than Mg2+ greater than Tris+ greater than K+ (15 mM). The requirement for Na+ was rather specific, because none of the other cations acted as a substitute for Na+. No anionic requirement was found: Cl-, Br-, and F- were equipotent. These results suggest that low Na+ concentrations are required for maximal binding; higher Na+ concentrations protect the specific binding site against the inhibitory effect of other cations.

Animals↗