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Biomedical subjects

A V Christensen

Publications and source records attributed to A V Christensen.

At least 37 records · Page 2Linked to original sources
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

Pharmacodynamic effects and possible therapeutic uses of THIP, a specific GABA-agonist.

THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) is a potent and specific GABA receptor agonist which does not influence the GABA uptake system or GABA metabolizing enzymes. The specificity for the GABA receptor is also demonstrated by lack of action on monoaminergic, cholinergic, histaminergic or opiate receptors. Since in recent years GABA receptor stimulants-among others THIP--have become available many have speculated as to what clinical indication GABA-ergic stimulation might be an important element. The first suggestion was that GABA-ergic drugs by an inhibitory effect on the dopamine neurons would improve the antischizophrenic effect of neuroleptics and improve tardive dyskinesia. Furthermore, studies on brains of deceased Parkinson and Huntington's chorea patients have demonstrated a low level of GABA and its synthesizing enzyme glutamic acid decarboxylase (GAD) in the basal ganglia. Also in epilepsy and diseases with dementia a deficit in the GABA system has been proposed. Therefore a therapeutic strategy for these diseases may be supplementary treatment with drugs which increase GABA receptor activity. Furthermore, recent results in humans have shown that GABA agonists perhaps also could be of benefit in mania and depressions. When considering the neurophysiological elements of nociception and muscle tone it is also reasonable to suggest that GABA-ergic stimulation may reduce pain perception and muscle tone.

Analgesics↗
PubMed1981

Differential reversal by scopolamine and THIP of the antistereotypic and cataleptic effects of neuroleptics.

Scopolamine reversed the neuroleptic-induced catalepsy and neuroleptic blockade of amphetamine-induced stereotypies in rats. The effect on catalepsy was the most pronounced. Butyrophenones were mainly sensitive to scopolamine reversal whereas the thioxanthenes cis-Z-flupentixol and piflutixol were not significantly influenced. THIP did not change the effects of cis-Z-flupentixol, fluphenazine and haloperidol. The relevance of these findings for the use of stereotypy and catalepsy tests as screening for antiscizophrenic and extrapyramidal side-effects, respectively, is discussed.

Amphetamine↗
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↗
PubMed1979

Dopaminergic supersensitivity: influence of dopamine agonists, cholinergics, anticholinergics, and drugs used for the treatment of tardive dyskinesia.

Single and repeated administration of neuroleptics induce supersensitivity to dopamine agonists like apomorphine and methylphenidate. The degree of this supersensitivity depends on the period of the preceding administration of the neuroleptic. In the development phase additional administration of apomorphine can reverse the hyperdopaminergic behaviour, whereas addition of cholinergic/anticholinergic treatment does not modify the enhanced receptor response. In the supersensitivity phase additional treatment with deanol does not modify the supersensitivity. Pheobarbital, diazepam, and muscimol increase and cis (Z)-flupenthixol decreases the supersensitivity. It is concluded that supersensitivity induced by neuroleptics is time-dependent and that it can be prevented by additional treatment with DA-agonists but not by cholinergic/anticholinergic treatment. In the supersensitivity phase, the syndrome is suppressed by dopamine antagonists but enhanced by GABA-agonists, benzodiazepine and phenobarbital.

Animals↗
PubMed1978

Muscimol antagonizes morphine hypermotility without potentiation of analgesia.

Muscimol, a very potent and specific GABA agonist, strongly depressed characteristic morphine-induced locomotor activity. Muscimol induced only a very weak increase in the morphine analgesia measured in the hot plate test which perhaps could be a result of a freezing reaction. No effect on morphine analgesia was observed in the wire grid test. These results indicate that GABA differentially influences morphine stimulation and analgesia.

Analgesia↗
PubMed1977

Pharmacology of a new phthalane (Lu 10-171), with specific 5-HT uptake inhibiting properties.

The pharmacological profile of a new bicyclic substance, Lu 10-171 (1-(3-(dimethylamino)propyl)-1-(p-fluorophenyl)-5-phthalancarbonitril), is described and compared with that of existing tricyclic thymoleptics. In mice and rats the compound exhibited marked 5-HT potentiating properties both in vivo and in vitro, being 5-10 times as active as chlorimipramine. The tests included 5-HT-, 5-HTP- and tryptophan-potentiation. In monoamine oxidase inhibitor treated dogs and rabbits the compound caused a marked hyperthermia. In rabbits this effect was completely blocked by pretreatment with the tryptophan hydroxylase inhibitor, p-chlorophenylalanine. Hyperthermia induced by the central catecholamine displacing substance H 77/77 in rats was not affected by Lu 10-171, whereas the substance abolished the temperature rise induced by H 75/12. Reserpine- and tetrabenazine-induced ptosis and tetrabenazine-induced immobility in mice were antagonized by relatively low doses of existing tricyclic thymoleptics, whereas Lu 10-171 was very weak in this respect. Very weak in vitro anticholinergic and antihistaminergic properties were also registered for Lu 10-171. It is concluded that Lu 10-171 is a very potent and highly specific potentiator of 5-HT both in vivo and in vitro probably due to inhibition of 5-HT uptake. Thus this compound might be a useful agent in studying the role of 5-HT neurone systems in the control of mood. The substance does not possess the NA potentiating and anticholinergic and antihistaminergic properties characteristic of the tricyclic antidepressants.

5-Hydroxytryptophan↗
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↗