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At least 19 recordsLinked to original sources
PubMed1987

Sodium independence of the binding of [3H]GBR 12783 and other dopamine uptake inhibitors to the dopamine uptake complex.

When Na+ was the only cation present in the incubation medium used for the determination of the specific binding of [3H]GBR 12783 in rat striatal membranes, the Na+-dependence between 10 and 210 mM Na+ was not observed. In media with low (10 mM) or high (130 mM) Na+ concentration, mazindol and nomifensine competed with [3H]GBR 12783 for its specific binding site with the same affinities. With the exception of amineptine, all the tested catecholamine uptake inhibitors were equally potent to compete with [3H]GBR 12783 when Na+ concentration was decreased from 130 to 10 mM. These data suggest that the media previously used for the binding studies of tritiated inhibitors of dopamine uptake (Tris-ions buffer and Krebs-Ringer medium) contain ions which could exert inhibitory effects on the specific binding at low Na+ concentration.

Animals↗
PubMed2006

Interactions of cocaine with dopamine uptake inhibitors or dopamine releasers in rats discriminating cocaine.

Several dopamine (DA) indirect agonists have been proposed as potential medications for treating cocaine abuse. The objective of the present study was to quantify the interactions among cocaine and DA uptake inhibitors or DA releasers to better understand how these drugs may be working when administered in combination. The DA uptake inhibitors GBR 12909 [1-{2-[bis-(4-fluorophenyl)methoxy]-ethyl}-4-(3-phenylpropyl)piperazine], WIN 35,428 [2beta-carbomethoxy-3beta-(4-fluorophenyl)tropane], methylphenidate, indatraline, nomifensine, and mazindol and DA releasers methamphetamine, d-amphetamine, methcathinone, cathinone, fencamfamine, and phentermine were examined alone and in combination with cocaine in rats trained to discriminate cocaine (10 mg/kg i.p.) from saline injections. All of the DA indirect agonists dose-dependently substituted for cocaine and shifted the cocaine dose-effect curve leftward. Isobolographic analysis indicated the interactions were generally additive, although both methamphetamine and d-amphetamine were quantitatively determined to be more potent than DA uptake inhibitors in shifting the cocaine dose-effect function to the left. The potential of d-amphetamine as an effective treatment for cocaine abuse and negative clinical results with dopamine uptake inhibitors suggest that differences in shifts in dose-effect curves should be further examined with emerging clinical data as a predictive index of potential treatments for cocaine abuse.

Animals↗
PubMed1995

Effects of various dopamine uptake inhibitors on striatal extracellular dopamine levels and behaviours in rats.

In vivo central effects of some dopamine uptake inhibitors were evaluated in both brain microdialysis and behavioural studies in rats, and compared with their in vitro affinities to dopamine uptake sites. IC50 values of GBR12909 (1-[2- bis(4-fluorophenyl)methoxy]ethyl]-4-(3- phenylpropyl)piperazine), diclofensine, mazindol, amfonelic acid and nomifensine for inhibiting 1 nM [3H]GBR12935 (1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine) binding to rat striatal membrane were 7.0, 36, 81, 187 and 290 nM, respectively. In the brain microdialysis study, dopamine levels in the striatal dialysates were increased to 16.3- (GBR12909), 14.1- (nomifensine), 4.8- (diclofensine) and 1.9-fold (amfonelic acid) the respective basal levels 40-60 min after i.p. administration (0.1 mmol/kg) and thereafter decreased slowly but remained at the elevated levels for a further 3 h, while mazindol gradually increased dopamine levels though less pronouncedly than others (1.7-fold 200 min after administration). Remarkable and comparable stereotyped behaviours (licking and forepaw treading) were continuously observed at least for 3 h after administration of GBR12909, nomifensine and amfonelic acid, while stereotypies induced by diclofensine and mazindol were moderate and marginal, respectively. In vivo potencies of dopamine uptake inhibitors to increase the extracellular dopamine levels in the striatum tended to correlate with their in vitro affinities to dopamine uptake sites except in the case of nomifensine, and correlated significantly with their potencies to induce stereotyped behaviours except in the case of amfonelic acid. Based on these findings, pharmacological characteristics of these dopamine uptake inhibitors are discussed.

Animals↗
PubMed1999

Continuous infusion of selective dopamine uptake inhibitors or cocaine produces time-dependent changes in rat locomotor activity.

Chronic continuous cocaine treatment produces a unique pattern of locomotor activation over time. An initial, progressive increase in locomotion is indicative of sensitization. Unlike intermittent cocaine, this increase is subsequently reversed during the continuous exposure, and activity returns to pre-sensitization levels within days. To study the pharmacological mechanisms that underlie this phenomenon, osmotic minipumps containing cocaine or selective uptake inhibitors of dopamine (GBR 12909 or RTI-117), serotonin (fluoxetine), or norepinephrine (nisoxetine) were implanted into rats. Locomotor activity was measured for 1 h each day, beginning 4 h after pumps were implanted. In the cocaine group, activity was significantly elevated on the first day, peaked between the second and third days, then decreased to a plateau which remained significantly above control levels through 14 days. Peak activity in the GBR 12909 and RTI-117 animals occurred on the first day, followed by a significant decrease 24-48 h later, but not complete tolerance. Neither fluoxetine nor nisoxetine altered locomotor activity. The selective dopamine uptake inhibitors produced some of the effects of cocaine. The possibilities that cocaine interacts with the dopamine transporter in a qualitatively different manner from that of these selective dopamine uptake inhibitors, or that other monoamine systems are involved, are discussed.

Adrenergic Uptake Inhibitors↗
PubMed1993

Extracellular catecholamine levels in rat hippocampus after a selective alpha-2 adrenoceptor antagonist or a selective dopamine uptake inhibitor: evidence for dopamine release from local dopaminergic nerve terminals.

The effect of 6-chloro-2,3,4,5-tetrahydro-3-methyl-1-H-3-benzazepine (SKF 86466), a selective nonimidazoline alpha-2 adrenoceptor antagonist, on hippocampal release of norepinephrine and dopamine in conscious rats was investigated by in vivo microdialysis and high-pressure liquid chromatography. Additionally, extracellular concentrations of hippocampal dopamine (DA) and norepinephrine (NE), during infusion of selective monoamine uptake inhibitors, were determined in freely moving rats. The basal concentration of NE in the dialysate was 4.9 +/- 0.3 pg/20 microliters. Intravenous administration of 5 or 10 mg/kg of SKF 86466 was associated with a transient increase (30 min) of 2-fold (12 +/- 1 pg/20 microliters; P < .05) and 8-fold (39 +/- 3 pg/20 microliters; P < .05), respectively, in dialysate NE, whereas a 1-mg/kg dose had no effect. DA was not detected in basal dialysates, but after the administration of 5 or 10 mg/kg of SKF 86466, 3.9 +/- 0.4 and 6.4 +/- 0.6 pg/20 microliters, respectively, was present in the dialysates. The maximum increase in dialysate DA was reached 60 to 90 min after SKF 86466. The DA was not derived from plasma because plasma NE was elevated after the 5 mg/kg dose of SKF 86466 whereas no plasma DA was detected. In order to determine whether DA was present in noradrenergic nerve terminals, the dopamine beta-hydroxylase inhibitor SKF 102698 was administered (50 mg/kg i.p.). The inhibitor decreased dialysate NE but DA was still not detected in the dialysate.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Antagonists↗
PubMed1995

Dopaminergic modulation of serotonin metabolism in rat striatum: a study with dopamine uptake inhibitor GBR-12909.

The dopamine (DA) uptake inhibitor, GBR 12909 (GBR) and a neonatal dopaminergic denervated rat model were used as tools to study the influence of DA on the serotonin (5HT) system in the striatum. The striatal levels of the amines and their acid metabolites (dihydroxyphenylacetic acid, DOPAC; 5-hydroxyindoleacetic acid, 5HIAA) were determined by HPLC. The administration of a single dose (20 mg/kg) of GBR failed to affect the steady-state levels of the amines or metabolites. Repeated administration of GBR (20 mg/kg/day) for 2 or 4 days decreased DA and DOPAC; only the 4-day regimen decreased 5HT and increased 5HIAA levels. The neonatal dopaminergic lesion with 6-hydroxydopamine (6OHDA) depleted (> 95%) DA and DOPAC and increased 5HT and 5HIAA levels in the striatum. Administration of GBR (20 mg/kg/day for 4 days) to lesioned animals failed to influence the lesion-induced increases in 5HT and 5HIAA levels. The results suggest GBR decreases the steady-state levels of DA, resulting in a compensatory increase in the turnover of 5HT that is dependent on the presence of intact dopaminergic terminals. Thus, the effect of GBR on 5HT turnover is indirect. The studies provide further support for a prominent dopaminergic influence on striatal 5HT metabolism.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2002

Chronic cocaine increases kappa-opioid receptor density: lack of effect by selective dopamine uptake inhibitors.

Continuous infusion of cocaine or the selective dopamine uptake inhibitors GBR 12909 or RTI-117 increases locomotor stimulation, to which partial tolerance occurs. In addition, all three drugs produce significant decreases in tyrosine hydroxylase immunoreactivity in caudate putamen and nucleus accumbens core, suggesting a decreased dopaminergic tone. An interaction between cocaine and opioids has long been documented. Chronic cocaine significantly increases mu and kappa-opioid receptors and treatment with a kappa-opioid agonist markedly reduces the behavioral effects of cocaine. In addition, chronic cocaine, but not GBR 12909, increases prodynorphin gene expression in caudate putamen. To further understand the interaction between cocaine and the kappa-opioid system, the effects of a chronic continuous infusion for 14 days of cocaine or one of the selective dopamine uptake inhibitors GBR 12909 or RTI-117 via osmotic minipump were examined on kappa-opioid receptors using the selective kappa-opioid ligand [3H] U-69593. [3H] U-69593 binding density was significantly increased in caudate putamen, nucleus accumbens shell, claustrum, and endopiriform nucleus after cocaine, while neither GBR 12909 nor RTI-117 had any effect. The increased kappa-opioid receptor densities observed following cocaine are likely not related to dopamine uptake inhibition, since they were not produced by selective dopamine uptake inhibitors. These findings suggest that regulation of kappa-opioid receptors by cocaine may be via inhibition of serotonin or norepinephrine uptake, by a combination of effects on two or three monoamine transporters, or by a mechanism unrelated to transporter inhibition.

Animals↗
PubMed2001

Negative interaction of dopamine D2 receptor antagonists and GBR 12909 and GBR 12935 dopamine uptake inhibitors in the nucleus accumbens.

The objective of this study was to examine the interaction of dopamine D2 receptor antagonists and dopamine uptake inhibitors on the regulation of extracellular dopamine release in the nucleus accumbens of Wistar rats employing in vivo microdialysis and in vitro dopamine uptake studies. Application of the D2 receptor antagonists raclopride (100 microm) or sulpiride (100 microm) alone through the microdialysis probe in the nucleus accumbens for 60 min increased the extracellular levels of dopamine in the nucleus accumbens to 150% and 200% of basal, respectively. Perfusion of the nucleus accumbens for 60 min with the dopamine uptake inhibitors, 1-[2-[bis(4-Fluorophenyl)methoxy]ethyl]-4-[3-phenylpropyl]piperazine dihydrochloride (GBR 12909; 100 microm) or 1-[2-(Diphenylmethoxy)ethyl]-4-(3-phenylpropyl)-piperazine dihydrochloride (GBR 12935; 100 microm) alone, increased the extracellular levels of dopamine in the nucleus accumbens to 400% and 350% of basal, respectively. Co-perfusion of 100 microM GBR 12909 or GBR 12935 with either 100 microM sulpiride or raclopride produced a significant reduction in the GBR 12909 or GBR 12935 induced increase in the extracellular levels of dopamine to basal levels. In vitro, GBR 12909 (1-9 nM) dose-dependently inhibited active uptake of [3H]dopamine in homogenates of the nucleus accumbens. Addition of 100 microm sulpiride had little effect on GBR 12909 inhibition of [3H] dopamine uptake, suggesting that dopamine D2 receptor antagonists are not blocking the actions of the GBR-type dopamine uptake inhibitors at the dopamine transporter. Overall, the data suggest that complex interactions occur in vivo between D2 antagonists and GBR-type dopamine uptake inhibitors, which negate their effects on elevating the extracellular levels of dopamine in the nucleus accumbens.

Animals↗
PubMed1991

Characteristics of the ambulation-increasing effect of GBR-12909, a selective dopamine uptake inhibitor, in mice.

Behavioral effects of a dopamine uptake inhibitor, GBR-12909 (GBR), were evaluated by ambulatory activity in mice. The single administration of over 10 mg/kg of GBR, i.p. and p.o., significantly increased the ambulatory activity. The repeated administration of GBR, at only 10 mg/kg, produced a reverse tolerance to its ambulation-increasing effect. However, a cross-reverse tolerance was induced between GBR (10 and 20 mg/kg) and methamphetamine (2 mg/kg) in both directions. Furthermore, 5 mg/kg of GBR significantly enhanced the effects of methamphetamine, cocaine, imipramine, morphine, scopolamine and caffeine. R-THBP, a coenzyme of tyrosine hydroxylase, also enhanced the effect of GBR. In contrast, the ambulation-increasing effect of 10 mg/kg of GBR was markedly reduced by haloperidol, chlorpromazine, tetrabenazine, oxypertine, reserpine and alpha-methyl-p-tyrosine. On the other hand, the effect of GBR was only slightly and/or scarcely modified by apomorphine, caerulein, physostigmine, pilocarpine, N6-(L-2-phenylisopropyl)-adenosine and naloxone. The neurochemical experiment in rats, not in mice, revealed that GBR possessed more dominant action on dopaminergic systems than noradrenergic or serotonergic systems. However, the behavioral characteristics of GBR are similar to those of methamphetamine and cocaine, which possess less selective action than GBR on dopaminergic and noradrenergic systems.

Animals↗
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↗
PubMed2002

Studies, using in vivo microdialysis, on the effect of the dopamine uptake inhibitor GBR 12909 on 3,4-methylenedioxymethamphetamine ('ecstasy')-induced dopamine release and free radical formation in the mouse striatum.

The present study examined the mechanisms by which 3,4-methylenedioxymethamphetamine (MDMA) produces long-term neurotoxicity of striatal dopamine neurones in mice and the protective action of the dopamine uptake inhibitor GBR 12909. MDMA (30 mg/kg, i.p.), given three times at 3-h intervals, produced a rapid increase in striatal dopamine release measured by in vivo microdialysis (maximum increase to 380 +/- 64% of baseline). This increase was enhanced to 576 +/- 109% of baseline by GBR 12909 (10 mg/kg, i.p.) administered 30 min before each dose of MDMA, supporting the contention that MDMA enters the terminal by diffusion and not via the dopamine uptake site. This, in addition to the fact that perfusion of the probe with a low Ca(2+) medium inhibited the MDMA-induced increase in extracellular dopamine, indicates that the neurotransmitter may be released by a Ca(2+) -dependent mechanism not related to the dopamine transporter. MDMA (30 mg/kg x 3) increased the formation of 2,3-dihydroxybenzoic acid (2,3-DHBA) from salicylic acid perfused through a probe implanted in the striatum, indicating that MDMA increased free radical formation. GBR 12909 pre-treatment attenuated the MDMA-induced increase in 2,3-DHBA formation by approximately 50%, but had no significant intrinsic radical trapping activity. MDMA administration increased lipid peroxidation in striatal synaptosomes, an effect reduced by approximately 60% by GBR 12909 pre-treatment. GBR 12909 did not modify the MDMA-induced changes in body temperature. These data suggest that MDMA-induced toxicity of dopamine neurones in mice results from free radical formation which in turn induces an oxidative stress process. The data also indicate that the free radical formation is probably not associated with the MDMA-induced dopamine release and that MDMA does not induce dopamine release via an action at the dopamine transporter.

Animals↗
PubMed1991

Microdialysis studies on 3,4-methylenedioxymethamphetamine-induced dopamine release: effect of dopamine uptake inhibitors.

The effect of dopamine (DA) and serotonin (5-HT) uptake inhibitors on 3,4-methylenedioxymethamphetamine (MDMA)-induced increase in DA efflux was studied using in vivo microdialysis. MDMA was infused directly into the anterolateral striatum via the dialysis probe. The local administration of MDMA produced a dose- and time-dependent increase in the extracellular concentration of DA in the striatum. Peripheral administration of the DA uptake blockers, mazindol (5 mg/kg, i.p.) or GBR 12909 (10 mg/kg, i.p.), produced a slight but significant increase in the extracellular concentration of DA. Moreover, pretreatment with either mazindol or GBR 12909 30 min before the infusion of MDMA (10 microM) significantly attenuated the MDMA-induced increase in the extracellular concentration of DA. Pretreatment with fluoxetine (10 mg/kg, i.p.), a 5-HT uptake blocker, 30 min before the infusion of MDMA produced a slight but significant inhibition of MDMA-induced increase in DA concentration. In contrast, pretreatment with the 5-HT2/1C antagonist, ketanserin (3 mg/kg, i.p.), had no significant effect on the increase in DA concentration produced by the local administration of MDMA. These data are suggestive that MDMA increases the concentration of DA in the striatum, in part, via a carrier-mediated mechanism which is largely independent of its effects on 5-HT release.

3,4-Methylenedioxyamphetamine↗
PubMed1996

Place conditioning with cocaine and the dopamine uptake inhibitor GBR12783.

The rewarding and locomotor effects of the specific dopamine uptake inhibitor GBR12783 (2.5-20 mg kg-1, i.p.) were compared with those of cocaine. For both drugs, all doses produced a conditioned place preference (CPP), even the dose of 2.5 mg kg-1, which did not modify the locomotor activity. Despite an equivalent locomotor stimulation, the magnitude of CPP induced by cocaine (10 mg kg-1) was greater than that induced by the same dose of GBR12783. This confirms the involvement of dopamine uptake inhibition in reward, but underlines differences in relative efficacies in rewarding and motor effects of both drugs and suggests that these two properties are, at least in part, separable anatomically or functionally.

Animals↗
PubMed1997

Chronic administration of the selective dopamine uptake inhibitor GBR 12,909, but not cocaine, produces marked decreases in dopamine transporter density.

The chronic continuous infusion of cocaine produces partial behavioral tolerance to cocaine and tolerance to the inhibition of dopamine uptake by cocaine, without changing dopamine transporter binding. In order to examine more closely the dopaminergic contribution to this effect, the selective dopamine uptake inhibitor GBR 12,909 (30 mg/kg/day), cocaine (50 mg/kg/day), or vehicle, were continuously infused via osmotic minipump, and their effects on the dopamine transporter examined. Drug and vehicle pumps were implanted into male Sprague-Dawley rats and removed after seven days. [3H]WIN 35,428 binding and [3H]dopamine uptake were measured in caudate putamen and nucleus accumbens at varying intervals after pump removal. The Bmax for [3H]WIN 35,428 binding was decreased by approximately 75% in the caudate putamen and by 40% in the nucleus accumbens of GBR 12,909-treated rats both 1 and 4 days after pump removal, and was still significantly decreased after 10 days, but had returned to normal by 20 days post-treatment. In contrast, cocaine did not significantly alter [3H]WIN 35,428 binding. GBR 12,909 produced both tolerance to the inhibition of [3H]dopamine uptake by cocaine, and a decrease in total uptake of dopamine, in the caudate putamen, with no change in the nucleus accumbens. The persistent reduction of [3H]WIN 35,428 binding following continuous GBR 12,909 does not appear to result from residual drug binding. These findings suggest that GBR 12,909 and cocaine may bind to and regulate the dopamine transporter in different ways.

Animals↗
PubMed2001

Differential interaction of GBR 12909, a dopamine uptake inhibitor, with cocaine and methamphetamine in rats discriminating cocaine.

RATIONALE: Inhibitors of neuronal dopamine uptake, such as GBR 12909, decrease IV cocaine self-administration by laboratory animals and have been proposed as potential therapeutic agents for abuse of psychomotor stimulant drugs. OBJECTIVES: This study was performed to determine how GBR 12909 alters the discriminative stimulus effects of methamphetamine and cocaine. METHODS: Rats were trained to discriminate between IP injections of 10 mg/kg cocaine and saline and were tested for stimulus generalization to cocaine, GBR 12909, and methamphetamine. Based upon the ED50 of the individual drugs, combinations of GBR 12909 and either cocaine or methamphetamine were tested that comprised a) 1 part GBR 12909 and 2 parts cocaine or methamphetamine, or b) 2 parts GBR 12909 and 1 part cocaine or methamphetamine. RESULTS: GBR 12909 and cocaine were equipotent and 30-fold less potent than methamphetamine in producing cocaine-like discriminative effects. GBR 12909 and cocaine produced cocaine-like discriminative effects synergistically in the ratio of 1 part GBR 12909:2 parts cocaine (0.16+0.32 to 1.92+ 3.87 mg/kg) and nearly synergistically in the ratio of 2 parts GBR 12909:1 part cocaine (0.32+0.16 to 3.92+ 1.91 mg/kg). GBR 12909 and methamphetamine (0.32+0.02 to 3.20+0.22 mg/kg or 0.65+0.01 to 6.53+0.1 mg/kg) were simply additive in both sets of fixed-ratio dose combinations. CONCLUSIONS: The synergy of GBR 12909 and cocaine and the additivity of GBR 12909 and methamphetamine run counter to the presumed mechanisms of action of these drugs at dopamine nerve terminals, which might have implications for the use of GBR 12909 in the treatment of addiction to cocaine or amphetamines.

Animals↗
PubMed1996

Locomotor sensitization to [D-Trp(11)]neurotensin after repeated injections of the dopamine uptake inhibitor GBR12783 in rats.

Rats received one daily i.p. injection of the dopamine uptake inhibitor GBR12783 (1-[2-(diphenylmethoxy)ethyl]4-(3-phenyl-2-(propenyl)-piperazine) (10mg/kg) or vehicle for 9 days. Fourteen days after discontinuing treatment, their locomotor activity was assessed after injection of GBR12783 (5 mg/kg) or vehicle, then 6 days later, after i.c.v. injection of [D-Trp(11)]neurotensin (750 ng) or saline. A sensitization to the stimulant locomotor effects of both GBR12783 and [D-Trp(11)]neurotensin occurred in rats exposed to the actimeter following the 1st, 5th and 9th injections of GBR12783. Rats without prior experience of the activity cages before the challenge tests showed no sensitization to either GBR12783 or [D-Trp(11)] neurotensin. Our data suggest that a similar mechanism may underlie the locomotor sensitization to GBR12783 and the heterosensitization to [D-Trp(11)]neurotensin.

Animals↗
PubMed1987

In vivo binding of [3H]GBR 12783, a selective dopamine uptake inhibitor, in mouse striatum.

[3H]GBR 12783 (1,2-(diphenylmethoxy)ethyl-4-(3-phenyl-2-propenyl)-piperazine), a specific dopamine uptake inhibitor, was tested for in vivo central binding in mice. The difference between the striatal and cerebellar levels of radioactivity was maximal 1 hour after the i.v. injection of a tracer dose of [3H]GBR 12783. The additional accumulation of radioactivity in striatum, relatively to cerebellum, was dose-dependently decreased by dopamine uptake inhibitors. It was unaffected by high doses of dopamine receptor agonists or antagonists and of serotonin or norepinephrine uptake blockers. The intrastriatal injection of 6-hydroxydopamine (6-OHDA) resulted in an almost similar decrease in both the synaptosomal [3H]dopamine uptake and the in vivo [3H]GBR 12783 binding. These data suggest that [3H]GBR 12783 injected i.v. labels the dopamine transport complex in the striatum and thus can be used for the in vivo assessment of the density of dopaminergic nerve endings in brain areas.

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↗