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Biomedical subjects

J Hyttel

Publications and source records attributed to J Hyttel.

At least 73 records · Page 4Linked to original sources
PubMed1984

Postsynaptic dopamine agonistic effects of 3-PPP enantiomers revealed by bilateral 6-hydroxy-dopamine lesions and by chronic reserpine treatment in rats.

The motor effects of some DA autoreceptor agonists and apomorphine in rats with bilateral 6-hydroxydopamine lesions of the median forebrain bundle were studied. Whereas (-)-3-PPP, (+)-3-phenethyl-PP and EMD 23448 decreased motility in sham-operated controls, a pronounced hypermotility was induced in 6-OHDA-lesioned rats. 3-PPP enantiomers and apomorphine had similar potency as that found in test models for DA autoreceptor activity in normal rats, e.g. motility inhibition. The DA receptor involvement in the effect of (-)-3-PPP was confirmed by neuroleptic antagonism. (-)-3-PPP and EMD 23448 had similar intrinsic activity as apomorphine, whereas (+)-3-phenethyl-PP and (+)-3-PPP had lower maximal effect. However, the DA autoreceptor agonists differed from apomorphine: The development of postsynaptic supersensitivity to these drugs appeared 4-7 days after the lesion compared to 1-2 days for apomorphine and (+)-3-PPP. Furthermore, no active oral stereotypy was induced by the autoreceptor selective compounds in contrast to the effect observed after apomorphine and (+)-3-PPP. In a separate experiment using circling behaviour in unilaterally 6-OHDA-lesioned rats the different time-course of appearance of supersensitivity to (-)-3-PPP, (+)-3-PPP and apomorphine was confirmed. After chronic reserpine treatment a similar postsynaptic supersensitivity to (-)-3-PPP was observed with a development time between 4 and 7 days and with a similar intensity as that observed in 6-OHDA-lesioned rats. In contrast, after chronic neuroleptic treatment for 12 days, (-)-3-PPP was unable to induce hyperactivity 3-7 days after withdrawal. The results indicate that DA autoreceptor agonists are able to stimulate postsynaptic DA receptors in conditions without endogenous transmitter supply for at least 4-7 days, but not after chronic receptor blockade in a similar period. This should lead to consideration of DA autoreceptor agonists as potential antiparkinsonian drugs without stimulant effects on normosensitive postsynaptic DA receptors.

Animals↗
PubMed1984

Functional evidence for selective dopamine D-1 receptor blockade by SCH 23390.

The selectivity of a new specific dopamine D-1 receptor antagonist SCH 23390, (R)-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin -7-ol hemimaleate, was investigated in functional neurochemical models. Inhibition of the activity of dopamine-stimulated adenylate cyclase in striatal homogenates of the rat represented an effect at dopamine D-1 receptors, whereas reversal of the decrease in electrically-induced release of tritium from striatal slices of the rabbit, preloaded with [3H]dopamine or [3H]choline by apomorphine, represented D-2 pre- and postsynaptic effects, respectively. The selectivity of the methods was checked by using known D-1 and D-2 agonists, SKF 38393 (2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine hydrochloride) and LY 141865 or LY 171555 (racemate and (-)-enantiomer, respectively; trans-4,4a,5,6,7,8,8a,9-octahydro-5-propyl-2H-pyrazolo [3,4-g]quinoline dihydrochloride), respectively. It was found that SCH 23390 competitively inhibited the activity of dopamine-stimulated adenylate cyclase with a Ki-value of 0.004 microM. In contrast to haloperidol, a specific dopamine D-2 antagonist, which inhibited the decline in release of both ligands from preloaded slices induced by apomorphine, SCH 23390 was without effect on this release from slices loaded with [3H]dopamine but had effect on release from slices loaded with [3H]choline, in concentrations 350 times greater than those of haloperidol (IC50 = 0.63 microM). The results confirm the dopamine D-1-selective blockade by SCH 23390, previously shown using dopamine-receptor binding techniques.

Adenylyl Cyclases↗
PubMed1984

The citalopram/5-HTP-induced head shake syndrome is correlated to 5-HT2 receptor affinity and also influenced by other transmitters.

Combination of the 5-HT-uptake inhibitor, citalopram, with 1-5-HTP induced a characteristic head shake syndrome in rats. This was blocked by a range of 5-HT antagonists, including the selective 5-HT2 antagonists, ketanserin and pirenperone and was also blocked by the alpha 1-adrenoceptor antagonists, prazosin and WB 4101, and the alpha 2-adrenoceptor agonist, clonidine. 1-5-HTP-antagonistic effect was also recorded for 26 neuroleptic drugs. Their inhibitory potencies showed close correlation to 5-HT2-receptor affinity in vitro and, slightly weaker, to alpha 1-adrenoceptor affinity. In contrast, no correlation to dopamine D-2 receptor affinity was found, indicating that the cataleptogenic and motility-inhibitory properties of neuroleptics did not unspecifically influence 1-5-HTP-induced head shakes. These were not influenced by a histaminic antagonist, muscarinic antagonist or alpha 2-adrenoceptor antagonist, but were inhibited by beta-adrenoceptor blockers, GABA agonists, a benzodiazepine and morphine. The results indicate that 1-5-HTP-induced head shakes are most sensitive to 5-HT2 antagonists, but that the syndrome is influenced by other neuronal systems. Since 5-HT2 affinity and alpha 1-adrenoceptor affinity of many compounds is found concomitantly, caution is needed to evaluate the relative importance of these properties for 1-5-HTP antagonism.

5-Hydroxytryptophan↗
PubMed1983

Dopamine receptor agonistic and antagonistic effects of 3-PPP enantiomers.

The pharmacological profile of the enantiomers of the proposed selective dopamine (DA) autoreceptor agonist 3-PPP [3-(3-hydroxyphenyl)-N-n-propylpiperidine] has been studied. In vitro both enantiomers showed weak DA agonistic activity, and (--)-3-PPP some DA antagonistic effect on DA-stimulated adenylate cyclase activity. Both enantiomers in low doses had a similar profile in vivo: Inhibition of locomotor activity of mice and rats, induction of contralateral circling behaviour in 6-hydroxy-DA-lesioned rats and an emetic effect in dogs. At higher doses, differential effects of the enantiomers were found: (+)-3-PPP induced hyperactivity, weak stereotyped behaviour and ipsilateral circling in hemitransected rats. (--)-3-PPP had depressant effects in high doses, inhibited d-amphetamine-induced hyperactivity and d-amphetamine-, methylphenidate- and apomorphine-induced stereotyped licking/biting in rats and antagonized apomorphine-induced emesis in dogs. However, (+)-3-PPP also showed a weak antagonistic activity against d-amphetamine-induced hyperactivity and d-amphetamine- and apomorphine-induced stereotypy in rats and inhibited apomorphine-induced emesis in dogs. It is suggested that both enantiomers have significant effects on postsynaptic DA receptors in high doses: (--)-3-PPP with weak antagonistic activity in some test models and (+)-3-PPP with agonistic and antagonistic effect. Since these effects of (+)-3-PPP were of low intensity at high doses, (+)-3-PPP may be a partial DA agonist at postsynaptic receptors in high doses.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗
PubMed1983

Biochemical and pharmacological differentiation of neuroleptic effect on dopamine D-1 and D-2 receptors.

In dopamine (DA) receptor binding tests two different receptor populations can be measured. By using 3H-haloperidol or 3H-spiroperidol as ligands D-2 receptors are detected. When the thioxanthene neuroleptics 3H-cis (Z)-flupenthixol or 3H-piflutixol are used as ligands D-1 receptors coupled to adenylate cyclase can be detected. In displacement experiments butyrophenones (haloperidol and spiroperidol) and diphenylbutylpiperidines (pimozide) interact with D-2 receptors only, whereas thioxanthenes (cis [Z]-flupenthixol, cis [Z]-piflutixol and cis [Z]-clopenthixol) have equal affinity for D-1 and D-2 receptors. A similar differentiation is also seen in behavioral studies. The methylphenidate antagonistic effect of butyrophenones and diphenylbutylpiperidines is dramatically attenuated by concomitant treatment with an anticholinergic agent or a GABA agonist. The effect of thioxanthenes is almost unchanged. When mice are treated for 12 days with neuroleptics, supersensitivity to methylphenidate is induced. The supersensitivity is reversed by thioxanthenes, whereas butyrophenones and diphenylbutylpiperidines have no effect at all. These differences do not appear to be due to a change in the affinity for DA receptors because the ability of cis (Z)-flupenthixol, haloperidol, DA or apomorphine to displace 3H-piflutixol or 3H-spiroperidol is the same in supersensitive and control mice. The results clearly demonstrate that neuroleptics acting on both D-1 and D-2 receptors have a behavioral profile different from that of neuroleptics acting exclusively on D-2 receptors.

Animals↗
PubMed1982

Citalopram--pharmacological profile of a specific serotonin uptake inhibitor with antidepressant activity.

1. Citalopram (Lu 10-171), a new bicyclic phthalane derivative, is an extremely potent inhibitor of neuronal serotonin (5-HT) uptake but has no effect on the uptake of noradrenaline (NA) and dopamine (DA). 2. Citalopram has no antagonistic activity towards DA, NA, 5-HT, histamine, gamma aminobutyric acid (GABA), acetylcholine, and morphine receptors. In this way it clearly deviates from many old and new antidepressant drugs which have antagonistic effects towards some of these transmitters. 3. In contrast to many tricyclic antidepressants citalopram is devoid of cardiotoxic effects, even when animals are exposed to concentrations far above the therapeutic level. 4. In man citalopram is metabolized to compounds which are also potent 5-HT-uptake inhibitors without effect of NA uptake and which are found in lower concentrations than citalopram itself. 5. In account of its extreme specificity as a 5-HT-uptake inhibitor citalopram should be considered as an experimental tool of the utmost importance. In preliminary clinical experiments citalopram has shown a clear antidepressant effect. This property together with the absence of troublesome anticholinergic adverse effects and cardiotoxic effects also make citalopram a most promising antidepressant drug.

Analgesics↗
PubMed1981

Kainate lesion dissociates striatal dopamine receptor radioligand binding sites.

Kainic acid lesion of rat striata reduces the specific dopamine receptor binding of the butyrophenone antagonist [3H]spiperone and the butyrophenone-like antagonist [3H]domperidone by 56% and 59% respectively. Significantly greater decreases in binding were observed with the agonist [3H]N-propylnorapomorphine (NPA) and the antagonist [3H]flupentixol which showed 79% and 73% losses of high affinity binding respectively. These data indicate that, in part, [3H]spiperone and [3H]domperidone label distinct dopamine receptors with different neuronal localizations from those labeled by [3H]flupentixol and [3H]NPA. Our data is consistent with the hypothesis that [3H]flupentixol and [3H]NPA bind preferentially to adenylate cyclase-linked dopamine (D1) receptors.

Animals↗
PubMed1980

Further evidence that 3H-cis(Z)flupenthixol binds to the adenylate cyclase-associated dopamine receptor (D-1) in rat corpus striatum.

The proposal that 3H-cis(Z)flupenthixol (3H-FPT) preferentially binds to striatal dopamine receptors associated with adenylate cyclase activity (D-1), distinct from dopamine receptors to which 3H-haloperidol (3H-hal) binds (D-2), has been investigated further. The dopamine agonists bromocriptine and ergotamine were 60-times more potent as displacers of 3H-hal than 3H-FPT binding. Other dopamine agonists (ergometrine, dopamine, apomorphine, 2-amino-6,7-dihydroxy-tetralin (ADTN), and ergocornine) also shared this profile, although a smaller ratio was found for these compounds. Substituted benzamides (clebopride greater than sultopride greater than sulpiride greater than metoclorpramide greater than tiapride) displace 3H-hal but have only a very slight displacing effect towards 3H-FPT, and did not inhibit dopamine-stimulated adenylate cyclase activity. The same pattern is shared by oxiperomide and molindone. Together, these results support the idea that 3H-FPT labels another class of dopamine receptors than does 3H-hal, and that the former class most likely is associated with adenylate cyclase.

Adenylyl Cyclases↗
PubMed1980

Neuropharmacological properties of amitriptyline, nortriptyline and their metabolites.

Amitriptyline, nortriptyline and their metabolites, desmethylnortriptyline, cis and trans 10-hydroxyamitriptyline, cis and trans 10-hydroxynortriptyline and amitriptyline-N-oxide, have been tested for inhibitory effect on the uptake of serotonin (rabbit thrombocytes in vitro) and noradrenaline (mouse atria in vitro and mouse heart in vivo), for anticholinergic activity (guinea-pig ileum in vitro) and for antagonism against tetrabenazine induced inactivity as well as apomorphine and 5-hydroxytryptophan potentiating effect in mice. Amitriptyline inhibits serotonin and noradrenaline uptake equally, whereas nortriptyline is a more potent inhibitor of noradrenaline than of serotonin uptake. The metabolites resemble nortriptyline in this respect. The 10-hydroxylated metabolites are equipotent with amitriptyline as regards noradrenaline uptake inhibition. All the metabolites are less anticholinergic than amitriptyline and nortriptyline. The in vitro results are reflected in the in vivo behavioural tests, although some discrepancies are found, probably due to differences in absorption, distribution, metabolism and excretion. The importance of knowledge concerning pharmacological properties of the metabolites in comparison with amitriptyline and nortriptyline for correlating plasma levels of these and their metabolites to clinical outcome is discussed.

Amitriptyline↗