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Biomedical subjects

J Hyttel

Publications and source records attributed to J Hyttel.

At least 37 records · Page 2Linked to original sources
PubMed1990

Effect of a dopamine D-1 agonist in rats treated chronically with zuclopenthixol.

We have previously demonstrated long-lasting increases in vacuous chewing movements (VCM) and tongue protrusions in rats treated discontinuously (DISC), but not continuously (CONT), with neuroleptics. To test whether this increase in mouth movements could be a result of exaggerated activity at the D-1 site, 34 rats were divided into three groups receiving the neuroleptic zuclopenthixol (ZU) DISC or CONT for 15 weeks, or no treatment. After withdrawal DISC treated animals showed an increase in oral activity compared to CONT treated. Two weeks after termination of medication the animals were tested with the D-1 agonist SK&F 38393. The increases in VCM after SK&F 38393 did not differ among the groups, but in contrast to control (CTRL) rats, treated rats showed a significant increase in tongue protrusions. There were no significant differences in the densities of D-1 and D-2 receptors in the striatum between the groups. The increase in tongue protrusions after SK&F 38393 in neuroleptic treated animals implies behavioural D-1 receptor supersensitivity. No significant differences in the rise in tongue protrusions and VCM after SK&F 38393 were seen between DISC and CONT treated animals. Our results thus do not indicate that increased D-1 receptor responsiveness is significant for the rise in spontaneous oral activity found after neuroleptic withdrawal.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1990

Pre- and postsynaptic dopaminergic activities of indolizidine and quinolizidine derivatives of 3-(3-hydroxyphenyl)-N-(n-propyl)piperidine (3-PPP). Further developments of a dopamine receptor model.

Pre- and postsynaptic dopaminergic activities of a series of indolizidine and quinolizidine analogues of 3-(3-hydroxyphenyl)-N-(n-propyl)piperidine (3-PPP) have been studied. The pharmacological data have been interpreted in terms of a previously reported model for interactions with dopamine pre- and postsynaptic D2-receptors and molecular mechanics (MM2(85] calculated geometries and conformational energies. The model has been further developed with respect to the receptor topography in the vicinity of the nitrogen binding site. In particular, a novel spatial orientation of the important "propyl cleft" has been proposed. This cleft is suggested to be located mainly above a plane through the receptor-bound substrate. The biologically active agonist and antagonist conformations of the enantiomers of 3-PPP have been reinvestigated.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1989

Facilitation of 8-OHDPAT-induced forepaw treading of rats by the 5-HT2 agonist DOI.

The potency of the serotonin 1A (5-HT1A) agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OHDPAT), to induce forepaw treading was increased 20-fold after co-treatment with the 5-HT2 agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI). DOI induced head twitches which were inhibited by 8-OHDPAT. The putative 5-HT1B agonist, 1-(3-trifluoromethylphenyl)piperazine (TFMPP), had a weak effect on the responses to DOI or 8-OHDPAT. The forepaw treading induced by 8-OHDPAT plus DOI was inhibited by high doses of (-)-alprenolol, ketanserin or ritanserin, but was not influenced by the beta-adrenoceptor antagonist, ICI 118.551, or the 5-HT3 antagonist, ICS 205-930. A non-effective dose of (-)-alprenolol increased the inhibitory effect of ketanserin and ritanserin. These results indicate a complex and different interaction between 5-HT1A and 5-HT2 receptors in the expression of two behavioural responses mediated by 5-HT.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1989

Parallel decrease in the density of dopamine D1 and D2 receptors in corpus striatum of rats from 3 to 25 months of age.

The density (Bmax) and apparent dissociation constant (KD) of dopamine D1 and D2 receptors in striatum was estimated in rats of different ages (from 3.5 to 25 months) using 3H-SCH 23390 and 3H-spiperone as ligands. The density of D1 and D2 receptors decreases with age attaining 70 and 69% of the 3.5 months' value, respectively, whereas the KD's remain constant. The decreases in density of D1 and D2 receptors are parallel. Thus, throughout life the ratio between the density of D1 and D2 receptors remains constant.

Age Factors↗
PubMed1989

Selective inactivation of dopamine D1 and D2 receptors in 6-hydroxydopamine-lesioned rats: evidence that the effect of D1 and D2 agonists can be expressed in the absence of the heterologous DA receptor.

EEDQ (N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline) markedly decreased the density of dopamine (DA) D1 and D2 receptors in the lesioned and normal striatae of rats lesioned unilaterally with 6-hydroxy-DA. By treatment with either the D1 antagonist SCH 23390 or the D2 antagonist raclopride, together with EEDQ selective inactivation of D2 and D1 receptors, respectively, are obtained. In rats with decreased density of D1 receptors the circling behaviour response to the D1 agonist SK&F 38393 was markedly inhibited 24 hours after EEDQ treatment, whereas the similar response to the D2 agonist pergolide was unchanged. In rats with decreased density of D2 receptors the effects of pergolide and the partial D2 agonist (-)-3-PPP were antagonized, while the effect of SK&F 38393 was unchanged. These results indicate that the effect of D1 and D2 agonists can be expressed in the absence of normal densities of the heterologous DA receptor. In contrast, the responses from homologous DA receptors, mediating the circling behaviour from the denervated side of the brain, are highly sensitive to the inactivating effect of EEDQ.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1988

Inactivation of dopamine D-1 or D-2 receptors differentially inhibits stereotypies induced by dopamine agonists in rats.

Ex vivo D-1 or D-2 receptor binding in the striatum was reduced by 65-78% after treatment with EEDQ (N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline) in combination with either the D-2 antagonist, raclopride, or the D-1 antagonist, SCH 23390, respectively. EEDQ induced a 65% reduction in D-1 receptor binding and a 51% decrease in cAMP production in striatal homogenates. Selective D-2 receptor inactivation inhibited the stereotyped behaviour induced by the mixed D-1/D-2 agonist, apomorphine, or by the D-2 agonist, quinpirole, when given alone and in combination with the D-1 agonist, SK&F 38393. Selective inactivation of D-1 receptors did not inhibit the behavioural effects of quinpirole when given alone and in combination with the D-1 agonists, SK&F 81297, SK&F 38393 or SK&F 75670. Likewise, the effect of apomorphine was unchanged. These results indicate that a normal density of D-2 receptors is critical for the expression of the stereotyped behaviour induced by DA agonists. In contrast, there is a large surplus of D-1 receptors to enable the response to a D-2 agonist. This is particularly illustrated by the persistent behavioural effects of the partial D-1 agonist, SK&F 75670, in rats with up to a 78% decrease in D-1 receptor binding.

Adenylyl Cyclases↗
PubMed1988

EEDQ, a tool for ex vivo measurement of occupancy of D-1 and D-2 dopamine receptors.

EEDQ (N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline) inactivates dopamine (DA) D-1 and D-2 receptors, measured by ex vivo [3H]SCH 23390 and [3H]spiperone binding in striatal homogenates. SCH 23390 (D-1 antagonist) and SK&F 38393 (D-1 agonist) protect against inactivation of D-1 receptors (ED50 values 0.075 and 53 mumol/kg, respectively). Raclopride (D-2 antagonist) and quinpirole (D-2 agonist) protect against inactivation of D-2 receptors (ED50 values 0.48 and 7.1 mumol/kg, respectively). The potencies correspond closely to those obtained by in vivo binding experiments using radioligands.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1988

Antihypertensive activity in a series of 1-piperazino-3-phenylindans with potent 5-HT2-antagonistic activity.

A series of trans-1-piperazino-3-phenylindans were synthesized with the goal of replacing their established neuroleptic profile with that of peripheral 5-hydroxytryptamine (5-HT2) antagonism. Compounds with an unsubstituted or fluoro-substituted 6-position in the indan ring, and which had a five- or six-membered heterocyclic ring attached by an ethylene chain to the piperazine ring, satisfied this objective. Some of the compounds had potent antihypertensive activity in conscious, spontaneously hypertensive rats (SHR). In pithed rats they antagonized the pressor effect induced by 5-HT in doses 100-1000 times lower than doses needed to antagonize the pressor effect of phenylephrine. The effect was stereoselective and associated with enantiomers with 1R,3S absolute configuration. 1S,3R enantiomers inhibited the uptake of dopamine and norepinephrine in vitro. The compound with the best antihypertensive activity was (+)-(1R,3S)-1-[2-[4-[3-(4-fluorophenyl)-1-indanyl]-1- piperazinyl]ethyl]-2-imidazolidinone (Lu 21-098, irindalone). Its pharmacological profile resembled that of the standard compound ketanserin. There was a close structural correspondence between ketanserin and irindalone in a conformation that we recently identified as a D-2 receptor-relevant configuration of its neuroleptic "parent" tefludazine. This suggests that the dopaminergic (D-2) and the serotonergic (5-HT2) pharmacophores are structurally closely related.

Animals↗
PubMed1988

Behavioral differentiation between effects elicited at dopamine D-1 and D-2 receptors in rats with normosensitive DA receptors.

The interaction between D-1 and D-2 receptor agonists was investigated in three behavioral test models. In two models (circling behavior in rats with hemitransection; stereotyped behavior in naive rats) an enabling role of D-1 receptor agonists in expressing the effect of D-2 agonists was found: D-1 agonists alone were ineffective, D-2 agonists had low maximum effects, whereas the combination induced marked activity. Consistent with this, the effect of combined D-1/D-2 receptor stimulation was antagonized either by D-1 or D-2 antagonists. In contrast, the effect of D-1 and D-2 agonists and antagonists were differentiated in drug discrimination studies, using the cue induced by the D-1 agonist SK & F 38393 or by the D-2 agonist (-)-NPA versus saline. The results thus indicate a functional relevance of D-1 receptors and show that the coupling between D-1 and D-2 receptors critically depends on the specific behavior under study.

Animals↗
PubMed1988

Ontogeny of dopamine D1 receptors in rat striatum.

The development of dopamine D1 receptors in rat striatum during the early postnatal period is described, using [3H]piflutixol as ligand. Dopamine D1 receptors increase in number from day of birth until about 21 days of age, when they reach adult levels. This increase in number parallels the increase in several other dopamine markers in striatum during the same time period. The increase is reflected in an increase in Bmax of ligand binding to D1 receptors. All other properties of D1 receptors that were examined do not change throughout this developmental period and are essentially the same as those found in adult tissue. These include association and dissociation rates, affinity for piflutixol as determined by kinetic and saturation studies, and pharmacology. These studies provide a biochemical and pharmacological basis for further studies on the ontogeny of dopamine receptors and of striatum and on factors regulating development of this region.

Aging↗
PubMed1988

Relative dopamine D1 and D2 receptor affinity and efficacy determine whether dopamine agonists induce hyperactivity or oral stereotypy in rats.

The effects of a range of dopamine (DA) agonists on stereotyped behaviour in rats were analysed and compared both with the affinity of the compounds for D1 and D2 receptor binding sites in vitro and their ability to stimulate the adenylate cyclase activity in rat striatal homogenates. Full and partial agonists at the D1 receptor coupled to adenylate cyclase do not induce sterotypies when given alone, whereas full D2 agonists (e.g. quinpirole) induce hyperactivity but not oral sterotypies. Partial D2 agonists (e.g. (-)-3-PPP) only induce sedation. Mixed D1/D2 agonists (e.g. apomorphine) induce both hyperactivity and oral stereotypies. Maximum stereotypies were induced by combination of SK & F 38393 and a series of D2 agonists, including full agonists and the partial D2 agonist B-HT 920, whereas partial agonists with low intrinsic activity (e.g. (-)-3-PPP, EMD 23448) did not induce stereotypies when given together with SK & F 38393. However, these partial agonists reduced the maximum effect of apomorphine, whereas the full agonists (e.g. quinpirole, (-)-NPA) and B-HT 920 had no apomorphine antagonistic activity. The mixed D1/D2 agonists apomorphine and N,N-dipropyl-5,6-ADTN were only weakly influenced by SK & F 38393, or not at all. D1 agonists with central effects, including SK & F 38393, SK & F 81297 (with relatively high efficacies), and the partial agonist SK & F 75670 with low efficacy, changed the hyperactivity induced by quinpirole into maximum oral stereotypy, whereas the peripheral D1 agonist fenoldopam had no such effect. Inhibition of DA and NA synthesis with alpha-methyl-p-tyrosine depleted striatal DA levels by 72 per cent and antagonized the hyperactivity induced by the D2 agonists quinpirole and (-)-NPA, but not that of apomorphine. Combination of SK & F 38393 and quinpirole induced maximum stereotypy in DA-depleted animals. These results suggest that D1 receptor tonus is a necessary prerequisite for the expression of a DA agonist's effect. The hyperactivity induced by full D2 agonists appears to be mediated by D1 tonus provided by endogenous DA activity, but stronger D1 stimulation is necessary to induce oral stereotypy. A high degree of D1 receptor activation increases the ability of partial D2 agonists to induce hyperactivity or oral stereotypies since treatment with both SK & F 38393 and B-HT 920 had marked effects while B-HT 920 was ineffective.(ABSTRACT TRUNCATED AT 400 WORDS)

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1987

Dopamine D-1 receptor agonists combined with the selective D-2 agonist quinpirole facilitate the expression of oral stereotyped behaviour in rats.

The behaviour of rats was studied after combined treatment with the selective DA D-2 agonist quinpirole and three selective D-1 agonists (SK & F 38393, SK & F 75670 and Lu 24-040). The effects on behaviour were compared with those on receptor binding and adenylate cyclase (AC). While the D-1 agonists alone did not induce stereotyped behaviour, quinpirole induced dose-dependent hyperactivity (locomotion, sniffing, head movements and rearing), whereas licking/biting was absent or seen only occasionally. Combined treatment with quinpirole and a D-1 agonist was followed by dose-dependent licking and occasional biting behaviour. The D-1 agonists had similar efficacies, but SK & F 75670 and Lu 24-040 were more potent than SK & F 38393. The maximal effects of SK & F 38393 plus quinpirole were effectively blocked by either a D-1 antagonist (SCH 23390) or a D-2 antagonist (YM 09151-2) confirming the close relation between D-1 and D-2 receptor sites in the brain. Good correspondence was found between affinities to D-1 receptors [( 3H]SCH 23390 binding) in vitro and the EC50 values for stimulation of AC activity. However, the maximal effects on DA-sensitive AC activity were less for SK & F 75670 and Lu 24-040 than for SK & F 38393. Thus, the results indicate that efficacies in the adenylate cyclase assay are dissociated from those on behaviour. Furthermore, the data indicate that in normal rats D-1 receptors are functionally relevant since D-1 agonists facilitate the expression of oral stereotyped behaviour after combination with a D-2 agonist.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1987

Characterization of binding of 3H-SCH 23390 to dopamine D-1 receptors. Correlation to other D-1 and D-2 measures and effect of selective lesions.

The binding of 3H-SCH 23390 to membranes from rat and mouse brain tissue has been investigated. The binding was saturable and reached equilibrium after 60 minutes. Nonspecific binding was low. Association and dissociation rates were Mg++-sensitive. In almost all respects the binding of 3H-SCH 23390 was comparable to the binding of 3H-piflutixol and 3H-cis(Z)-flupentixol. The density of binding sites in striatum was greater than in limbic structures which in turn was greater than in frontal cortex. The density of binding sites in these structures were comparable with those of 3H-piflutixol and 3H-cis(Z)-flupenthixol, 2-3 times higher than the D-2-receptor density. Whereas an increase was seen in 3H-SCH 23390 binding. The binding was decreased approximately 72% 3 weeks after unilateral kainic acid lesion whereas that of 3H-spiperone was only decreased 56%. Finally, the affinities of neuroleptics to the 3H-SCH 23390-binding sites correlated to the affinities to 3H-piflutixol-binding sites and to the effects on DA-sensitive adenylate cyclase. Agonist competition curves were shallow and the data best fit a two-site model composed of a high and a low affinity component. Thus, 3H-SCH 23390 is regarded as a highly selective ligand for brain dopamine D-1 receptors in vitro.

Animals↗
PubMed1987

Target size of dopamine D-1 receptors in rat corpus striatum estimated by binding of the benzazepine 3H-SCH 23390.

The binding characteristics of 3H-SCH 23390 in rat striatum prepared in potassium phosphate buffer are described. The amount of binding sites labeled by 3H-SCH 23390 decreased monoexponentially when exposed to increasing radiation dose. The molecular weight was determined to 78,000 daltons similar to the molecular mass of 3H-piflutixol binding to D-1 receptor previously reported, however lower than the molecular mass of dopamine D-1 agonist binding sites (Gredal & Nielsen 1987).

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1987

Age related decrease in the density of dopamine D1 and D2 receptors in corpus striatum of rats.

The densities (Bmax) and apparent dissociation constants (Kd) of D1 and D2 receptors in striatum and of 5-HT2 receptors in cortex of rats aged 1, 3, 7 and 12 months have been determined using 3H-SCH 23390, 3H-spiperone and 3H-ketanserin, respectively, as ligands. No changes in Kd's were seen. The density of D1 receptors decreases continuously from 1 month, attaining approximately 65% at 12 months of age. The density of D2 receptors increases slightly from 1 to 3 months, followed by a decrease until 12 months of age, where the level is approximately 80% of the 1 month value. The rise D2 receptor density is less apparent when calculated on a protein basis due to a concomitant increase in protein content of corpus striatum. The ratio between D1 and D2 receptors remains constant, approximately 4.2, from 1 to 12 months of age. The density of 5-HT2 receptors decreased from 1 to 7 months and remained at this level also after 12 months.

Aging↗
PubMed1986

The St 587-induced flexor reflex in pithed rats: a model to evaluate central alpha 1-receptor blocking properties.

A combination of reserpine, nialamide and the specific alpha 1-adrenoceptor agonist St 587 [2-(2-chloro-5-trifluoromethylphenylimino)-imidazolidine] induced a marked increase of the electrically stimulated flexor reflex in pithed rats. This increased reflex - which lasted for more than 3 h - could be inhibited by the alpha 1-receptor antagonist prazosin but not by the alpha 2-adrenoceptor antagonist idazoxan (RX 781094). A range of different drugs was tested, including 17 neuroleptics. Most of the neuroleptics showed marked inhibition of the St 587-induced reflex. Bromperidol, butaclamol and fluperlapine were weak inhibitors while pimozide was without effect. The results showed close correlation to alpha 1-receptor affinities in vitro (r = 0.84, P less than 0.001) while no correlation was found to either D-2 receptor affinities or to 5-HT2 receptor affinities in vitro (r = 0.43, P less than 0.2 and r = 0.41, P less than 0.05, respectively). It is concluded that inhibition of the St 587-induced flexor reflex in pithed rats is an in vivo test model for central alpha 1-receptor blocking properties.

Adrenergic alpha-Antagonists↗