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Choline acetyltransferase and acetylcholinesterase activities in mice brain during the antagonistic action of antidepressant drugs and Ro 4--1284.

Choline acetyltransferase (Ach-T) and acetylcholinesterase (Ach-E) activities in mice brain during the reverse action by imipramine, pheniprazine and pargyline to the syndrome elicited by intraperitoneal administration of Ro 4--1284 were investigated. A single dose of imipramine did not reverse reserpine-like syndrome whereas inhibited Ach-E activity and increased Ach-T activity at the same time. The reversal of reserpine-like syndrome by administration of pargyline, pheniprazine or chronic administration of imipramine was accompanied by no changes in Ach-E and Ach-T activities.

2H-Benzo(a)quinolizin-2-ol, 2-Ethyl-1,3,4,6,7,11b-↗

PubMed1980

[Studies on As2O3-induced rabbit hypothermia and brain monoamines (author's transl)].

It has been suggested that hypothermia induced in rabbits by As2O3 3 mg/kg (i.v.) depends mostly on the blocking of the thermo-regulatory center. The relationship between hypothermia induced by As2O3 and brain monoamine levels in rabbits was investigated. To clarify the mechanism of the hypothermia, the influence of pretreatment with several agents on As2O3-induced hypothermia and on monoamine levels in the hypothalamus was examined. The core temperature was measured by inserting the thermister probe into the rectum and noradrenaline(NA), 5-hydroxytryptamine(5-HT) and 5-hydroxyindoleacetic acid(5-HIAA) levels in the hypothalamus were estimated fluorometrically. Pretreatment with p-chlorophenylalanine(PCPA), alpha-methyl-p-tyrosine(alpha-MPT) or 5-hydroxytryptophan(5-HTP) did not inhibit the hypothermia induced by As2O3 but did decrease NA levels in the hypothalamus. On the contrary, pretreatment with barbital sodium, pheniprazine, 1-DOPA and 1-tyrosine significantly inhibited the hypothermia or exhibited the hyperthermia. As2O3-induced hypothermia in rabbits was followed by a decrease in NA levels and an increase in 5-HT levels in the hypothalamus. On the other hand, when the hypothermia induced by As2O3 was inhibited by pretreatment with barbital sodium, pheniprazine, 1-DOPA and 1-tyrosine, both NA and 5-HT levels in the hypothalamus were significantly increased. These results suggest that As2O3-induced hypothermia is due to a decrease in NA levels and inhibition of the hypothermia is due to an increase in NA levels, in the rabbit hypothalamus.

Animals↗

PubMed1977

Influence of MAO inhibitors on uptake and release of norepinephrine in rat brain in vitro.

MAO inhibitors of diverse chemical structures were found to inhibit the uptake of 3H-NE into chopped rat cerebral cortex in vitro. The following molar (M) IC50 values to inhibit 3H-NE uptake were obtained: iproniazid, 7.9 X 10(-4)M; pargyline, 3.1 X 10(-4)M; pheniprazine, 6.3 X 10(-6)M; phenelzine, 3.9 X 10(-6)M; tranylcypromine, 2.5 X 10(-6)M; amphetamine, 2.5 X10(-7)M. In addition to decreasing deaminative catabolism, 5 X 10(-5)M amphetamine, tranylcypromine and pheniprazine plus 10(-3)M phenelzine produced a release of 3H-NE from tissue stores into incubation media. Similar concentrations of pargyline and iproniazid were ineffective to release 3H-NE from brain tissue.

Animals↗

PubMed1979

Inhibition of diamine oxidase by antihistaminic agents and related drugs.

Various drugs were tested as inhibitors of diamine oxidase on the basis of chemical relationships to the enzyme substrates. It was found that serotonine tryptamine and phenformin are good competitive inhibitors while cimetidine and pheniprazine are non-competitive inhibitors. Other antihistaminic drugs like promethazine are less powerful inhibitors.

Amine Oxidase (Copper-Containing)↗

PubMed1986

Inhibition of monoamine oxidase in monoaminergic neurones in the rat brain by irreversible inhibitors.

The irreversible inhibition of monoamine oxidase (MAO) inside and outside monoaminergic neurones in the rat brain by the suicide inhibitors clorgyline, selegiline (l-deprenyl), pheniprazine, phenelzine, iproniazid, pargyline and the d- and l-enantiomers of tranylcypromine was determined. This was achieved by incubating crude synaptosomal preparations of hypothalamus and striatum from rats treated with the inhibitors 24 hr earlier, with low concentrations of [14C]serotonin (0.1 microM), [14C]-noradrenaline (0.25 microM) and [14C]dopamine (0.25 microM) in the absence and presence of selective uptake inhibitors (citalopram, maprotiline and amfonelic acid, respectively). It was found that all inhibitors inhibited the deamination of serotonin and noradrenaline outside the amine neurons at slightly lower doses than that within these neurones. This could at least in part be due to protection of MAO by the endogenous amines in these neurones. The deamination of dopamine was rather more strongly inhibited inside the neutrons than outside, particularly at higher doses. There was no indication that tranylcypromine or phenelzine was accumulated in the neurones by the membranous amine uptake mechanisms. The rate of the recovery of the deaminating activities inside and outside the serotonergic and noradrenergic neurones in hypothalamus after phenelzine and clorgyline inhibition was the same (50% recovery after 12-15 days), which indicates similar rate of synthesis of MAO in different cell types.

Animals↗

PubMed1979

Mode of action of formamidine pesticides: an evaluation of monoamine oxidase as the target.

The ability of formamidine pesticide, chlordimeform (N'-(4-chloro-o-toyl)-N,N-dimethylformamidine) (CDM), and several of its major metabolites to inhibit monoamine oxidase (MAO) in mouse tissues in vitro and in vivo was examined, and related to the hypothesis that inhibition of MAO is responsible for the lethal effects of CDM. CDM was a readily reversible inhibitor of MAO of medium potency as were most of its metabolites. However, the hydrolysis product, N-formyl-4-chloro-o-toludine (CT) was a significantly more potent reversible inhibitor. A comparison of MAO from brain, liver, and intestine showed no marked variations in their sensitivity to these inhibitors. Greater inhibitory potency was found using Type A substrates (5-hydroxytryptamine) than Type B substrates (beta-phenylethylamine). The activity of MAO in vivo after pretreatment of mice with CDM or its metabolites was assessed in liver and intestine by measuring the amount of [14C] tryptamine which still survived 5 min after an intraperitoneal injection. Established inhibitors of MAO gave appropriate results with this method. CDM also increased tryptamine recoveries but only at does which caused mortality, and then to a lesser extent than MAO inhibitors such as tranylcypromine, pheniprazine, and harmaline at sub lethal doses. For this reason, and in view of the lack of correlation of toxicity to MAO-inhibitory potency among CDM and its metabolites, and because the symptoms of poisoning are inappropriate, it is concluded that MAO inhibition is not an important factor in the acute lethality of CDM.

Amidines↗

PubMed1977

The anticonvulsant action of methazolamide in mice: antagonism by various inhibitors of dopamine beta-hydroxylase.

The dopamine beta-hydroxylase inhibitors, FLA-63 and picolinic acid, antagonized the anticonvulsant action of methazolamine in mice; disulfiram and pyrimidinethiol were inactive. FLA-63 and picolinic acid, but not disulfiram or pyrimidinethiol prevented pheniprazine restoration of the anticonvulsant action of methazolamide in reserpinized mice. The present findings clearly demonstrate that differences exist among inhibitors of dopamine beta-hydroxylase regarding their ability to antagonize the anticonvulsant action of methazolamide under various test conditions.

Animals↗

PubMed1982

A simple method for screening monoamine oxidase (MAO) inhibitory drugs for type preference.

A simple method is described for screening monoamine oxidase (MAO) inhibitors for preferential action on either type A or type B MAO. Kynuramine, a substrate for both types of MAO, was used and the sources of enzyme were rat heart (type A) and mouse heart (type B). The method clearly showed that clorgyline (a preferential type A inhibitor) preferentially inhibited rat heart MAO; whereas pargyline (a preferential type B inhibitor) preferentially inhibited mouse heart MAO. Pheniprazine, an inhibitor without type preference, was equally effective in the two tissues. The method was used to substantiate a report by others that amphetamine has preferential inhibitory action against type A MAO.

Animals↗

PubMed1987

Gas chromatographic analysis of monoalkylhydrazines.

A quantitative electron-capture gas chromatographic assay procedure was developed for the analysis of monoalkylhydrazines in biological samples. Application to the analysis of phenelzine was demonstrated. Four monoalkylhydrazines were analyzed in whole blood by reaction with pentafluorobenzaldehyde to form stable hydrazone derivatives which were extracted and subsequently reacted with pentafluoropropionic anhydride to give products which were very sensitive to electron-capture detection when analyzed by gas chromatography. Methylhydrazine, benzylhydrazine, phenelzine and pheniprazine each yielded single derivatives with this procedure suggesting that the analytical procedure has a broad application to the analysis of other monoalkylated hydrazines. The method was applied to monitor whole blood levels of phenelzine in rats treated intravenously with phenelzine sulphate.

Animals↗

PubMed1961

Relative activity of some inhibitors of mono-amine oxidase in potentiating the action of tryptamine in vitro and in vivo.

Several known inhibitors of mono-amine oxidase (iproniazid, isocarboxazid, nialamide, phenelzine, pheniprazine and tranylcypromine) were tested for their ability to (i) inhibit the mono-amine oxidase activity of a rat brain mitochondrial preparation in vitro; (ii) potentiate the action of tryptamine on the isolated rat fundal strip preparation; and (iii) potentiate the acute toxicity of tryptamine in mice. There was some correlation between the order of potency of the drugs in the three tests, particularly in inhibiting the enzyme activity in the Warburg and in the tryptamine toxicity test in mice. Exceptions to this were isocarboxazid which had unexpectedly high activity on the rat fundal strip preparation, and tranylcypromine which was devoid of tryptamine-potentiation action on the rat fundus preparation although it inhibited rat brain mono-amine oxidase in vitro and potentiated the action of tryptamine in vivo. Tranylcypromine was considerably less active in inhibiting the mono-amine oxidase of rat fundus than rat brain tissue in vitro, while iproniazid and isocarboxazid had about the same potency on the enzyme from the two tissues.

Animals↗

PubMed1962

Effect of drugs on the noradrenaline content of brain and peripheral tissues and its significance.

Large single doses of methoserpidine (12 mg/kg) given to rabbits lowered the noradrenaline content of sympathetic ganglia but not that of brain; no sedation was observed. Cats responded to doses ranging from 12 to 0.5 mg/kg with loss of noradrenaline from ganglia as well as from brain, and were sedated by the drug. The effect in man resembles that in the rabbit. Only within the group of reserpine-like drugs do sedation and loss in hypothalamic noradrenaline run parallel. These effects are therefore not causally related. Guanethidine lowers the noradrenaline content of sympathetic ganglia (cats and rabbits), but this effect does not explain the blocking action of the drug on the adrenergic nerve. Effects on the noradrenaline of the brain are variable and may be caused reflexly rather than by direct central action of guanethidine. Repeated intravenous injections of dimethylphenylpiperazinium iodide for a period of 4 hr did not produce any significant change in the noradrenaline content of ganglia or brain of rabbits. In contrast, dexamphetamine (20 mg/kg) produced a small but significant mean fall in noradrenaline content of the superior cervical ganglia and in that of the brain, but the effects were not seen in every rabbit. Prolonged administration of the mono-amine oxidase inhibitors pheniprazine and phenylhydrazinobutane raised the noradrenaline content of the brain of rabbits but not that of cats, whereas it raised the noradrenaline of the ganglia of cats but not (or rarely) that of rabbits. The question of correlation between a rise in the noradrenaline content of the brain and certain clinical signs is discussed. Finally, a comparison is made in rabbits between the changes produced by drugs in the noradrenaline content of the heart and of the superior cervical ganglion. The changes run parallel and are only occasionally more pronounced in the heart.

Animals↗

PubMed1962

Effect of sympathomimetic amines on the blocking action of guanethidine, bretylium and xylocholine.

Experiments were carried out in which the adrenergic neurone blocking activity of xylocholine, bretylium and guanethidine was studied by the use of the inhibitory responses of the isolated rabbit ileum to lumbar sympathetic nerve stimulation, and the contractions of the nictitating membrane of the anaesthetized cat in response to stimulation of the cervical sympathetic nerves. In both these preparations, after blockade of the effects of sympathetic nerve stimulation had been produced with xylocholine, bretylium or guanethicdine, the sympathomimetic amines, dexamphetamine, mephentermine, hydroxyamphetamine, ephedrine and phenethylamine, reversed the blockade; if these amines were given first, then the adrenergic neurone blocking agents were ineffective. Tyramine and dopamine were effective on the isolated rabbit ileum but not on the cat's nictitating membrane. Effective antagonism of the adrenergic neurone blocking drugs was also shown by some substances which inhibit mono-amine oxidase but only those which in addition possess sympathomimetic effects. Thus phenelzine, pheniprazine and tranylcypromine were effective whereas iproniazid and nialamide were not. Since xylocholine, bretylium and guanethidine were all antagonized by the same agents, it seems likely that they all produce sympathetic blockade by a similar mechanism. The possibility is discussed that the sympathomimetic amines which antagonize the adrenergic neurone blocking drugs are competing with these substances for the same receptor sites.

Amidines↗

PubMed1963

Mechanism of the positive inotropic responses to bretylium and guanethidine.

Isolated, atropinized, rat atria exhibited positive inotropic responses to bretylium, guanethidine and tyramine. These responses were prevented by treatment of the animal with reserpine, or by addition of dichloroisoprenaline to the organ bath. The positive inotropic effects of these compounds on atria from reserpinized animals were restored by incubation of the tissue with noradrenaline. On the basis of these findings it is concluded that the cardiac stimulation by bretylium, guanethidine and tyramine involves the release of catechol amines. The usually reported increase in sensitivity of the myocardium from reserpinized animals to noradrenaline was not observed. The influence of bretylium and guanethidine on cardiac uptake and release of noradrenaline was also studied with the rat. Guanethidine decreased the concentration of catechol amines and inhibited the uptake of exogenous noradrenaline, while bretylium had no effect on either. The decrease in concentration of cardiac catechol amines produced by guanethidine was prevented by treatment of the animal with bretylium or with 1-phenyl-2-hydrazinopropane (pheniprazine), a monoamine oxidase inhibitor.

Animals↗

PubMed1969

Effect of monoamineoxidase inhibitors on 5-hydroxytryptamine output from perfused cerebral ventricles of anaesthetized cats.

1. In cats anaesthetized with pentobarbitone sodium, intraperitoneal injections of four inhibitors of monoamine oxidase (MAO) were shown to increase the 5-hydroxytryptamine (5-HT) in the effluent from the perfused cerebral ventricles.2. Weight for weight, tranylcypromine was found to be about twice as potent as pheniprazine, eight times as potent as nialamide and sixty times as potent as pargyline.3. The effect of tranylcypromine was also examined after reserpine had been injected into the cerebral ventricles or after p-chlorophenylalanine, given intraperitoneally. In both conditions tranylcypromine retained its ability to increase the 5-HT output from the perfused cerebral ventricle, but the effect was attenuated, more after p-chlorophenylalanine than after reserpine.4. Evidence is put forward that in both conditions the brain is not completely depleted of its 5-HT, but that the 5-HT is only reduced, more after p-chlorophenylalanine than after reserpine.

Animals↗

PubMed1970

Restoration of tyramine responses by bretylium, BW392C60, bethanidine and monoamine oxidase inhibitors in reserpine-treated rats.

1. Bretylium, BW392C60, bethanidine, nialamide and pheniprazine, but not guanethidine or ouabain, were all capable of restoring the cardiovascular response to tyramine in reserpine pretreated rats anaesthetized with sodium pentobarbitone.2. In parallel with their recorded in vitro activity as monoamine oxidase inhibitors, BW392C60 was found to be more potent at restoring the response to tyramine than bretylium or bethanidine.3. The restored responses to tyramine were completely blocked by desmethyl-imipramine or by a combination of phentolamine and propranolol.4. The effect of bretylium on the tyramine response was not influenced by bilateral adrenal demedullation, urethane anaesthesia, the dose or duration of the reserpine pretreatment and was not dependent upon the frequency of the tyramine injections.5. Bretylium, BW392C60 or bethanidine did not alter the pressor response to intravenous noradrenaline.6. Nialamide-induced restorations of the responses to tyramine were not further enhanced by the administration of bretylium, BW392C60 or bethanidine.7. In pithed reserpine-treated rats the ability of bretylium and BW392C60 to restore the response to tyramine was reduced.8. It is concluded that all the drugs which reversed the reserpine-induced subsensitivity to tyramine were acting as monoamine oxidase inhibitors, thus allowing the intra-neuronal accumulation of endogenously formed catecholamines. The presence of nerve impulses in the adrenergic fibres of reserpinized rats appears to be an important factor in mediating this effect.

Adrenalectomy↗

PubMed1980

Structural requirements for uptake into serotoninergic neurones.

Experiments were performed to examine whether non-hydroxylated tryptamines and 4-chloroamphetamine utilize the membrane 5-hydroxytryptamine carrier to pass into serotoninergic neurones. The accumulation and deamination of 14C-tryptamine by mouse brain slices or homogenates of rat hypothalamus were not inhibited by cocaine or norzimelidine, a selective inhibitor of the neuronal 5-HT uptake. The prevention by alpha-methyltryptamine (10 mg/kg, intraperitoneally), alpha-ethyltryptamine (20 mg/kg intraperitoneally) and 4-chloroamphetamine (20 mg/kg intraperitoneally) of the irreversible inhibtion of monoamine oxidase by pheniprazine (2.5 mg/kg intraperitoneally) and clorgyline (5 mg/kg intraperitoneally) in serotoninergic synaptosomes from mouse brain was not antagonized by pretreatment of the animals with norzimelidine (20 mg/kg intraperitoneally). The partial preventing effect of alpha-ethyl-4-methyl-m-tyramine (H 75/12)(2 X 50 mg/kg intraperitoneally) was, on the other hand, antagonized by norzimelidine. These results do not support the hypothesis that non-hydroxylated tryptamines and 4-chloroamphetamine are transported by the 5-HT carrier.

Animals↗

PubMed1979

p-Chloroamphetamine-induced hyperthermia pharmacologically distinct from fenfluramine-induced hyperthermia.

The influence of various drug pretreatments upon the responses of rabbits to the putative indirect 5-hydroxytryptaminergic agonists p-chloroamphetamine (PCA) and fenfluramine were examined. In naive rabbits PCA evoked hyperthermia, behavioural excitation and prominent forepaw clonic activity, while fenfluramine produced only hyperthermia and behavioural stimulation. The hyperthermic and behavioural responses of both agents were reduced by the 5-hydroxytryptamine (5-HT) uptake inhibitor, fluoxetine, potentiated by the monoamine oxidase inhibitor, pheniprazine, and unaltered by the dopaminergic antagonist, haloperidol. Pretreatment with the 5-hydroxytryptaminergic receptor blockers cinanserin, cyproheptadine or D-2-bromolysergic acid diethylamide markedly attenuated the effects of fenfluramine but only slightly influenced the responses to PCA. Depeletion of central 5-HT stores with p-chlorophenylalanine also affected responses to fenfluramine more than responses to PCA. The tryptaminergic receptor blocker methergoline abolished both PCA-induced hyperthermia and forepaw clonus--but not behavioural stimulation--while the effects of flenfluramine were only partly reduced. We interpret these data to mean that PCA- and fenfluramine-induced drug effects have different underlying mechanisms, the PCA responses relying possibly upon tryptamine while the fenfluramine responses are 5-hydroxytryptaminergic.

Amphetamines↗

PubMed1977

The effects of dopamine on renin release in vitro.

To examine the direct effects of dopamine on renin release, the in vitro rat kidney slice system, devoid of hemodynamic and humoral effects, was chosen. In the presence of an antioxidant, ascorbic acid (6 X 10(-4)M), a significant dose-related stimulation of renin release was observed with addition of 10(-5)M and higher concentrations of dopamine. When the monoamine oxidase inhibitor, pheniprazine (1 X 10(-5)M) was added, significant, dose-related stimulation of renin release was observed with 10(-8)M and higher concentrations of dopamine. Dopamine-induced renin release was not inhibited by the presence of the alpha-adrenergic antagonist, phentolamine (9 X 10(-4)M), the dopaminergic antagonist, haloperidol (5 X 10(-5)M) or the neural uptake inhibitor, cocaine (1 X 10(-5)M). However, the presence of the beta-adrenergic antagonist, propranolol (2 X 10(-4)M) completely inhibited dopamine-induced renin release. These studies indicate that dopamine can directly stimulate renin release in the absence of effects of hemodynamic factors, alterations in sodium metabolism or release of endogenous adrenergic agents. Further, this direct effect of dopamine on renin release appears to be mediated by an agonistic effect on the juxtaglomerular beta receptor rather than by the presence of a specific dopaminergic receptor for renin release.

Animals↗