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J C Stoof

Publications and source records attributed to J C Stoof.

At least 55 records · Page 3Linked to original sources
PubMed1994

Dopamine D1 receptor agonists display a different intrinsic activity in rat, monkey and human astrocytes.

Measuring dopamine D1 receptor stimulated cyclic AMP production in cultured astrocytes from rat, monkey and human brain, we demonstrate that the 'classical' drug SKF 38393 (7,8-dihydroxy-1- phenyl-2,3,4,5-tetrahydro-1 H-3-benzazepine) is a partial agonist with particularly low intrinsic activity in primates. Furthermore, its analogue SKF 81297 (6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5- tetrahydro-1 H-3-benzazepine) is shown to be a full agonist in rats but a partial, albeit more efficacious, agonist in primates, whereas the benzopyran A 68930 ((1R,3S)-1-aminomethyl-5,6- dihydroxy-3-phenyl-isochroman HCl) displays full efficacy in both species. The data suggest that cultured astrocytes provide a good model to study species differences in the pharmacological characteristics of dopamine D1 receptor agonists and indicate that SKF 38393 is not suited to study dopamine D1 receptor function in primates.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1994

The dopamine D1 agonist SKF 81297 and the dopamine D2 agonist LY 171555 act synergistically to stimulate motor behavior of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned parkinsonian rhesus monkeys.

At present, the pharmacotherapy of Parkinson's disease (PD) consists mainly of L-dihydroxyphenylalanine (L-DOPA) and/or dopamine D2 receptor agonists. However, in general the clinical efficacy of D2 agonists is less than that of L-DOPA. Therefore, attention is being focussed on the role of the D1 receptor as a target for therapeutic intervention in PD. Recently, we reported that SKF 81297 is a selective D1 agonist that stimulates motor behavior of unilaterally MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-lesioned rhesus monkeys. Presently, we studied the effect of coadministration of SKF 81297 and the D2 agonist LY 171555 using the same model of PD. Coadministration of behaviorally active doses of SKF 81297 (0.3 mg/kg) and LY 171555 (0.01 mg/kg) resulted in a prolongation of the motor stimulation induced by either of the drugs alone. Neither administration of SKF 81297, in a dose of 0.03 mg/kg, nor of LY 171555, in a dose of 0.003 mg/kg, were behaviorally active, whereas the combined administration of these compounds induced a significant stimulation of motor behavior. These data suggest that (a) D1 receptor stimulation will prove to be useful in the treatment of PD and (b) better therapeutic results will be obtained by simultaneous stimulation of D1 and D2 receptors as compared with stimulation of both receptors alone.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1994

No direct correlation between behaviorally active doses of the dopamine D2 agonist LY 171555 and displacement of [123I]IBZM as measured with SPECT in MPTP monkeys.

Almost no information is available concerning the link between clinical effects of dopamine D2 receptor agonists in the treatment of Parkinson's disease (PD) and the extent of D2 receptor occupancy in the brain. Therefore, we investigated the possible correlation between administration of behaviorally active doses of the selective D2 agonist LY 171555 and in vivo D2 receptor occupancy in the unilateral 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-lesioned rhesus monkey model of PD. Single photon emission computed tomography (SPECT) with the D2 receptor antagonist [123I]IBZM (iodobenzamide) as radioligand was used to estimate the receptor occupancy. The MPTP-lesioned monkeys consistently showed signs of unilateral parkinsonism. LY 171555 (0.01 or 0.3 mg/kg) significantly increased contralateral rotation (away from the lesion), being most effective at the lower dose. In the MPTP-lesioned monkeys [123I]IBZM activity in the left (lesioned) striatum was significantly higher as compared to that in the right striatum. Only upon administration of 0.3 mg/kg LY 171555 a significant amount of receptor occupancy by LY 171555, as measured with [123I]IBZM SPECT, at both lesioned and non-lesioned side, was detected. Using D2 receptor mediated inhibition of the evoked release of [3H]acetylcholine from rat striatal tissue as a functional model, we showed that the lack of effect with 0.01 mg/kg LY 171555 was not due to non-competitive interaction between LY 171555 and IBZM at the D2 receptor. We conclude that the D2 antagonist [123I]IBZM is not a suitable SPECT ligand to study the relationship between behavioral effects of the selective D2 agonist LY 171555 in unilaterally MPTP-lesioned monkeys and the D2 receptor occupancy in vivo in this animal model of PD.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1994

Dopamine displays an identical apparent affinity towards functional dopamine D1 and D2 receptors in rat striatal slices: possible implications for the regulatory role of D2 receptors.

In this study we examined the selectivity of dopamine (DA) for rat striatal DA D1 and D2 receptors. In a Krebs-HEPES buffer, the Ki values of DA for D1 binding sites (labelled with [3H]SCH23390) and D2 binding sites (labelled with [3H]spiroperidol) in striatal membranes amounted to about 30 and 0.3 microM, respectively. However, the EC50s of DA (3 microM) and the DA releasing drug amphetamine (1 microM) were identical considering D1 receptor-stimulated and D2 receptor-inhibited adenylate cyclase activity in superfused striatal slices. Moreover, these EC50 values were also obtained studying DA- and amphetamine-induced D2 receptor activation, resulting in inhibition of the electrically evoked release of [14C]acetylcholine from the slices. Therefore, with regard to the apparent affinity of exogenous and endogenous DA for D1 and D2 receptors in rat striatal slices, the ligand-receptor binding data appeared to be misleading. Thus, our data show that in rat striatal slices DA has an identical apparent affinity towards functional D1 and D2 receptors, which is particularly intriguing in view of the very high receptor selectivity of synthetic D1 and D2 receptor agonists for these functional receptors in superfused brain slices as predicted on the basis of binding assays. This may have important implications for our understanding of central DA neurotransmission. For instance, since the inhibitory effect of opioid and muscarinic receptor activation on adenylate cyclase activity has been shown to be inversely related to the degree of DA D2 receptor activation, the degree of activation of D1 and D2 receptors by released DA is suggested to act as a functional gate allowing distinct neurotransmitters to play a role in striatal neurotransmission.

Acetylcholine↗
PubMed1994

Dopamine D-2 autoreceptors regulating the release of dopamine from cultured rat fetal dopaminergic neurons do not desensitize upon sustained activation: implications for the combined pharmaco- and grafting therapy in parkinsonian patients.

Cultured rat fetal mesencephalic dopaminergic neurons exhibit specific high-affinity uptake for [3H]dopamine (DA) and express DA D-2 autoreceptors, functionally coupled to the inhibition of depolarization evoked [3H]DA release. In this study, we examined the effect of short- and long-term sustained agonist exposure on the responsiveness of these DAD-2 receptors, expressed on cultured fetal mesencephalic dopaminergic neurons. Therefore, cultures were incubated in the absence or presence of the selective D-2 receptor agonist LY 171555 (Quinpirole, 1 microM) before the DA D-2 receptor-mediated inhibition of depolarization-induced [3H]DA release was determined. Short-term preincubation of cultures for 4 h did not lead to any change in the K(+)-evoked [3H]DA release nor to a change in the efficacy of LY 171555 (1 microM) to inhibit this release. Similar results were obtained after long-term agonist exposure for 6 days. Only after exposure for 12 consecutive days was a small reduction of the LY 171555 mediated inhibitory effect on DA release observed, while the IC50 value was slightly shifted to the right as compared to control cultures. Additionally, in pretreated cultures, a statistically significant increase was observed in the depolarization-induced release of [3H]DA in the absence of drugs. In the same model, activation of muscarinic acetylcholine (M-ACh) receptors was shown to potentiate the depolarization-induced release of [3H]DA. Preincubation for 4 h with the muscarinic agonist carbachol (100 microM) induced a strong reduction in the M-ACh receptor-mediated effect on [3H]DA release, indicative of a rapid desensitization of M-ACh receptors. It is concluded that, while no functional desensitization of DA D-2 autoreceptors is apparent, the depolarization-induced release of DA from cultured fetal dopaminergic neurons is enhanced upon long-term sustained activation of DA D-2 receptors.

Animals↗
PubMed1994

Subchronic treatment with the neuroleptic-like peptide desenkephalin-gamma-endorphin may decrease dopaminergic neurotransmission in the nucleus accumbens of rats.

In rats, subchronic administration of desenkephalin-gamma-endorphin (DE gamma E) into the nucleus accumbens or subcutaneously for 10 days resulted in hypoactivity. Intra-accumbens administration caused a significant reduction in the nucleus accumbens tissue levels of the dopamine (DA) metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). Systemic administration of DE gamma E decreased DOPAC and 5-hydroxyindoleacetic acid (5-HIAA) levels in nucleus accumbens tissue. Subchronic subcutaneous DE gamma E treatment reduced the basal release of [3H]DA from rat nucleus accumbens slices in vitro and the basal release of endogenous DA and DOPAC in vivo as assessed with on-line dialysis in the nucleus accumbens of freely moving rats. The DA agonist N,N-dipropyl-7-hydroxy-2-aminotetralin (DP-7-ATN) was equally effective in inhibiting [3H]DA release elicited by electrical stimulation from slices of subchronically DE gamma E and placebo treated rats. Administration of a small dose of apomorphine caused similar reductions of the in vivo release of DA and DOPAC in both placebo and DE gamma E treated rats. These results indicate that subchronic DE gamma E treatment may decrease dopaminergic neurotransmission in the nucleus accumbens. This effect is probably not due to alterations in the sensitivity of presynaptically located DA autoreceptors mediating DA release in vitro and in vivo.

Animals↗
PubMed1993

Regional differences in the dopaminergic regulation of cyclic AMP formation within the rat nucleus accumbens: comparison with the striatal complex of the lizard Gekko gecko.

Effects of dopamine D2 receptor activation on the forskolin or D1 receptor stimulated formation of cyclic adenosine monophosphate (cyclic AMP) were investigated in tissue slices of two subregions of the rat nucleus accumbens and in the striatal complex of a lizard. Cyclic AMP production in the tissue was estimated by measuring the conversion of [3H]adenine in a superfusion system. Activation of a D2 receptor appeared to inhibit the D1 receptor agonists or forskolin stimulated formation of cAMP in the rostrolateral but not in the caudomedial part of the rat nucleus accumbens. In the striatal complex of the lizard the formation of cAMP was dramatically stimulated by forskolin, but only marginally by dopamine. Neither the forskolin, nor the dopamine stimulated cyclic AMP formation could be inhibited by activation of D2 receptors. These findings are compatible with previously obtained functional data indicating that especially the caudomedial part of the rat nucleus accumbens has much in common with the striatal complex of the lizard.

Animals↗
PubMed1993

The selective dopamine D1 receptor agonist, SKF 81297, stimulates motor behaviour of MPTP-lesioned monkeys.

The alleged selective, high efficacy dopamine D1 receptor agonist, SKF 81297 (0.05-0.3 mg/kg i.m.), induced rotational behaviour away from the lesion and stimulated use of the dominant right hand in unilaterally (left side) 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned rhesus monkeys (Macaca mulatta). The effects of SKF 81297 were completely blocked by the dopamine D1 receptor antagonist, SCH 23390 (0.05 mg/kg), but not by the dopamine D2 receptor antagonist, remoxipride (1 mg/kg), and were similar to those induced by the selective dopamine D2 agonist, LY 171555 (0.01 mg/kg). These results suggest a functional stimulatory role for the dopamine D1 receptor on motor behaviour in a non-human primate model of Parkinson's disease when stimulated with a high efficacy selective dopamine D1 receptor agonist.

Analysis of Variance↗
PubMed1993

Chronic dopamine D2 receptor activation does not affect survival and differentiation of cultured dopaminergic neurons: morphological and neurochemical observations.

Primary cultures of rat ventral mesencephalon were used to elucidate the role of chronic stimulation of dopamine (DA) D2 autoreceptors in the development of fetal dopaminergic neurons in vitro. Cultured dopaminergic neurons, as visualized by tyrosine hydroxylase immunocytochemistry, became more differentiated in the course of cultivation time and exhibited specific high-affinity uptake for [3H]DA. In rat striatal tissue, activation of D2 receptors has been shown to inhibit the release of DA. Previously accumulated [3H]DA was released from the cultures upon depolarization in a Ca(2+)-dependent manner. K(+)-evoked [3H]DA release could be inhibited by the selective D2 receptor agonists LY 171555 and N0437 in a concentration-dependent manner. The inhibitory effects of LY 171555 and N0437 were antagonized by the selective DA D2 receptor antagonist sulpiride. These observations are indicative for the expression of functional D2 receptors in the cultures. Daily treatment of these cultures for 7 days with LY 171555 or sulpiride did not lead to any change in protein content, the number of tyrosine hydroxylase-immunoreactive neurons, or the uptake capacity for [3H]DA. Our data demonstrate that chronic stimulation of DA D2 receptors does not impair survival or differentiation of cultured fetal dopaminergic neurons.

Animals↗
PubMed1992

Growth inhibition of human glioma cells induced by 8-chloroadenosine, an active metabolite of 8-chloro cyclic adenosine 3':5'-monophosphate.

8-Chloroadenosine 3':5'-monophosphate (8ClcAMP) inhibits the growth of human glioma cell lines at much lower concentrations than more commonly used cyclic AMP analogues, without inducing morphological differentiation. The mechanism by which 8ClcAMP exerts this effect is not fully understood. We examined whether the growth-inhibitory effect of this compound is due to an active metabolite, using a sulforhodamine protein stain assay to determine the proliferation rate of the WF human glioma cell line. 8-Chloroadenosine, one of the metabolites, inhibited the proliferation of WF human glioma cells more potently than 8ClcAMP. In the presence of adenosine deaminase, which converts 8-chloroadenosine into 8-chloroinosine, 8-chloroadenosine no longer inhibited human glioma cell growth. Addition of adenosine deaminase also largely reduced the growth-inhibitory effect of 8ClcAMP, but not of 8-(4-chlorophenylthio)cAMP. High performance liquid chromatography analysis revealed that at least part of the 8ClcAMP in the culture medium is converted into 8-chloroadenosine. We concluded that 8ClcAMP exerts its growth-inhibitory effect through its active metabolite 8-chloroadenosine. Adenylate cyclase assays showed that 8-chloroadenosine does not affect the intracellular cAMP production through adenosine A1 or A2 receptor activation, which makes it unlikely that 8-chloroadenosine inhibits glioma cell growth by increasing the intracellular cyclic AMP concentration.

2-Chloroadenosine↗
PubMed1992

The anti-parkinsonian drug amantadine inhibits the N-methyl-D-aspartic acid-evoked release of acetylcholine from rat neostriatum in a non-competitive way.

The anti-viral drug amantadine is used in the treatment of Parkinson's disease without the drug having a well established mechanism of action. Amantadine is reported to displace the non-competitive NMDA receptor antagonist MK-801 from its binding site in the central nervous system. We show that amantadine inhibits, in a non-competitive way, the NMDA receptor-mediated stimulation of acetylcholine release from rat neostriatum in vitro in 'therapeutic' (i.e. low micromolar range) concentrations. Moreover, contrary to previous reports, amantadine, in this concentration range, did not affect the in vitro release of dopamine from neostriatal tissue.

Acetylcholine↗
PubMed1992

Implication of glucocorticoid receptors in the stimulation of human glioma cell proliferation by dexamethasone.

Dexamethasone is frequently used in the therapy of brain tumor patients. We investigated the effect of dexamethasone on the proliferation of three short-term and four established human glioma cell lines in vitro, using a microculture tetrazolium assay to determine growth rates. In one short-term culture and in one established cell line dexamethasone consistently stimulated the proliferation in a concentration-dependent way. The proliferation was maximally enhanced at a concentration of approximately 0.1 microM. In these two cell lines a relatively high level of glucocorticoid receptors was present, whereas low levels of glucocorticoid receptors were found in the other cell lines. In addition, we demonstrated that the stimulatory effects of dexamethasone on the proliferation of the glioma cell lines can be antagonized by the antiglucocorticoid RU38486. The results demonstrate unequivocally that the glucocorticoid receptor plays a role in the growth stimulating effect of dexamethasone.

Cell Division↗
PubMed1992

The effect of intrastriatal application of directly and indirectly acting dopamine agonists and antagonists on the in vivo release of acetylcholine measured by brain microdialysis. The importance of the post-surgery interval.

The effect of intrastriatal application of D-1, D-2 and indirect dopaminergic drugs on the release of striatal acetylcholine as a function of the post-implantation intervals was studied using in vivo microdialysis. The dopamine D-2 agonists LY 171555 and (-)N0437 inhibited the release of striatal acetylcholine to 40% of control values 16-24 h after implantation of the dialysis cannula. When LY 171555 was infused 40-48 h after implantation of the dialysis cannula, the response was attenuated to 20% of control values. Meanwhile, the effectiveness of infusions of the antagonists (-)sulpiride and haloperidol was augmented from a non significant effect at 16-24 h to a 150% increase 40-48 h after implantation of the cannula. Infusions of the dopamine releasing agent amphetamine or the dopamine uptake inhibitor nomifensine resulted in a dose-dependent increase in the overflow of dopamine. Not until a sevenfold increase in the level of dopamine was seen, the release of acetylcholine was significantly affected. This hyporesponsiveness of the striatal cholinergic interneurons to endogenous dopamine could not be attributed to dopamine D-1 receptor activation, since no effects on striatal acetylcholine release were found by intrastriatal infusions of the selective D-1 agonist CY 208-243 or the selective D-1 antagonist SCH 23390. The results indicate that dopamine D-2 receptors are involved in the regulation of striatal acetylcholine release and that these receptors are tonically occupied by endogenous dopamine under the present experimental conditions 40-48 h after probe implantation.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1992

8-Chloro-cyclic adenosine monophosphate, a novel cyclic AMP analog that inhibits human glioma cell growth in concentrations that do not induce differentiation.

Cyclic AMP is supposed to play a role in cell growth and differentiation via activation of protein kinase A. The cAMP signal transduction pathway may therefore be used as a target for the development of anticancer drugs. We compared the effects of 8ClcAMP, a newly developed cAMP analog, to the effects of more commonly used cAMP analogs on the morphology and the proliferation of three human glioma cell lines. 8ClcAMP was the most potent growth inhibitor, exhibiting an IC50 of approximately 10 microM and inducing growth arrest in all three glioma cell lines at a concentration of 100 microM. The cAMP analogs 8CPTcAMP, dibutyryl cAMP, and 8BrcAMP were much less potent. If used in concentrations that induce growth arrest, both 8CPTcAMP and IBMX, but not 8ClcAMP, induced morphological differentiation of the glioma cells. Apparently, the growth-inhibiting effect of 8ClcAMP is not paralleled by its ability to induce morphological differentiation. The explanation for this phenomenon may be that 8ClcAMP does not exert its growth-inhibiting effect via activation of cAMP-dependent protein kinase. Two alternative mechanisms of action are discussed. Since 100 microM 8ClcAMP retarded the growth of normal rat astrocytes only to a marginal extent, without cytotoxic effects, it is concluded that 8ClcAMP may offer interesting perspectives in the treatment of malignant glioma.

1-Methyl-3-isobutylxanthine↗
PubMed1992

Amantadine as N-methyl-D-aspartic acid receptor antagonist: new possibilities for therapeutic applications?

The N-methyl-D-aspartic acid (NMDA) receptor is an intriguing target for the development of drugs with anti-Parkinsonian activity as well as with protective actions against degenerative processes induced by brain ischemia. Amantadine is used in the treatment of Parkinson's disease without a well established mechanism of action. We show here that amantadine inhibits, in a non-competitive way, the NMDA receptor-mediated stimulation of acetylcholine release from rat neostriatum in vitro in "therapeutic" (i.e., low micromolar) concentrations. This indicates that amantadine might exert its anti-Parkinsonian effect via blockade of NMDA receptors. Sustained stimulation of NMDA receptors induces so-called excitotoxicity. Recently, it was demonstrated that amantadine is able to inhibit NMDA induced cell death in a neuronal culture. On the basis of these findings it seems worth investigating if amantadine is also able to protect against neurodegenerative processes caused by brain ischemia in vivo.

Acetylcholine↗