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Biomedical subjects

J Hyttel

Publications and source records attributed to J Hyttel.

At least 91 records · Page 5Linked to original sources
PubMed1979

Characterization of 3H-GABA receptor binding to rat brain synaptosomal membranes: effect of non GABAergic compounds.

Characteristics of 3H-GABA binding to rat brain synaptic membranes in vitro have been investigated. The specific binding of 3H-GABA displays saturation kinetics. Only one single population of receptor sites was found (Km = 31.3 nM) with a concentration of 2.09 pmol/mg protein. Only GABA agonists show inhibitory effect on the binding, whereas GABA antagonists, GABA-uptake inhibitors, and inhibitors of GAD and GABA-T are without effect. The order of potencies for GABA agonists are: Muscimol greater than GABA greater than or equal to 4,5-dihydromuscimol greater than 3-aminoproprane sulphonic acid greater than isoguvacine greater than THIP greater than 3-hydroxy-GABA greater than imidazol-4-acetic acid. Agonists and antagonists from other neurone systems as well as neuroleptics and benzodiazepines had no or only a very slight potency in the binding test.

Animals↗
PubMed1978

Effect of a specific 5-HT uptake inhibitor, citalopram (Lu 10-171), on 3H-5-HT uptake in rat brain synaptosomes in vitro.

The uptake of 3H-5-HT in synaptosomes from rat brains was investigated. Addition of DA or NA had only a slight or no effect on the uptake. When the uptake into NA and DA neurons was inhibited by the addition of high concentrations of NA and DA, the uptake of 3H-5-HT was unchanged. This was also found after destruction of NA and DA neurons by 6-hydroxydopamine treatment. Furthermore, the uptake of 3H-5-HT was almost equal in different brain parts containing NA and DA in very different amounts. These observations show that the uptake measured with 3H-5-HT is specific for 5-HT neurons. The present study revealed that citalopram and chlorimipramine inhibited uptake competitively, and in this respect the two drugs were equipotent. Compared with a series of tricyclic thymoleptics, the two drugs were the most potent inhibitors of 5-HT uptake, about 20 to 35 times more active than imipramine and amitriptyline. The metabolites of citalopram were also rather potent. The results obtained in the present study correlate closely with those obtained using inhibition of 14C-5-HT uptake in blood platelets, or using the inhibition of H 75/12-induced 5-HT depletion in rat brain. When rats were treated orally with citalopram or chlorimipramine, the inhibition of 3H-5-HT uptake in synaptosomes derived from these rats was two times greater after citalopram than after chlorimipramine.

Animals↗
PubMed1977

Neurochemical characterization of a new potent and selective serotonin uptake inhibitor: Lu 10-171.

The neurochemical characteristics of a new bicyclic phthalane derivative-Lu10-171 [1-(3-(dimethylamino)propyl)-1-(p-fluorophenyl)-5-phthalancarbonitrile; citalopram]-have been investigated. Lu 10-171 and its metabolites were compared with tricyclic thymoleptics in several tests for serotonin (5-HT),noradrenaline (NA), and dopamine (DA) uptake inhibiton in vitro and in vivo. Lu 10-171 is a very potent and completely selective inhibitor of the 5-HT reuptake mechanism, being 2-10 times as active as chlorimipramine. The metabolites of Lu 10-171 show weak 5-HT uptake inhibiting properties. Lu10-171 and its metabolites are devoid of NA uptake inhibiting properties and in this respect they clearly differ from the tricyclic antidepressants, which posses effects both on 5-HT and NA uptake. The inhibition of 5-HT uptake in vitro is competitive and not connected with an increased efflux of 5-HT. Lu10-171 and its metabolites only inhibit DA uptake in extremely high concentrations and in this respect they are even weaker than chlorimipramine and other tricyclic thymoleptics. Like the tricycle thymoleptics, Lu 10-171 is without effect on MAO and does not change the endogenous levels of brain monoamines. Due to the selective action on 5-HT uptake, Lu 10-171 seems to be a valuable tool in studying the role of central 5-HT neurone systems in experimental neuropharmacology as well as in the ethiology of depressive illness.

Animals↗
PubMed1977

Changes in dopamine synthesis rate in the supersensitivity phase after treatment with a single dose of neuroleptics.

The changes in 14C-dopamine accumulation formed from 14C-tyrosine in mice after treatment with three neuroleptics, cis (Z)-flupenthixol, fluphenazine, and haloperidol, were followed for 6 days. The neuroleptics all changed DA synthesis rate in the same way, initially causing an increase which was followed by a decrease after approximately 3 days. The results are compared with pharmacological results (Christensen et al., 1976) and there seems to be a very close correlation between receptor blockade and increase in DA synthesis on the one hand and on the other hand receptor supersensitivity and decrease in DA synthesis, as was also shown previously for teflutixol (Hyttel, 1975). It is concluded that the changes in receptor activity are always followed by compensatory changes in DA synthesis rate.

Animals↗
PubMed1977

Peripheral and central muscarinic receptor affinity of psychotropic drugs.

The muscarinic receptor affinity of 27 psychotropic and 5 anticholinergic substances was examined in 2 in-vivo and 2 in-vitro models. A highly significant correlation was obtained between the effect of all compounds examined on the atropine sensitive binding of 3H-PrBCM and the effect in the conventional guinea-pig ileum preparation. Antagonism of oxotremorine induced tremors in mice by anticholinergics and neuroleptics was also significantly correlated to the corresponding data obtained in the in-vitro tests. Due to very low potency in the physostigmine induced mortality test in mice too few ED50 values were obtained to perform statistical comparisons. It is concluded, that the conventional guinea-pig ileum model and the 3h-prBCM binding model are equally predictive as tests for antimuscarinic properties. When in-vivo anticholinergic data for neuroleptics are used it must be considered that a possible dopamine receptor blockade may diminish the antimuscarinic effect of the substance.

Acetylcholine↗
PubMed1977

Effect of piflutixol on turnover of catecholamines in mouse brain and rat corpus striatum.

Dopamine metabolism in vivo was studied after treatment with piflutixol (6-fluoro-9-[3-(4-(2-hydroxyethyl)piperidino)propylidene]-2-trifluoromethyl-thioxanthene) a novel thioxanthene derivative with potent neuroleptic properties and sedative effects. In mice piflutixol increased both noradrenaline (NA) and dopamine (DA) turnover rate measured as increased disappearance of 14C-amines formed from 14C-L-tyrosine. The ratio between the minimal effective doses for 14C-NA and 14C-DA disappearance was 2, which is of the same order of magnitude as obtained with cis(Z)-chlorprothixene, pimozide and chlorpromazine. After 14C-L-tyrosine the accumulation of 14C-dopamine was initially increased after which it decreased from day 4--5. These changes resemble those obtained after other neuroleptics and parallel the initial receptor blockade and the subsequent receptor supersensitivity found in pharmacological experiments (MOLLER NIELSEN et al. 1977). Piflutixol induced a rapid increase in both DOPAC and HVA with a maximal effect after 2--6 hours. After 2--3 days the levels had returned to normal. The doses of piflutixol which at 24 hours doubled the levels of DOPAC and HVA were found to be 0.055 and 0.021 mg/kg subcutaneously, respectively. It is concluded that piflutixol is a powerful and long lasting DA receptor blocking agent, which changes the synthesis and release of DA in a way similar to basic neuroleptics.

Animals↗
PubMed1977

The pharmacology of a new potent, long acting neuroleptic, piflutixol.

Piflutixol, 6-fluoro-9-[3-(4-(2-hydroxyethyl)piperidino)propylidene]-2-trifluoromethyl-thioxanthene, has been shown to have pronounced neuroleptic properties. It is a very potent inhibitor of methylphenidate-induced stereotypies in mice, amphetamine and apomorphine-induced stereotypies in rats, apomorphine-induced stereotypies and vomiting in dogs. Furthermore piflutixol causes cataleptic reaction in small doses and inhibits conditioned avoidance reaction in rats. The compound is equally potent orally and parenterally and has a prolonged effect. Piflutixol has up to the present proved to be the most potent inhibitor of dopamine-stimulated adenylate cyclase in rat striatum in vitro. Piflutixol has a stron sedative effect (inhibition of spontaneous motor activity, induction of ptosis and potentiation of barbiturate anaesthesia) and in addition inhibits reticular arousal reaction in very low doses. Thus piflutixol constitutes a unique combination of potent anti-stereotyped activity with potent sedative effects. This means that piflutixol may prove to be a low-dose basic neuroleptic with long duration of action.

Adenylyl Cyclases↗
PubMed1977

Effect of a selective 5-HT uptake inhibitor--Lu 10-171--on rat brain 5-HT turnover.

Changes in endogenous concentrations of 5-HT and 5-HIAA as well as the turnover rate of 5-HT was studied in rat brain after treatment with a new potent and selective inhibitor of the neuronal 5-HT reuptake mechanism, Lu 10-171(1-(3-dimethylamino)propyl)-1-(p-fluorophenyl)-5-phthalancarbonitrile). After a single dose of Lu 10-171 the concentration of 5-HIAA was reduced from 1 to 24 hours after treatment, whereas that of 5-HT was practically unchanged, indicating decreased turnover of 5-HT in the brain. This was confirmed using three different methods for measuring 5-HT turnover. Thus the rate of 5-HIAA accumulation in the brain after probenecid was reduced after Lu 10-171. Likewise treatment with Lu 10-171 led to a decreased fall in 5-HT and an increased fall in 5-HIAA after inhibition of 5-HT synthesis with parachlorophenylalanine (PCPA). Unexpectedly Lu 10-171 did not change either the accumulation of 5-HT or the decrease in 5-HIAA after inhibition of MAO with pargyline. By and large the results are consistent with the proposed negative feed-back regulation of 5-HT neuronal firing rate due to the abundance of 5-HT at postsynaptic receptors after inhibition of the reuptake mechanism.

Animals↗
PubMed1976

[Receptor-blockade and receptor-hypersensitivity following neuroleptic treatment (author's transl)].

Neurolepitcs induce a receptor-blocking effect at central dopaminergic neurons. This may be demonstrated in mice by inhibition of methylphenidate induced compulsive gnawing. In the post-receptor-blocking phase the receptor is temporarily hypersensitive to dopaminergic agonists like methylphenidate and apomorphine. By repeated dosage a competition is created between receptor-blockade and hypersensitivity, often in favour of the latter.

Animals↗