PubMed Health⌕ Search

Biomedical subjects

A V Christensen

Publications and source records attributed to A V Christensen.

44 records · Page 3Linked to original sources
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↗
PubMed1976

On the supersensitivity of dopamine receptors, induced by neuroleptics.

Different neuroleptics caused dopamine receptor blockade (antagonism against methylphenidate-induced compulsive gnawing) for varying lengths of time. When the receptor blockade had expired, supersensitivity to dopamine agonists (occurrence of apomorphine-induced compulsive gnawing and enhancement of methylphenidate-induced gnawing) developed and persisted for varying periods of time. The degree and duration of supersensitivity was related to the degree and duration of the preceding receptor blockade. Inhibition of catecholamine or 5-HT synthesis had no influence on development of supersensitivity. Stimulation with a dopamine agonist, apomorphine, during the period of the development of supersensitivity did not modify the enhanced receptor supersensitivity. A cholinergic-dopaminergic balance was shown to be involved in the manifestation of compulsive behavior during the supersensitivity phase. Tolerance to the dopamine antagonistic effect of a neuroleptic also developed after a single neuroleptic treatment, most likely due to increased sensitivity of the receptors for the dopamine agonist. It is concluded, that the dopamine receptor blockade induced by a single dose of a neuroleptic agent is a dynamic phenomenon which in the course of time is replaced by an increased sensitivity of the receptors to dopamine agonists. Noradrenergic or 5-HT neuron systems do not seem to be involved in the neuroleptic-induced supersensitivity, whereas a dopaminergic-cholinergic balance is operative in the supersensitivity situation.

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↗
PubMedDate not supplied

Classification of neuroleptics: implications for tardive dyskinesia.

The dopamine (DA) receptor blocking effect of neuroleptics is believed to be responsible for their antipsychotic effect. This blockade can be demonstrated in experimental animals by the ability of neuroleptics to antagonize stereotypies induced by DA agonists. Biochemically DA receptor-blocking properties of neuroleptics are illustrated by direct binding to DA receptors or by measuring inhibition of DA-stimulated adenylate cyclase activity. Most pharmacological and biochemical experiments with neuroleptics have concentrated on dopaminergic effects of the compounds both after acute and long-term treatment. After long-term treatment with neuroleptics an increase in DA receptor number and an increase in stereotyped behavior are seen. DA supersensitivity have been implied in the development of tardive dyskinesia (TD) in patients on long-term neuroleptic medication. In search for neuroleptics which would be less prone to induce TD and more effective in treating dyskinesia we have looked at the profile of a series of neuroleptics in in vitro experiments and in acute and long-term in vivo experiments. Since neuroleptics also influence other transmitter systems than the dopaminergic we have investigated interactions with drugs affecting these transmitter systems. According to their differential effects on DA receptors (D1 and D2) and their ability to develop tolerance and supersensitivity, the neuroleptics can be classified into different groups, some of which might be expected to induce less TD and be preferred for treating dyskinesia.

Animals↗
PubMedDate not supplied

Behavioural correlates to the dopamine D-1 and D-2 antagonists.

The acute dopamine (DA) receptor blockade of neuroleptics can be demonstrated in mice by antagonism of stereotypies induced by the DA-agonist methylphenidate and in rats by antagonism of stereotypies induced by the DA-agonists amphetamine or apomorphine. Neuroleptics such as the thioxanthene, cis(Z)-flupentixol, the phenothiazine, fluphenazine, the butyrophenone, haloperidol and the benzamide clebopride are equipotent behaviourally as well as clinically. Also the D-1 receptor-antagonist SCH 23390 has the same pharmacological effects. In a series of experiments where the methylphenidate-induced stereotyped gnawing in mice was inhibited by neuroleptics it was shown that the effect of butyrophenones was greatly attenuated by concomitant treatment with scopolamine and diazepam. Similar results were obtained in rats experiments. The effect of phenothiazines was less influenced and that of thioxanthenes and SCH 23390 remained nearly unchanged. Besides, a clear differentiation of these drugs was seen when they were tested in mice rendered supersensitive by 12 days treatment with different neuroleptics. In the withdrawal phase the decrease effects against methylphenidate were shown by increased ED50 values for methylphenidate antagonism and an increased response to methylphenidate. The thioxanthenes and SCH 23390 retained the ability to antagonize the stereotyped gnawing, the phenothiazines showed a reduced effect, whereas the butyrophenones showed both tolerance and cross tolerance to the stereotyped behaviour. This behavioural classification of neuroleptics into three different groups is comparable with the classification obtained by DA-receptor binding techniques in vitro.

Adenylyl Cyclases↗