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S Urwyler

Publications and source records attributed to S Urwyler.

29 records · Page 2Linked to original sources
PubMed1987

Binding of 3H-spiperone and 3H-(-)-sulpiride to dopamine D2 receptors in rat striatal membranes: methodological considerations and demonstration of the identical nature of the binding sites for the two ligands.

In order to test the hypothesis emerging from the literature that 3H-sulpiride and 3H-spiperone might label different subclasses of dopamine D2 receptors in the brain, the binding properties of the two ligands were compared under optimized conditions. 3H-sulpiride was found to show a very fast rate of dissociation from the receptor. Furthermore, with this ligand, an apparently "specific" binding to glass fiber filters was observed. A centrifugation assay was therefore used for the characterization of 3H-sulpiride binding. The binding of 3H-spiperone was measured in a way which prevented its attachment to sites other than D2 receptors. Under these conditions, the two ligands were found to label identical dopaminergic recognition sites (D2 receptors) according to the following criteria: 3H-sulpiride and 3H-spiperone both labelled only one single site with a comparable density. Identical changes in the receptor number for both ligands were found in the tissue from animals with nigrostriatal 6-hydroxydopamine lesions. The potencies of various dopamine agonists and antagonists in displacing 3H-sulpiride or 3H-spiperone from their binding sites showed a highly significant one to one correlation. Finally, the binding of both ligands could be inactivated by pretreatment of the membranes with N-ethylmaleimide, with or without Na+-ions being present. This inactivation followed exactly the same kinetics for both radioligands. Thus, no indication supporting the hypothesis that 3H-sulpiride and 3H-spiperone might label different subsets of dopamine D2 receptors in the rat brain could be found.

Animals↗
PubMed1987

Affinity shifts induced by cations do not reliably predict the agonistic or antagonistic nature of ligands at brain dopamine receptors.

The effects of Ca2+ and Na+ ions on the affinities of rat striatal dopamine D1 and D2 receptors for a wide range of agonists and antagonists were investigated. These experiments were performed at 37 degrees C, since it was found that at this physiological temperature D2 receptor affinities for dopamine and 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene were clearly lower than at room temperature. No correlation was found between the effects of the cations on the affinities of compounds for D1 and D2 receptors and their agonistic or antagonistic nature. On the other hand, the Hill coefficients of agonists but not of antagonists were consistently and significantly below unity, with either Ca2+ or Na+ ions present and at both receptors. This suggests the existence of yet another type of heterogeneity of D1 and D2 receptor forms, to which agonists but not antagonists are sensitive. It is thus concluded that changes in D1 and D2 receptor affinities induced by cations do not predict the agonistic or antagonistic nature of a compound. However, since dopamine itself was sensitive to Na+ or Ca2+ ions, this mechanism might play a role in the regulation of receptor affinities in synaptic transmission, in addition to that exerted by guanyl nucleotides.

Animals↗
PubMed1986

Biochemical and pharmacological effects of fluperlapine on noradrenaline and acetylcholine systems in some rodent, bovine and crustacean preparations.

Fluperlapine was compared with clozapine, chlorpromazine, haloperidol and imipramine regarding its effects on some cholinergic and noradrenergic animal systems. Fluperlapine and clozapine showed the most pronounced anticholinergic effects. Fluperlapine was equipotent with clozapine in displacing [3H]-QNB from muscarinic receptors of the calf cerebral cortex (IC50 about 15 nM). In the mydriasis test in the mouse and in the crayfish hindgut bioassay the differences between fluperlapine and clozapine were small. Like the other antischizophrenic drugs tested, fluperlapine displayed a marked affinity for alpha 1-adrenoceptors (calf cerebral cortex: IC50 about 10 nM) but a negligible affinity for alpha 2-adrenoceptors in the same tissue. Only clozapine showed a weak affinity for the latter receptor type. Fluperlapine was as effective as imipramine in antagonizing tetrabenazine-induced ptosis in the rat, the anti-ptotic effect remaining constant after up to ten daily drug administrations. Still, imipramine was stronger than fluperlapine as an inhibitor of the accumulation of [3H]-noradrenaline ([3H]-NA) in rat cerebral cortex slices. Fluperlapine's effects on the spontaneous and the electrically-induced release of [3H]-NA from rat cerebral cortex slices, with and without protriptyline, showed it to be an inhibitor of the reuptake of NA. The results indicate that the pharmacological profile of fluperlapine is similar to that of clozapine, with additional antidepressant properties.

Acetylcholine↗
PubMed1986

Identification of dopamine "D3" and "D4" binding sites, labelled with [3H]2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene, as high agonist affinity states of the D1 and D2 dopamine receptors, respectively.

On the basis of affinity differences for spiperone, two binding sites for [3H](+/-)-2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene ([3H]ADTN) in the rat brain could be distinguished: "D3" with a low and "D4" with a high affinity for spiperone. Evidence is provided that D3 and D4 sites are related to high agonist affinity states of the D1 and D2 dopamine receptors, respectively. Various well-known selective D1 and D2 agonists and antagonists showed potencies at these sites in agreement with this hypothesis. A comparison of the Bmax values for [3H]ADTN binding to D3 and D4 sites with the numbers of D1 receptors (labelled by [3H]SCH 23390) and of D2 receptors (labelled by [3H]spiperone), both in the striatum and in the mesolimbic system, indicated that under the conditions used for 3H-agonist binding experiments, both populations of D1 and D2 receptors were converted to their high agonist affinity states to a considerable, although different extent. In fact, when competition experiments with [3H]spiperone were performed under the conditions otherwise used for [3H]ADTN binding experiments (instead of the conditions usually used for antagonist binding), substantial shifts of the displacement curves of 3,4-dihydroxyphenylethylamine (dopamine) and ADTN toward higher affinities were observed. A comparison of the effects of various agonists and antagonists in the [3H]ADTN binding experiments and in functional tests revealed a significant correlation between their potencies at D4 binding sites and at D2 receptors modulating the release of [3H]acetylcholine from striatal slices. However, in the situation of the D1/D3 pair, when the measurement of adenylate cyclase activity was taken as a functional test for D1 receptors, agonists were more active in the binding than in the functional test, whereas for many antagonists the opposite was found. The results are discussed with regard to the classification and functional aspects of brain dopamine receptors.

Acetylcholine↗
PubMed1982

Alterations in opiate receptor function after chronic ethanol exposure.

The dose-response curve for morphine-induced stimulation of striatal dopamine metabolism was shifted to the right in mice which had been withdrawn for 24 hours after chronic consumption of an ethanol-containing liquid diet. The apparent ED50 for morphine was increased by 33% in ethanol-treated mice. Concomitant with the shift in the dose-response curve, the affinity for dihydromorphine of the high-affinity caudate morphine receptor was decreased in ethanol-treated mice. The change in receptor properties after ethanol treatment included a decreased sensitivity of the receptor to the effects of sodium ion on morphine binding. The results suggest: 1) that the effect of morphine on dopamine metabolism in the mouse striatum is, at least in part, mediated by receptors that exhibit a high affinity for dihydromorphine: and 2) that ethanol treatment and withdrawal may induce specific changes in these particular opiate receptors.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1981

Ethanol alters kinetic characteristics and function of striatal morphine receptors.

Morphine was shown to promote dopamine (DA) synthesis and release in mouse striatum, but mice rendered tolerant and dependent on ethanol were found to be less responsive to morphine's effects on striatal DA metabolism than control animals. Ethanol feeding also produced a change in the affinity of striatal "opiate" receptors for [3H]dihydromorphine, and these ethanol-induced receptor changes may be responsible for the altered biological effect of morphine.

Animals↗
PubMed1980

Alterations in neurotransmitter function during the development of ethanol tolerance and dependence.

Current studies demonstrate that alcohol tolerance and alcohol dependence are neurochemically dissociable processes. Development of tolerance seems to be accompanied by changes in neuronal membrane structure which, in turn, affects the function of membrane-bound dopaminergic receptors. On the other hand, changes in cholinergic receptor number in certain brain areas may be responsible for certain signs of physical dependence during ethanol withdrawal.

Alcoholism↗