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PubMed2003

Open space swimming test to index antidepressant activity.

Depression is characterized by a lack of "motivation" rather than a lack of "physical space" to move around. This study was designed to evaluate predictivity of an open space swimming test for antidepressant activity of various antidepressants in rats. Without drug treatment, rats showed a significant reduction in the distance moved (increased immobility) over successive trials in an open space water pool. Three major classes of antidepressants and a selective serotonin reuptake inhibitor (SSRI) were tested. Repeated treatment (10 mg/kg x 3 per day) of imipramine, a prototypical tricyclic antidepressant, iproniazid, a monoamine oxidase inhibitor, mianserin, an atypical antidepressant, and alaproclate, an SSRI, all significantly reduced the immobility. These results suggest that the open space swimming test is highly predictive of antidepressant action and is more sensitive to the drug treatments. The measurement is more objective than that of the forced swimming test and does not involve judging and scoring the animals' movement or lack of movement by investigators. The demonstrated effectiveness of three major types of antidepressants and an SSRI suggests that the effects on the test are not restricted to a particular underlying molecular mechanism of action. Thus, this swimming test shows promising potential as a screen for novel antidepressants and, perhaps, for revealing some of the underlying pathophysiology of depression.

Alanine↗
PubMed1975

Tonic immobility in chickens: possible involvement of monoamines.

Tonic immobility in chickens was affected by a variety of drugs that act on monoaminergic systems. Compounds that enhanced the duration of tonic immobility were d-LSD, BOL-148, pargyline, and iproniazid; 5-hydroxytryptophan, p-CPA, and atropine had no effect. Injections of serotonin depressed response duration. A suggestive parallel was noted between the results of the present study and those of previous work reporting drug-induced suppression of raphe electrical activity. The data appear to implicate monoamines, especially serotonin, in the mediation of behavioral activation and suppression.

5-Hydroxytryptophan↗
PubMed1972

Stimulation of the production of unesterified fatty acids in nerve endings of guinea-pig brain in vitro by noradrenaline and 5-hydroxytryptamine.

1. Noradrenaline (1mm) and 5-hydroxytryptamine (1mm) stimulated the production of unesterified palmitate, oleate, stearate and arachidonate in nerve endings (synaptosomes) isolated from combined guinea-pig cerebral cortex and cerebellum. 2. Iproniazid phosphate (0.36mm) increased the concentrations of the same acids in osmotically ruptured synaptosomes. Further addition of 1mm-noradrenaline or 1mm-5-hydroxytryptamine reversed this increase. 3. Noradrenaline (0.01mm) stimulated the production of unesterified fatty acids in isolated synaptic membranes. 5-Hydroxytryptamine (0.01mm) stimulated the production of unesterified fatty acids in synaptic membranes and synaptic vesicles.

Animals↗
PubMed1980

The inhibitory action of L-dihydroxyphenylalanine (L-dopa) in the presence of a monoamine oxidase inhibitor on protein synthesis in vivo and the partial amelioration of this by methionine supplementation.

Male Wistar rats of various age groups were injected daily over a period of 3 weeks with iproniazid (10 micrograms/g body wt.) and L-dihydroxyphenylalanine (L-dopa; 0.1 mg/g body wt.). On the final day 1 h before the termination of the experiment the animals were injected with L-[14C]valine (0.1 microCi/g body wt.). The specific radioactivity of the valine in the proteins of the subcellular fractions of the tissues examined, relative to the time-integrated mean specific radioactivity of this amino acid in the acid-soluble pools of these tissues, was used to assess protein synthesis. The L-dopa/monoamine oxidase-inhibitor treatment was associated with 30--40% inhibition of protein synthesis. Supplementation of the dietary methionine intake by injection of this amino acid markedly diminished the inhibitory action of the L-dopa/monoamine oxidase-inhibitor treatment on protein synthesis in all fractions examined.

Age Factors↗
PubMed1974

Monoamine oxidase and cerebral uptake of dopaminergic drugs.

The brain uptake of amines that do not enter the brain or enter it poorly was promoted by noncompetitive inhibitors of monoamine oxidase, as shown by behavioral and chemical criteria. Mice pretreated with water or enzyme inhibitors other than those mentioned were placid after receiving dopamine (3,4-dihydroxyphenethylamine). Mice pretreated with monoamine oxidase inhibitors (nialamide or iproniazid) showed upon treatment with dopamine the brisk motor responses characteristic of treatment with its precursor, L-dopa (3,4-dihydroxyphenylalanine). After receiving dopamine, intact nialamide-pretreated mice showed marked increases of brain dopamine, in contrast to water-pretreated test mice or water-treated controls. In unilaterally caudectomized, nialamide-pretreated mice, dopamine induced marked lateral curving of the body toward the lesion followed by running in that direction. Noradrenaline or adrenaline induced curving in caudectomized mice, whereas intact ones remained placid.These catecholamines are bound and inactivated by monoamine oxidase. The cerebral uptakes of chemicals that are bound but not inactivated by monoamine oxidase were thereafter tested. Nialamide induced increased behavioral responses to apomorphine and to N-propyl noraporphine, increased cerebral concentrations of both, and a deep coloration of the brain from methylene blue (bound by monoamine oxidase) but not Evans blue (bound by albumin). Even large doses of nialamide, however, failed to affect the behavioral responses to oxotremorine, which has cholinergic rather than adrenergic or dopaminergic properties. Mitochondrial monoamine oxidase seems therefore to play a specific regulatory role in the transport of substances that it binds, either to inactivate or to release them.

Animals↗
PubMed1972

Radioautographic demonstration of 5-hydroxytryptamine- 3 H uptake by pulmonary endothelial cells.

The lung is able to rapidly remove 5-hydroxytryptamme (5-HT) from the circulation by a Na(+)-dependent transport mechanism. In order to identify the sites of uptake, radioautographic studies were done on rat lungs which had been isolated and perfused with 5-HT-(3)H and 0 5 mM iproniazid, a monoamine oxidase inhibitor. In control experiments 10(-4)M imipramine was added to the perfusate to inhibit the membrane transport of 5-HT At the light microscope level, silver grains were seen concentrated near capillaries and in the endothelium of large vessels From electron microscope radioautographs a semiquantitative grain count was made and 90% of the silver grains were observed over capillary endothelial cells. The grains were found over the nucleus and cytoplasm of the cell and shewed no preferential association with any particular cytoplasmic inclusion bodies, organelles, or vesicles Other cell types were unlabeled except for a few mast cells, certain vascular smooth muscle cells, and one nerve ending. This radioautographic demonstration of the cell type responsible for the rapid removal of 5-HT from the lung circulation clearly establishes the existence of a new metabolic role for pulmonary endothelial cells.

Animals↗
PubMed1974

Role of the sympathetic innervation of the pacinian corpuscle.

An investigation was made into the nature of the role played by the noradrenergic innervation of the pacinian corpuscle. Corpuscles of the cat mesentery and mesocolon were used in all experiments. Blockade of noradrenergic beta receptors by dichloroisoproterenol and interference with norepinephrine release by reserpine are each capable of reversibly blocking mechanoelectric transduction by the pacinian corpuscle. The monoamine oxidase inhibitors iproniazid and phenelzine are capable of protecting the transducer from the blocking effects of reserpine. It is concluded that the presence of norepinephrine, as maintained by sympathetic tonus, is required for the afferent nerve terminal of the pacinian corpuscle to be mechanosensitive.

Animals↗
PubMed1958

The urinary excretion of adrenaline and noradrenaline by rats under various experimental conditions.

A study has been made of the excretion of adrenaline and noradrenaline in the urine of normal male rats and in the urine of these animals after the subcutaneous injection of saline, adrenaline, noradrenaline, morphine, insulin, iproniazid and thyroxine. The effects of thyroidectomy, adrenal demedullation and ether anaesthesia on the urinary output of adrenaline and noradrenaline have also been investigated. The findings are discussed against the background of the known effects of these treatments on the activity of the sympathetic nervous system.The results demonstrate that urinary adrenaline and noradrenaline estimations in the rat can, under favourable conditions, serve as an indicator of an alteration of sympathetic activity following the administration of a drug or some other deviation from normal.

Animals↗
PubMed1961

The formation of an isoprenaline-like substance from adrenaline.

Intravenous injections of adrenaline, but not those of noradrenaline, caused the appearance of a substance which resembled isoprenaline in R(F) value and pharmacological activity in blood withdrawn from the lower abdominal aortae of chloralosed cats rested after acute adrenalectomy and induction of lasting block in autonomic ganglia with hexamethonium. The formation of the isoprenaline-like compound was prevented by pretreatment with pyrogallol but not by pretreatment with reserpine, cocaine, phentolamine, dibenamine, harmaline, or iproniazid. The liver proved a main site of the origin of this isoprenaline-like substance.

Animals↗
PubMed1969

The interaction between monoamine oxidase inhibitors and narcotic analgesics in mice.

1. The administration of either iproniazid or tranylcypromine to mice potentiates the acute toxicity of pethidine, morphine, pentazocine and phenazocine.2. Blood levels of pentazocine in mice pretreated with tranylcypromine do not differ from the levels in animals not receiving the monoamine oxidase (MAO) inhibitor.3. There is no correlation between changes in brain and liver MAO activity and the increased pethidine toxicity.4. A comparison is made between the change in pethidine toxicity and the changes in the concentration of cerebral noradrenaline, dopamine and 5-hydroxytryptamine following the injection of tranylcypromine.5. It is concluded that the increased toxicity of potent analgesics in combination with MAO inhibitors is not due to a decelerated metabolism of the analgesic drug, but is related to an increased concentration of cerebral 5-hydroxytryptamine. A critical level of this monoamine, in the brain, may be necessary before the drug interaction will take place.

Analgesics↗
PubMed1969

The possible role of histamine in the coritsone induced gastric acid hypersecretion of the guinea-pig.

1. The effects of cortisone treatment combined with agents influencing histamine metabolism were studied on the free and total acid output in pylorus ligated guinea-pigs.2. It was found that reduction in the synthesis of histamine produced by the administration of alpha-methylDOPA significantly inhibited the acid response to cortisone.3. Enhancement of the oxidative deamination of histamine brought about by the administration of diamine oxidase or heparin inhibited cortisone induced acid hypersecretion significantly.4. Inhibition of the oxidative deamination of histamine by aminoguanidine and iproniazid resulted in a significant increase of the cortisone induced acid hypersecretory response.5. Inhibition of the methylation of histamine by chlorpromazine or 1,4-methylhistamine inhibited the cortisone induced hypersecretory response significantly.6. Studies with labelled histamine indicated that cortisone increases the sequestration of histamine to the stomach.

Amine Oxidase (Copper-Containing)↗
PubMed1970

The role of monoamine oxidase in the response of the isolated central artery of the rabbit ear to tyramine.

1. Monoamine oxidase activity was demonstrated histochemically throughout the media of the rabbit ear artery but not in the adventitia at its border with the media where the sympathetic nerve terminals are concentrated. Neither intensity nor distribution of enzyme activity was perceptibly altered up to 60 days after sympathetic denervation.2. Iproniazid and nialamide increased the sensitivity of the artery to intraluminal tyramine much more than that to extraluminal tyramine, so that the difference between the potencies for the two routes of administration became less marked.3. The results indicate that inactivation by monoamine oxidase in the media is a factor contributing to the relatively low potency of intraluminal tyramine on the artery.

Animals↗
PubMed1972

Analysis of the inhibition of pethidine N-demethylation by monoamine oxidase inhibitors and some other drugs with special reference to drug interactions in man.

1. N-Demethylation of pethidine was studied in microsomal suspensions from unstarved male rat liver and the N-demethylase identified as belonging to the class of hepatic microsomal mixed function oxidases.2. A study of the structure/action relationships of compounds inhibiting pethidine N-demethylase revealed that hydrazine derivatives including phenylhydrazine, methylphenylhydrazine and mebanazine were all potent competitive inhibitors.3. Pethidine N-demethylase was only slightly inhibited by histamine and amphetamine but not by adrenaline and ephedrine nor by several miscellaneous compounds including piperidine, N-ethylpiperidine, N-methylpiperidine, N-methylammonium, hydrallazine or pethidinic acid.4. Several psychotropic drugs were all found to be potent competitive inhibitors of pethidine N-demethylase. These included monoaminoxidase inhibitors (the most active being nialamide and phenoxypropazine [K(i)=0.01 mM]; the least active iproniazid [K(i)=1.05 mM]); the tranquillizers promazine, propiomazine and chlorpromazine and tricyclic antidepressants (opipramol [K(i)=0.01 mM], imipramine [K(i)=0.03 mM], desipramine [K(i)=0.03 mM] and amitryptyline [K(i)=0.03 mM]). Hydrocortisone [K(i)=0.3 mM], prednisolone [2.8 mM] and nalorphine [0.07 mM] were also inhibitors, whilst SKF 525A was the most active of all [K(i)=0.002 mM].5. These results are discussed in relation to the clinically observed drug interactions which may occur between monoamineoxidase inhibitors and pethidine. It is concluded that since many different groups of drugs, including monoamineoxidase inhibitors, tranquillizers, tricyclic antidepressants, steroids, nalorphine, SKF 525A and barbiturates compete for cytochrome P(450) reductase, it is possible that this mechanism may account, at least in part, for the observed interactions of these various drugs in man.

Amphetamine↗
PubMed1972

Effect of sympathomimetic drugs in eliciting hypertensive responses to reserpine in the rat, after pretreatment with monoamineoxidase inhibitors.

1. The effects of some rapidly metabolized sympathomimetic amines, such as beta-phenylethylamine and p-tyramine, in eliciting hypertensive responses to reserpine in the anaesthetized rat, have been studied.2. Retardation of metabolism, by pretreatment with the monoamineoxidase inhibitors iproniazid or phenelzine, causes beta-phenylethylamine (which in untreated rats has no effect) to induce hypertensive responses to reserpine. Tyramine and other hydroxy substituted phenylethylamines are much less active in this respect, probably because of relatively poor lipid solubility.3. Hypertensive responses to reserpine are due to catecholamine release, which is believed to be from stores made accessible to indirectly acting sympathomimetic amines with high lipid solubility by an action of reserpine on cell membranes.

Animals↗
PubMed1974

Interaction of cannabis and general anaesthetic agents in mice.

1 A cannabis extract (I) (in a concentration equivalent to 10 mg Delta(9)-tetrahydro-cannabinol(THC)/kg) prolonged pentobarbitone anaesthesia in mice maximally 20 min to 2 h after medication. The effect was still significant after 8 h, but less than at 2 hours.2 The cannabis extract (I) (equivalent to 10 mg Delta(9)-THC/kg) prolonged both pentobarbitone and ether anaesthesia in mice when administered 20 min before the anaesthetic. After eight consecutive daily doses of cannabis, the pentobarbitone anaesthesia was still significantly longer than a control group, while ether anaesthesia was not significantly prolonged.3 A second cannabis extract (II) with a different ratio of cannabinoids (also administered in dosage equivalent to 10 mg Delta(9)-THC/kg) failed to affect pentobarbitone anaesthesia in mice. This extract presented about 4% the dose of cannabidiol as extract I.4 Delta(8)-THC, Delta(9)-THC and cannabidiol prolonged pentobarbitone anaesthesia with cannabidiol being generally more active than Delta(9)-THC. Cannabinol (10 mg/kg) was inactive.5 The effects of cannabidiol and Delta(9)-THC were found to be additive, and there was a consistent trend for cannabinol to reduce the effectiveness of Delta(9)-THC and cannabidiol when given in combination.6 Premedication with phenoxybenzamine, phentolamine, propranolol, iproniazid, protriptyline, desipramine, reserpine, alpha-methyl tyrosine or parachlorophenylalanine did not affect the extract I-induced prolongation of pentobarbitone anaesthesia.7 It is concluded that cannabis may affect pentobarbitone and ether anaesthesia in mice at least partially by a direct depressant effect, and that the cannabis-induced prolongation of anaesthesia is probably unrelated to any effect on central 5-hydroxytryptamine or catecholamine neurones.

Anesthesia, General↗
PubMed1975

An electrophysiological analysis of the effects of reserpine on adrenergic neuromuscular transmission.

1 An electrophysiological study has been made of the effects of depleting synaptic vesicles (i.e. small vesicles less than 60 nm diameter) of their transmitter with reserpine on the quantity of transmitter released by nerve impulses, using the amplitude of the synaptic potential as a measure of transmitter release. 2 Pretreatment of adrenergic nerve terminals with reserpine sufficient to deplete the terminals of 70% of their noradrenaline (NA) did not change the total number of synaptic vesicles in the terminals, but did reduce the number with a large granular core as well as the quantity of NA released by a single nerve impulse by 80%. 3 Pretreatment of adrenergic nerve terminals with reserpine and iproniazid, to decrease vesicular NA but enhance cytoplasmic NA, had the same effect on synaptic vesicles and on the NA released by a single nerve impulse as did reserpine alone. 4 During a short train of impulses at high frequencies in reserpine pretreated terminals, the quantity of NA released by successive impulses increased until a steady-state release was reached comparable to that in untreated preparations. This facilitated release could be quantitatively predicted in terms of the addition of the individual potentiations introduced by each impulse in the train. 5 These results are consistent with the idea that each quantum of transmitter is stored in a synaptic vesicle, and that these may be released by nerve impulses directly from the terminal by a process of exocytosis.

Animals↗
PubMed1981

Characterization of 5-hydroxytryptamine uptake in sliced rat lung.

Slices of rat lung were incubated with tritiated 5-hydroxytryptamine and the tissue uptake of tritium was studied after separating the free and bound radioactivity by filtration on glass fiber filters. At 37 degrees a rapid uptake occurred during the first 10 min. After that time the uptake was less marked but it was still present after 60 min. The uptake was moderately potentiated by the MAO inhibitor iproniazid (3 micrometers) after 30-60 min. incubation. The 5-hydroxytryptamine uptake was inhibited by some uptake inhibitors, their order of potency beeing: clomipramine greater than imipramine greater than or equal to nortriptyline greater than or equal to cocaine greater than or equal to desipramine greater than maprotiline. At 0 degrees the uptake of 5-hydroxytryptamine was negligible. Non-linear regression analysis of uptake data indicated that 5-hydroxytryptamine was taken up by two different mechanisms. One of the uptake processes was saturated by high concentrations of 5-hydroxytryptamine and showed an apparent Km of 8 X 10(-7) M. The other uptake was linearly related to the 5-hydroxytryptamine concentration and could not be saturated even by concentration up to 5 X 10(-5) M of the amine.

Animals↗