ChemInform Abstract: ARYL 1,4‐DIALK(EN)YLPIPERAZINES AS SELECTIVE AND VERY POTENT INHIBITORS OF DOPAMINE UPTAKE

Zee, P. van der; Koger, H. S.; Gootjes, J.; Hespe, W.

doi:10.1002/chin.198102262

Cited by 110 publications

(211 citation statements)

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“…The lack of increase in the ratio of 3MT to DOPAC rates of formation after GBR 12909 (Table 5) suggests that, although GBR 12909 is a potent DA uptake blocker in vitro ( Van der Zee et al, 1980;Heikkila & Manzino, 1984;Nomikos et al, 1990) and apparently also in vivo (Vaugeois et al, 1993), its in vivo effects on synaptic DA metabolism and perhaps behaviour may not be entirely related to DA reuptake inhibition. This view is consistent with observations in which voltammetry was used to compare the effects of GBR 12909 with those of amphetamine and nomifensine on extracellular DA content in the nucleus accumbens and striatum (May et al, 1988).…”

Section: Discussionmentioning

confidence: 99%

“…The uptake inhibitors employed here were selected because they either are or can potentially be abused, and because of their different biochemical (Gerhards et al, 1974;Nomikos et al, 1990), pharmacological (Hunt et al, 1974;Kuczenski, 1983) and electrophysiological effects (Bunney & Aghajanian, 1978). Thus, while the behavioural effects of amphetamine and, to a certain extent, nomifensine (Braestrup & ScheelKruger, 1976;Broch, 1979;Hunt et al, 1979;Schacht et al, 1982;Kruk & Stamford, 1985;Hurd & Ungerstedt, 1989) have been attributed to stimulation of DA release as well as to its reuptake inhibition, those behavioural effects exhibited by cocaine and GBR 12909 are believed to result primarily from their potent DA reuptake inhibitory effects (Heikkila et al, 1975;Van der Zee et al, 1980;Heikkila & Manzino, 1984;Ritz et al, 1987 The treatment schedules were as follows. Five groups of rats were used; one group was given saline and the other four groups were injected with one psychostimulant each at 0 min.…”

Section: Introductionmentioning

confidence: 99%

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Regional effects of amphetamine, cocaine, nomifensine and GBR 12909 on the dynamics of dopamine release and metabolism in the rat brain

Karoum

Chrapusta

Brinjak

et al. 1994

British J Pharmacology

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1 The effects of single-dose regimens of amphetamine, cocaine, nomifensine and GBR 12909 on the dynamics of dopamine (DA) release and metabolism were evaluated in the frontal cortex, hypothalamus, nucleus accumbens and striatum. The regimens selected are known to produce substantial behavioural effects. 2 3-Methoxytyramine (3MT) and 3,4-dihydroxyphenylacetic acid (DOPAC) rates of formation were used to assess DA metabolism by catechol-O-methyltransferase and monoamine oxidase respectively. The rate of formation of 3MT was used as an index of synaptic DA. The ratio and sum, respectively, of 3MT and DOPAC rates of formation were used to assess DA reuptake inhibition and turnover. 3 The effects of amphetamine on 3MT production and DOPAC steady-state levels were similar in all regions, suggesting similar pharmacodynamic actions. Amphetamine increased 3MT formation and steady-state levels, and reduced DOPAC steady-state levels. DOPAC formation was significantly reduced only in the nucleus accumbens and striatum. Total DA turnover remained unchanged except in the nucleus accumbens. Apparently, the amphetamine-induced increase in DA release occurred at the expense of intraneuronal DA metabolism and did not require stimulation of synthesis. 4 Nomifensine elevated 3MT formation in all regions. A similar effect was produced by cocaine except in the nucleus accumbens. GBR 12909 elevated 3MT production only in the hypothalamus, the striatum and the nucleus accumbens. 5 Cocaine selectively reduced DOPAC formation in the frontal cortex. Nomifensine increased and reduced, respectively, DOPAC formation in striatum and hypothalamus. GBR 12909 elevated DOPAC formation in all regions except the cortex, where pargyline did not reduce DOPAC levels in GBR 12909-treated rats. 6 Ratios and sum of 3MT and DOPAC rates of formation also exhibited wide regional variations for each drug. In contrast to the other drugs, the ratio was not increased after GBR 12909. Apparently, the DA uptake properties of this drug are poorly related to its in vivo effects on the ratio of 3MT production to that of DOPAC, which should increase when DA reuptake is inhibited. 7 Total DA turnover was increased by GBR 12909 in the hypothalamus, nucleus accumbens and striatum, while cocaine and nomifensine increased it only in the nucleus accumbens and striatum respectively. 8 It is concluded that: (a) 3MT and DOPAC rates of formation provide better indices of DA release and metabolism than do their steady-state concentrations. (b) Some effects of DA uptake blockers on DA transmission, especially those of nomifensine and cocaine, may be attributed to increased DA release. (c) Patterns of regional effects of psychostimulants on the dynamics of DA release and metabolism may be better biochemical correlates of stimulant-induced behaviours than would changes in any single region.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Regional effects of amphetamine, cocaine, nomifensine and GBR 12909 on the dynamics of dopamine release and metabolism in the rat brain

Karoum

Chrapusta

Brinjak

et al. 1994

British J Pharmacology

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“…Unlabeled (-)-cocaine was supplied by Dr Rapaka of NIDA. GBR12909-(HCl)2 was synthesized in Laboratory of Medical Chemistry, NIDDK, as described [22). Other reagents were purchased from Sigma Chemical Co.…”

Section: Gbr12909mentioning

confidence: 99%

Tight binding dopamine reuptake inhibitors as cocaine antagonists

Rothman¹,

Mele²,

Reid³

et al. 1989

FEBS Letters

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The experiments reported in this study tested the hypothesis that tight binding dopamine (DA) reuptake inhibitors might act as cocaine antagonists. Binding studies demonstrated that the high affinity dopamine reuptake inhibitor, I-[2-[bis(efluorophenyl)methoxy]ethyl]-4_raz-ine (GBR12909) produced a wash-resistant inhibition of the DA transporter in rat striatal membranes as labeled by PHIcocaine or PH]l-[2-(diphenyl-methoxy)ethyl]-4-(3-phenylpropyl)piperazine(PH]GBR12935), indicative of tight binding. In vivo microdialysis experiments showed that administration of 25 mg/kg GBR12909 to rats produced a modest, but not statistically significant, increase in the extracellular levels of striatal DA, while this same dose of GBR12909 inhibited the ability of cocaine to elevate extracellular DA levels by 64%. These data suggest that tight binding DA reuptake blockers may provide a fruitful approach for developing a cocaine antagonist.Cocaine; Dopamine reuptake inhibitor; Microdialysis, in vivo; Dopamine

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“…Single neural lobes with the stalk held in the electrode were incubated at 37 "C in Krebs solution of the following composition (mM): NaCl 118.5; KCI 5.7; CaC1, 1.25; MgCI, 1.2; sodium EDTA 0.03; (+ )ascorbic acid 0.06; HEPES 20.0 (pH 7.4) and D-glucose 11.1. The medium also contained the dopamine uptake inhibitor, GBR 12921 (200 nM) (40) and in some experiments additionally the monoamine oxidase inhibitor, pargyline (10 pM). For the first 30 min of incubation the bath volume was 5 ml.…”

Section: Methodsmentioning

confidence: 99%

Effects of Different Opioid Receptor Antagonists on the Electrically‐Evoked Release of Endogenous Dopamine from the Isolated Neural Lobe of the Rat Pituitary Gland in vitro

Racké

Hering

Weber

1990

J Neuroendocrinology

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Isolated neural lobes of the rat pituitary gland were incubated in Krebs-HEPES solution which contained the dopamine uptake inhibitor GBR 12921 and in some experiments additionally pargyline. The release of endogenous dopamine evoked by electrical stimulation of the pituitary stalk was determined by high-performance liquid chromatography with electrochemical detection. (*)-Naloxone increased the evoked dopamine release maximally by 440% (EC,, 209 nM). The (+)-enantiomer of naloxone (up to 10 pM) did not affect the release of dopamine. The preferential rc-opioid receptor antagonist M R 2266 increased the evoked dopamine release maximally by 135% (EC,, 7 nM). M R 2267, the inactive (+)-enantiomer of M R 2266, had no effect on dopamine release. The 8-opioid receptor selective antagonist ICI 174864 increased the release of dopamine maximally by 120% (EC,, 10 nM). The nonselective opioid receptor agonist etorphine up to 10 pM had no effect on the evoked dopamine release. In conclusion, endogenous opioids in the neurohypophysis strongly inhibit the release of endogenous dopamine from this gland. Activation of K-and 8-opioid receptors appears to be involved in the inhibitory action of the endogenous opioids on the neurohypophysial release of dopamine.The rat neurohypophysis contains, beside the classical neurohormones vasopressin and oxytocin, a number of other biologically active neuropeptides and neurotransmitters. Thus, dopaminergic and noradrenergic nerve fibres innervate this gland (1-4). There is considerable evidence that dopamine and noradrenaline may play a significant role as local modulators of the release of vasopressin and oxytocin (4-9). In addition, different opioid peptides are present in the neurohypophysis in high concentrations. They appear to be co-localized with the neurohormones in the neurosecretory nerve endings, those derived from pro-dynorphin with vasopressin and those derived from pro-enkephalin with oxytocin (10-13). In addition, depolarizing stimuli which are known to induce the release of vasopressin and oxytocin (14-16) also evoke the release of the opioid peptides Since the opioid receptor antagonist naloxone increased the release of vasopressin (20, 21) and particularly that of oxytocin (21-28), it was concluded that the endogenous opioids in the neurohypophysis may modulate directly the release of these neurohormones. Furthermore, these opioids also appear to inhibit the release of noradrenaline and dopamine in this gland, since naloxone also enhanced the electrically-evoked release of [3H]-noradrenaline (2 I ) and that of endogenous dopamine (29) from the isolated neurohypophysis. Thus, the endogenous opioids in (1 7-19).the neurohypophysis appear to control the release of several neurotransmitters and neurohormones.It is now clear that opioid receptors consist of several subtypes (30). Therefore, it appears possible that the different opioid peptides in the neurohypophysis may modulate the release of the neurohormones and that of the catecholamines via different opioid recep...

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ChemInform Abstract: ARYL 1,4‐DIALK(EN)YLPIPERAZINES AS SELECTIVE AND VERY POTENT INHIBITORS OF DOPAMINE UPTAKE

Cited by 110 publications

References 0 publications

Regional effects of amphetamine, cocaine, nomifensine and GBR 12909 on the dynamics of dopamine release and metabolism in the rat brain

Regional effects of amphetamine, cocaine, nomifensine and GBR 12909 on the dynamics of dopamine release and metabolism in the rat brain

Tight binding dopamine reuptake inhibitors as cocaine antagonists

Effects of Different Opioid Receptor Antagonists on the Electrically‐Evoked Release of Endogenous Dopamine from the Isolated Neural Lobe of the Rat Pituitary Gland in vitro

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