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Biomedical subjects

J Hyttel

Publications and source records attributed to J Hyttel.

At least 55 records · Page 3Linked to original sources
PubMed1986

Inhibition of SKF 38393- and pergolide-induced circling in rats with unilateral 6-OHDA lesion is correlated to dopamine D-1 and D-2 receptor affinities in vitro.

The effects of 30 dopamine (DA) antagonists, including 4 as stereoisomeric pairs, on circling behaviour induced by the D-1 agonist SKF 38393 and the D-2 agonist pergolide in rats with unilateral 6-hydroxy-DA lesions have been studied. SKF 38393-induced circling was selectively blocked by the specific D-1 antagonists SCH 23390 and SKF 83566, and was furthermore blocked by other DA antagonists with potencies correlating to their affinities to D-1 receptors labelled by 3H-SCH 23390 in vitro. Pergolide-antagonistic potencies in contrast correlated to affinities to D-2 receptors labelled by 3H-spiperone in vitro. Pergolide-induced circling was selectively blocked by the specific D-2 antagonists in the benzamide series. No interaction between D-1 and D-2 antagonists was observed in combination experiments with SCH 23390 and YM 09151-2 in both circling models. Among other reference neurotransmitter antagonists acting on alpha- and beta-adrenoceptors, histamine, serotonin and muscarinic receptors, only the alpha 1-adrenoceptor antagonist prazosin was effective in high doses. In contrast, the alpha 2- and beta-adrenoceptor agonists clonidine and clenbuterol as well as the muscarinic agonist RS 86 inhibited circling induced by SKF 38393 as well as pergolide. The 5-HT1A agonist 8-OHDPAT inhibited pergolide-induced circling only. It is concluded that these two behavioural models are selective in vivo measures of relative D-1 and D-2 receptor activity of DA antagonists.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1986

Further studies of the mechanism behind scopolamine-induced reversal of antistereotypic and cataleptogenic effects of neuroleptics in rats.

Scopolamine is known to attenuate the amphetamine antagonistic and cataleptogenic effect of selective DA D-2 antagonists. To study further the influence of other receptor systems three approaches were taken: concomitant treatment with receptor blockers (scopolamine, prazosin and ketanserin) and a selective D-2 antagonist YM 09151-2, testing of a neuroleptic droperidol, with mixed D-2, alpha 1 and 5-HT2 antagonistic properties and testing a selective D-1 antagonist SCH 23390. Scopolamine markedly attenuated both effects of YM 09151-2 and droperidol. In contrast neither prazosin nor ketanserin influenced the effects of YM 09151-2. Furthermore, prazosin did not influence the interaction between scopolamine and YM 09151-2 in the tests of stereotypy and catalepsy. Scopolamine did not change the amphetamine antagonistic potency of SCH 23390, but decreased moderately its cataleptogenic potency. It is concluded that 5-HT2 and alpha 1-adrenergic receptor blockade are of minor importance in order to determine the sensitivity of a DA D-2 antagonist to the reversal induced by scopolamine. Thus, our earlier hypothesis, that DA D-1 receptor blockade is the main mechanism stabilizing these neuroleptic effects against scopolamine reversal, are further supported by the present experiments.

Animals↗
PubMed1986

Effect of prolonged treatment with neuroleptics on dopamine D-1 and D-2 receptor density in corpus striatum of mice.

The effects of long-term treatment with neuroleptics on D-1 and D-2 receptor parameters in corpus striatum were studied in mice. Mice were treated daily for 12 days with the selective D-1 antagonist, the benzazepine SCH 23390, the mixed D-1/D-2 antagonist zuclopenthixol or the selective D-2 antagonist haloperidol. Three days after withdrawal Bmax and KD for 3H-SCH 23390 binding to D-1 receptors and 3H-spiperone binding to D-2 receptors were determined. The study showed that the density of D-2 receptors increased after haloperidol whereas no changes were seen after SCH 23390 or zuclopenthixol. No changes in D-1 receptor density were seen after either treatment. The results are in full agreement with published behavioural results where haloperidol induces tolerance whereas SCH 23390 or zuclopenthixol do not. Some changes in KD values were seen. The cause and meaning of these changes await further investigation.

Animals↗
PubMed1985

Receptor-binding profiles of neuroleptics.

Dopamine-receptor blockade seems to be a prominent effect of neuroleptics. Blockade of other receptors might, however, contribute to the therapeutic effect. A series of neuroleptics have been tested for affinity to DA D-1 and D-2 receptors, serotonin receptors (S2), alpha-adrenoceptors (alpha 1), histamine receptors (H1), and muscarinic cholinergic receptors. According to the affinity to DA D-1 and D-2 receptors, neuroleptics can be divided into different groups. Thioxanthenes have affinity for both D-1 and D-2 receptors; phenothiazines have affinity for D-2 receptors and considerably lower affinity for D-1 receptors; and butyrophenones, diphenylbutylpiperidines, and benzamides have affinity only for D-2 receptors. Concerning affinity to other receptors the only consistent finding is affinity for S2 receptors. The clinical significance of these findings is speculative. In several behavioral tests the D-1/D-2 classification is also observed, and it is suggested that D-1-receptor activation is responsible for dyskinesia, and that thioxanthenes - due to their D-1 receptor blocking effect-induce less dyskinesia than other neuroleptics.

Antipsychotic Agents↗
PubMed1985

Differential involvement of dopamine D-1 and D-2 receptors in the circling behaviour induced by apomorphine, SK & F 38393, pergolide and LY 171555 in 6-hydroxydopamine-lesioned rats.

The antagonistic effect of dopamine (DA) D-1 and D-2 antagonists against circling behaviour induced by various DA agonists in 6-OHDA-lesioned rats has been investigated. DA D-1/D-2 selectivity of agonists in vitro was measured by the stimulatory effect on DA-sensitive adenylate cyclase in rat striatal homogenates (D-1), the inhibitory effect on electrically-induced release of 3H-DA in rabbit striatal slices (D-2) and the affinity to 3H-piflutixol (D-1) and 3H-spiroperidol (D-2) binding sites in rat striatal membranes. The contralateral circling behaviour induced by the DA D-1 agonist SK & F 38393 was blocked by the DA D-1 antagonist, SCH 23390, and by the mixed DA D-1/D-2 antagonist cis(Z)-flupentixol, but was not influenced by the DA D-2 antagonists spiroperidol and clebopride. In contrast, circling behaviour induced by the preferential DA D-2 agonists pergolide and LY 171555 was blocked by clebopride, spiroperidol, and cis(Z)-flupentixol, but weakly or not influenced by SCH 23390. Apomorphine-induced circling behaviour was blocked by cis(Z)-flupentixol, partially antagonized by SCH 23390 and clebopride but not inhibited by spiroperidol, although the time-course of circling was changed. Combinations of SCH 23390 with spiroperidol or clebopride in low doses completely blocked the effect of apomorphine. These results indicate that DA D-1 and D-2 receptors mediate circling behaviour through separate mechanisms which can be independently manipulated with respective agonists and antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1985

Pharmacology in vivo of the phenylindan derivative, Lu 19-005, a new potent inhibitor of dopamine, noradrenaline and 5-hydroxytryptamine uptake in rat brain.

Behavioural effects on dopaminergic transmission of a phenylindane derivative, Lu 19-005 [(+/-)-trans-3-(3,4-dichlorophenyl)-N-methyl-l-indanamine, HCI], with potent inhibitory effect on dopamine (DA), noradrenaline (NA) and serotonin (5-HT) uptake in rats and the effect on DA, NA and 5-HT activity in mice have been studied and compared with those of other known DA, NA and 5-HT uptake inhibitors with different selectivity ratios. Lu 19-005 induced stereotyped behaviour after parenteral and oral administration with a duration of action of more than 24 h. The stereotyped licking and biting induced by Lu 19-005 was antagonized by reserpine and cis(Z)-flupentixol, but not affected by prazosin, p-chlorophenylalanine and alpha-methyl-p-tyrosine pretreatments. Metergoline slightly facilitated the onset of stereotypy. Lower doses of Lu 19-005 induced ipsilateral circling in unilaterally 6-hydroxy-DA-lesioned rats. Finally, Lu 19-005 antagonized the catalepsy induced by perphenazine. In mice, Lu 19-005 potentiated the apomorphine-induced gnawing, reversed tetrabenazine-induced ptosis and potentiated the behavioural effects of 5-HTP within a similar dose range. The effects of Lu 19-005 were compared with those of other reference compounds. Nomifensine had qualitatively similar effects in rats although of much shorter duration. In mice, nomifensine selectively reversed tetrabenazine-induced ptosis. Weaker effects in all test models were found with bupropion, LR 5182 and GBR 13.069, compounds with inhibitory effect on DA and NA uptake. The DA-, NA- and 5-HT-uptake inhibitor diclofensine, however, had no effect in rats except in the 6-hydroxy-DA-circling test and had low potency in mice. The specific 5-HT- and NA-uptake inhibitors citalopram and talsupram, respectively, were ineffective in all rat models.(ABSTRACT TRUNCATED AT 250 WORDS)

5-Hydroxytryptophan↗
PubMed1985

Down-regulation of dopamine D-2, 5-HT2 receptors and beta-adrenoceptors in rat brain after prolonged treatment with a new potential antidepressant, Lu 19-005.

Lu 19-005 is a new phenylindan derivative with strong and equipotent inhibitory effect on dopamine (DA), noradrenaline (NA) and serotonin (5-HT) uptake. The adaptive effects of 2 weeks treatment with Lu 19-005, on receptor binding in vitro and on d-amphetamine responsiveness in vivo have been investigated in rats. One or 3 days after the final dose the number of beta-adrenoceptors and of 5-HT2 and DA D-2 receptors was decreased by 20-30%, whereas alpha 1-adrenoceptor number was slightly decreased only 1 day after withdrawal. The DA D-2 receptor number remained decreased at 7 days withdrawal, but returned to normal after another 3 days. The brain levels of DA, NA and 5-HT were not changed by 2 weeks' Lu 19-005 treatment. The down-regulation of DA D-2 receptors was accompanied by tolerance to d-amphetamine-induced hypermotility (after low doses) and stereotyped licking or biting (after a high dose). The tolerance to d-amphetamine-induced hypermotility was maximal at 3-5 days withdrawal time, and remained significant also 15 days after the last dose. An acute dose of Lu 19-005 did not modify the effects of d-amphetamine. The results are discussed in relation to the effect of prolonged treatment with other antidepressant drugs.

Animals↗
PubMed1985

3-Phenyl-1-indanamines. Potential antidepressant activity and potent inhibition of dopamine, norepinephrine, and serotonin uptake.

A series of 3-phenyl-1-indanamines was synthesized and tested for potential antidepressant activity and for inhibition of dopamine (DA), norepinephrine (NE), and serotonin (5-HT) uptake. Trans isomers were generally potent inhibitors of DA, NE, and 5-HT uptake, while cis isomers preferentially inhibited the uptake of 5-HT. The affinity for the DA-uptake site was very dependent on the aromatic substitution pattern where highest potency was found for 3',4'-dichloro substituted compounds (45). This substitution pattern also resulted in high affinity for the NE-and 5-HT-uptake sites, but potent 5-HT-uptake inhibiting activity could also be obtained with other substitution patterns. Only small amines could be accommodated at the 5-HT-uptake site while larger amines such as piperazine could be accommodated both at the DA-and NE-uptake sites. The observed structure-activity relationships were explained from the results of superimpositions of a trans (45) and cis (72) isomer with 5-HT and DA, respectively, in relation to a proposed three-point binding of the uptake inhibitors at the uptake sites. Finally, comparison of the structures of the 3-phenyl-1-indanamines with other newer bicyclic catecholamine- and/or serotonin-uptake inhibitors revealed common structural elements important for potent DA-, NE-, and/or 5-HT-uptake inhibition.

Animals↗
PubMed1985

5-HT-uptake inhibition potentiates antinociception induced by morphine, pethidine, methadone and ketobemidone in rats.

The effect of the specific 5-HT-uptake inhibitor citalopram on the antinociception induced by morphine, pethidine, methadone and ketobemidone was examined in rats by means of the hot plate test. Further the 5-HT-uptake-inhibiting potency of these opioid-receptor stimulants was examined in vitro in rat brain synaptosomes. In doses devoid of antinociceptive activity, citalopram in a dose-dependent manner potentiated the antinociception induced by the four opioid analgesics. The potentiation of the ketobemidone-induced antinociception was not influenced by the spasmolytic agent A 29 (N,N-dimethyl-3,3-diphenyl-1-methylallylamine) which together with ketobemidone constitutes the active substances in Ketogan. The 5-HT-uptake-inhibiting potencies of the opioid receptor stimulants were from 21 to more than 56000 times lower than that of citalopram, the order of potency being methadone greater than pethidine greater than ketobemidone greater than morphine. The results support the suggested role of 5-HT in morphine-induced antinociception and indicate a similar role in the antinociceptive effect induced by other opioid-receptor stimulants.

Analgesics↗
PubMed1985

Neurochemical profile of Lu 19-005, a potent inhibitor of uptake of dopamine, noradrenaline, and serotonin.

The neurochemical profile of a new compound, Lu 19-005 [(+/-)trans-3-(3,4-dichlorophenyl)-N-methyl-1-indanamine hydrochloride], has been investigated. Lu 19-005 is a potent inhibitor of the synaptosomal uptake of 3,4-dihydroxyphenylethylamine (dopamine, DA), noradrenaline (NA), and 5-hydroxytryptamine (5-HT, serotonin). In this respect it resembles diclofensine, whereas compounds such as GBR 13.069 and bupropion are more selective DA-uptake inhibitors. Although Lu 19-005 releases DA in in higher concentrations it must be considered as an uptake inhibitor, as the accumulation of DA is inhibited in much lower concentrations. Lu 19-005 attenuates the DA and NA depletion caused by 6-hydroxydopamine in mouse brain. These properties confirm the DA- and NA-uptake-inhibitory properties of the compound. In receptor-binding models and functional in vitro tests Lu 19-005 is devoid of dopaminergic-, serotonergic-, noradrenergic-, histaminergic-, and cholinergic-inhibiting properties. Since DA, NA, and 5-HT seem to be involved in depression, the profile of Lu 19-005--with equally potent activity on the three neuronal systems--makes it an interesting experimental tool and a potential new antidepressant agent.

Animals↗
PubMed1984

Distinct target size of dopamine D-1 and D-2 receptors in rat striatum.

Frozen rat striatal tissue was exposed to 10 MeV electrons from a linear accelerator. Based on the theory of target size analysis, the molecular weights of dopamine D-1 receptors (labelled by 3H-piflutixol) and dopamine D-2 receptors (labelled by 3H-spiroperidol) were 79,500 daltons and 136,700 daltons, respectively. The size of the dopamine-stimulated adenylate cyclase was 202,000 daltons. The estimated molecular sizes were deduced by reference to proteins with known molecular weights which were irradiated in parallel. The results showed that the molecular entities for 3H-piflutixol binding and 3H-spiroperidol binding were not identical. The present results do not allow conclusions as to whether D-1 and D-2 receptors are two distinct proteins in the membrane, or whether the receptors are located on the same protein. In the latter case the binding of 3H-spiroperidol needs the presence of a second molecule.

Adenylyl Cyclases↗
PubMed1984

Differential inhibition by dopamine D-1 and D-2 antagonists of circling behaviour induced by dopamine agonists in rats with unilateral 6-hydroxydopamine lesions.

The selective dopamine (DA) D-1 antagonist SCH 23390 antagonized the contralateral circling behaviour induced by the DA D-1 agonist SK & F 38393 in rats lesioned unilaterally with 6-hydroxy-DA but had a 600 times weaker effect against the preferential DA D-2 agonist pergolide. The D-2 antagonists clebopride and spiroperidol had the reverse selectivity. The mixed D-1/D-2 antagonists cis(Z)-flupentixol and cis(Z)-clopenthixol blocked the circling induced by either agonist. It is concluded that circling behaviour is mediated by closely related but independent DA D-1 and D-2 receptor sites.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1984

Effects of S (+)-3-phenethyl-PP, a putative dopamine autoreceptors agonist with greater autoreceptor selectivity than 3-PPP enantiomers.

The experiments concerned the pharmacology of the enantiomers of the phenethyl-analogue (3-phenethyl-PP) of the putative dopamine (DA) autoreceptor agonist 3-PPP. In contrast to the almost equipotency of 3-PPP enantiomers, the phenethyl enantiomers showed marked stereoselectivity. S(+)-3-Phenethyl-PP had 25 times higher affinity to D-2 DA receptors in vitro than the R(-)-enantiomer. In vivo a similar potency difference was seen for the inhibition of motility, induction of circling behaviour in 6-OHDA-lesioned rats and emetic effect in dogs. None of the enantiomers induced stereotypy and hypermotility in normal rats or in rats pretreated with reserpine and alpha-methyl-p-tyrosine. In test models for antidopaminergic activity only slight activity of either enantiomer was observed. The S(+)-enantiomer had no antagonistic effect against apomorphine- and amphetamine-induced stereotypies, no cataleptogenic activity and only partially antagonized amphetamine-induced hypermotility. Apomorphine-induced emesis was weakly antagonized. The results indicate a greater and higher selectivity of S(+)-3-phenethyl-PP for DA receptors mediating sedation compared with 3-PPP enantiomers which previously have been shown to exert significant effects on postsynaptic DA receptors. Thus S(+)-3-phenethyl-PP may be a more selective model compound for the differential study of effects elicited by stimulation of pre- and postsynaptic DA receptors.

Adenylyl Cyclases↗
PubMed1984

Pharmacological effects of a specific dopamine D-1 antagonist SCH 23390 in comparison with neuroleptics.

Neuroleptics such as thioxanthenes (cis(Z)-flupentixol and cis(Z)-clopenthixol) and phenothiazines (fluphenazine and perphenazine), which block both dopamine (DA) D-1 and D-2 receptors and the butyrophenones (haloperidol and spiroperidol), which block D-2 receptors only, are equipotent both behaviorally and clinically. A new compound SCH 23390 which selectively blocks DA D-1 receptors, resembles many neuroleptics in its pharmacological profile: antistereotypic effects in mice, rats and dogs, cataleptogenic effect and inhibitory effect on amphetamine circling. In contrast SCH 23390 has no effect on apomorphine-induced vomiting in dogs and little effects on 6-OHDA-denervated supersensitive DA receptors, stimulated by the DA agonist 3-PPP. In a series of experiments where methylphenidate-induced stereotyped gnawing in mice was inhibited by neuroleptics, it was shown that concomitant treatment with scopolamine or diazepam attenuated the effect of butyrophenones (D-2 antagonists). The same treatment attenuated the effect of phenothiazines, to a lesser extent, and hardly attenuated the effect of thioxanthenes and SCH 23390 at all. It is concluded that DA D-1 receptors are as important as D-2 receptors for the expression of neuroleptic activity in most animal models believed to be predictive of antipsychotic and extrapyramidal side-effect potential. However, the D-1 antagonist is less sensitive than D-2 antagonists to antimuscarinic compounds and benzodiazepines.

Adrenergic alpha-Antagonists↗
PubMed1984

Biochemical effects and drug levels in rats after long-term treatment with the specific 5-HT-uptake inhibitor, citalopram.

The effects in rats of long-term administration of the potent, specific 5-HT uptake inhibitor citalopram have been investigated. Citalopram hydrobromide (MW = 405) was given in the diet, 99 or 25 mumol/kg daily, for 13 days or orally, 49 mumol/kg twice a day, for 14 days. High plasma and brain levels of citalopram were found during the treatment period, whereas negligible amounts were found 24 h after withdrawal. The 5-HT uptake mechanism in blood platelets was completely blocked, since levels of whole blood 5-HT during and shortly (2 days) after treatment were decreased by 75-90%. The drug load after the two highest doses in terms of plasma drug levels was the same as in depressed patients treated with citalopram. Receptor binding technique ex vivo was applied to different brain parts to measure receptor parameters for several neurotransmitters. All data were evaluated by Eadie- Hoffstee analysis. No changes were seen in Bmax and Kd for beta-receptors (3H-dihydroalprenolol) in frontal cortex, occipital + temporal cortex, whole cortex and limbic structures, 5-HT2 receptors (3H-spiroperidol) in frontal and whole cortex, alpha 1-receptors (3H-prazosin) in "rest of brain" and DA D-2 receptors (3H-spiroperidol) in corpus striatum and limbic structures. The uptake mechanism for 5-HT as well as the inhibitory effect of citalopram on this uptake remained unaffected in brain synaptosomes derived from control and from citalopram (99 mumol/kg)-treated rats. Thus long-term treatment with citalopram does not induce changes in neurotransmitter receptors as seen with most tricyclic as well as newer " atypical " antidepressants.(ABSTRACT TRUNCATED AT 250 WORDS)

Amphetamines↗
PubMed1984

Changes in rat dopamine- and serotonin function in vivo after prolonged administration of the specific 5-HT uptake inhibitor, citalopram.

The effect of prolonged administration of the potent and specific 5-HT uptake inhibitor citalopram on behavioural measures of dopaminergic and serotonergic activity has been studied in rats. Administration of citalopram in the diet at a daily dose of 99 mumol/kg led to supersensitivity to d-amphetamine-induced hypermotility and stereotypy and to subsensitivity to apomorphine-induced hypomotility 2 h after withdrawal. Forepaw clonus induced by 5-methoxy-N,N-dimethyltryptamine was decreased 2 h and 24 h after withdrawal and the number of head shakes induced by 1-5-HTP and citalopram were decreased 24 h after withdrawal. The d-amphetamine potentiation was still seen after 24 h, whereas the response had returned to normal 3 and 7 days after withdrawal. The content of amphetamine in three different brain regions was about 50% higher compared with controls 24 h after withdrawal of prolonged citalopram administration. At this time citalopram had been eliminated, and citalopram itself could not affect amphetamine metabolism. Other experiments indicated a linear relation between d-amphetamine brain concentration and motility level. Thus, a 50% increase in citalopram-treated rats cannot alone account for 3-fold increase in d-amphetamine-induced motility. Potentiation of d-amphetamine-induced hypermotility was also found after citalopram in a daily dietary dose of 25 mumol/kg for 13 days and after oral bolus injection (49 mumol/kg twice daily for 14 days). Acute citalopram injection had no effect in any of these models. The results suggest increased responsiveness of dopaminergic mechanisms mediating hypermotility, and decreased sensitivity of dopamine receptors mediating sedation (proposed autoreceptors). Sensitivity of 5-HT receptors was also decreased. The mechanisms by which citalopram induces d-amphetamine supersensitivity as well as subsensitivity to apomorphine and 5-HT agonists are presently unknown, since no changes in dopaminergic and serotonergic receptor binding have been found after an identical dose regimen.

5-Hydroxytryptophan↗