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PubMed1975

The behavioural effects of dopamine applied intracerebrally to areas of the mesolimbic system.

The intracerebral injection technique was used to apply dopamine directly into dopamine-containing areas of the mesolimbic system, the nucleus accumbens septi, tuberculum olfactorium and nucleus amygdaloideus centralis. 200 mug dopamine injected bilaterally into the nucleus accumbens septi caused a stereotyped sniffing behaviour and hyperactivity but only a periodic hyperactivity developed after similar injections into the tuberculum olfactorium and no change in behaviour was observed following injections into the nucleus amygdaloideus centralis. After pretreatment with nialamide, the effects of intracerebral dopamine were enhanced, doses of 1-50 mug dopamine causing consistent stereotyped sniffing and a dose-dependent hyperactivity on injection into the nucleus accumbens septi or tuberculum olfactorium. The effects initiated from the nucleus accumbens septi were most marked. In addition, 50-100 mug dopamine injected into the tuberculum olfactorium caused a periodic biting behaviour. Biting was not observed after injections into the nucleus accumbens septi and, even in the presence of nialamide, injections of dopamine into the nucleus amygdaloideus centralis failed to cause any change in motor behaviour.

Animals↗

PubMed1986

Monoamine oxidase: an important intracellular regulator of gastrin release in the rat.

The role of monoamine oxidase (MAO) in the meal-induced or amino acid-induced release of gastrin was investigated. Rats that were pretreated with the nonspecific MAO inhibitor nialamide (200 mg/kg) showed a greater rise in meal-induced serum gastrin than did untreated controls. In vitro experiments demonstrated that gastrin secretion from dispersed antral G cells in response to a stimulatory dose of phenylalanine or methylbenzylamine (10 mM) was markedly enhanced if the cells were treated with nialamide. Studies with the more specific MAO inhibitors clorgyline and deprenyl indicated that antral mucosa contained predominantly type A activity. Inhibition of MAO type A with clorgyline, both in vivo and in vitro, resulted in a greater release of gastrin after stimulation by a meal or phenylalanine. It is concluded that MAO may play an important role in the regulation of gastrin release from the G cell by partially controlling the level of amines within the cell.

Animals↗

PubMed1982

Ketamine inhibits serotonin uptake in vivo.

Anesthetic (120 and 160 mg/kg. i.p.) and subanesthetic (80 mg/kg) doses of ketamine HCl were found to prevent completely the depletion of whole brain serotonin (5-HT) by p-chloramphetamine (PCA). Furthermore, ketamine HCl (160 mg/kg) completely blocked the depletion of 5-HT by PCA in every individual brain region studied (Midbrain-thalamus, hypothalamus, striatum, hippocampus and cortex). Administration of ketamine alone had no effect on brain 5-HT levels. Nialamide (a monoamine oxidase (MAO) inhibitor) and fluoxetine (a selective 5-HT uptake inhibitor) also prevented the depletion of 5-HT by PCA. However, of these three agents, only nialamide prevented the depletion of 5-HT by reserpine. These results suggest that ketamine blocks PCA-induced 5-HT depletion by inhibiting 5-HT uptake and not by inhibiting MAO. Ketamine only weakly affected either [3H]5-HT or [3H]spiroperidol binding to 5-HT1 and 5-HT2 receptors respectively even at concentrations as high as 1 mM. These data support the contention that the primary direct effect of ketamine on serotonergic systems is the blockade of 5-HT uptake and that blockade of 5-HT uptake may mediate some of the behavioral effects of ketamine, such as analgesia.

Animals↗

PubMed1980

Evidence that a preferred substrate for type B monoamine oxidase mediates stimulus properties of MAO inhibitors: a possible role for beta-phenylethylamine in the cocaine cue.

In the experiment, rats were trained to discriminate 5 mg/kg cocaine HCl from saline in a two-bar drug discrimination procedure. Stimulus generalization experiments were carried out with six inhibitor drugs of monoamine oxidase. The rank order of absolute potency of these drugs in inducing stimulus generalization with cocaine was: tranylcypromine (ED50 in mg/kg; 1.2)>pheniprazine (3.5)>deprenyl (5)>pargyline (28)>nialamide (approximately 170); at up to 40 mg/kg, clorgyline failed to produce 50% generalization. All six drugs also potentiated tryptamine in producing body tremors and clonic seizures, the rank order of potency being tranylcypromine (0.081)>clorgyline (0.14) greater than or equal to pheniprazine (0.15)>pargyline (1.97)>deprenyl (15.5)>nialamide (18.7). Tryptamine is a common substrate for both type A and type B monoamine oxidase, so that tryptamine potentiation may serve to determine the relative specificity of the doses at which the inhibitor drugs generalized with cocaine. The present data may suggest that endogenous substances which are preferred substrates for type B monoamine oxidase in rat brain can exert control of behavior by virtue of cocaine-like stimulus properties. beta-Phenylethylamine, more so than dopamine, appears to be candidate substance for mediating the discriminative stimulus properties of cocaine and, perhaps, of other central nervous system stimulants.

Animals↗

PubMed1982

Anorexic properties of three monoamine oxidase inhibitors.

The anorexic properties of 3 monoamine oxidase (MAO) inhibitors, pargyline, tranylcypromine and nialamide were determined 24 hr after their intra-peritoneal administration. The duration of anorexia occurring after the peripheral administration of the dose of pargyline commonly used in conjunction with 6-hydroxydopamine (6-OHDA) to enhance its dopamine-depleting properties was also determined. Body weight regulation and the control of food and water intake were severely impaired 24 hr after the administration of the three highest doses of pargyline, tranylcypromine and nialamide employed. Impairment in the ability to regulate body weight lasted for as long as 6 days in some animals injected with 50 mg/kg of pargyline. These findings bring to light the problems in interpretation of results from studies which employ MAO inhibitors and 6-OHDA simultaneously to enhance dopamine depleting properties of 6-OHDA.

Animals↗

PubMed1979

Effects of levodopa and dopamine on plasma 11-hydroxycorticosteroid concentrations in mice.

The effects of levodopa on the plasma concentration of 11-hydroxycorticosteroids and glucose were examined in mice. In fasted, nialamide treated mice, but not in fed mice, levodopa produced a significant decrease in the plasma concentration of 11-hydroxycorticosteroids. This was accompanied by a significant and marked decrease in the plasma glucose concentration. These effects of levodopa could be mimicked by relatively small doses of dopamine injected intracerebroventricularly but not intravenously. The integrity of the hypothalamic-pituitary adrenal axis in nialamide-treated mice was suggested by the elevation in plasma 11-hydroxycorticosteroids produced by fasting or by insulin induced hypoglycaemia. These results indicate that in the mouse, as in other species, levodopa can inhibit stress provoked increases in the secretion of 11-hydroxycorticosteroids.

11-Hydroxycorticosteroids↗

PubMed1969

Effects of monoamine oxidase inhibitors on the hypothermia produced in cats by halothane.

1. In cats, the effects of intraperitoneal injections of four monoamine oxidase (MAO) inhibitors, tranylcypromine, pheniprazine, pargyline, and nialamide, were examined on rectal temperature and on the hypothermia during anaesthesia produced by a 2 hr period of halothane inhalation.2. A 2 hr period of halothane inhalation produced a steady fall in temperature amounting to between 2 degrees and 3.5 degrees C. After discontinuation of halothane inhalation, temperature quickly returned to the pre-anaesthetic level but no pyrexia developed. A peculiar stiffness of the leg muscles occurred in several experiments either at the beginning of the inhalation or after its discontinuation.3. An injection of tranylcypromine (5 mg/kg) caused a rise in rectal temperature and prevented the hypothermia of halothane anaesthesia. This effect lasted for at least 4 hr; 20 hr after the injection, halothane again caused hypothermia.4. An injection of pheniprazine (10 mg/kg) usually caused a small rise in temperature which was not sustained. Pheniprazine not only prevented the hypothermia of halothane anaesthesia during the subsequent 20 hr, but during the first few hours after the injection halothane inhalation actually produced a steep rise in temperature.5. An injection of pargyline (50 mg/kg) had no effect on temperature but the hypothermia due to halothane inhalation was prevented 1 hr after the injection and attenuated after 20 hr. Injection of 200 mg/kg caused a steady rise in temperature which was accelerated when halothane was administered 1 hr later.6. An injection of nialamide (10, 25 or 50 mg/kg) had no immediate effect on temperature, but pyrexia developed overnight after the two larger doses. The effect on the hypothermia due to halothane inhalation was greater 20 hr after the injection than it was after 1 to 2 hr. Twenty hours after injection of the two larger doses, halothane no longer produced hypothermia but caused a lethal rise in temperature either during or after its inhalation.7. In rabbits, the effect on temperature of halothane inhalation varied. Either temperature rose slightly or it fell, but not as much as in cats. In one rabbit in which the inhalation had produced a transient rise, pyrexia developed 40 min after discontinuation of halothane.

Anesthesia, Inhalation↗

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↗

PubMed1988

The mechanism by which monoamine oxidase inhibitors give rise to a non-calcium-dependent component in the depolarization-induced release of 5-HT from rat brain synaptosomes.

1. The effects of the monoamine oxidase inhibitors pargyline and nialamide on the Ca2+-dependency of [3H]-5-hydroxytryptamine release from superfused rat brain synaptosomes has been studied in order to evaluate the discrepancies that have occasionally been observed in studying transmitter release by in vivo and in vitro techniques. 2. The application of K+ pulses of low concentration (12.5-20 mM) caused an essentially Ca2+-dependent release of [3H]-5-HT. However, at K+ concentrations above 30 mM, a small non-Ca2+-dependent component appeared. 3. At high concentrations of K+ (30-55 mM), nialamide (18 microM) or pargyline (7 microM) increased the amount of [3H]-5-HT released which could be accounted for by an increase in the non-Ca2+-dependent component of release. 4. The elevation of the non-Ca2+-dependent component of release caused by the monoamine oxidase inhibitors was totally abolished by the inhibitors of the plasma membrane 5-HT carrier, chlomipramine (500 nM), citalopram (50 nM) and fluoxetine (1 microM). 5. The results suggest that the non-Ca2+-dependent component of release seen with high depolarizing concentrations of K+, particularly in the presence of monoamine oxidase inhibitors, is caused by the efflux of [3H]-5-HT through the plasma membrane carrier which seems to be activated during depolarization. 6. The significance of these findings to the physiological in vivo situation, and to the use of in vitro preparations in the study of transmitter release is discussed.

Animals↗

PubMed1985

Effects of 5-hydroxytryptamine and related agents on endothelial cell oxidative metabolism in vitro.

A recently described microrespirometric method was used to determine the influence of 5-hydroxytryptamine (5-HT), nialamide, imipramine and ouabain alone and in combinations on oxidative metabolism in monolayer cultures of endothelial cells from the rat pulmonary artery. It was found that exposure to 5-HT increased oxygen uptake in the cultures, while imipramine or ouabain decreased respiration; nialamide had no obvious effect. When used in combinations, the effect of ouabain or imipramine dominated over the 5-HT effect. The explanation for this 5-HT stimulating effect on endothelial cell oxidative metabolism, previously undescribed, is suggested to be that 5-HT exposure stimulated individual cells to contract. This active contraction resulted in an increased energy demand reflected in elevated oxygen consumption, an effect inhibited by ouabain or imipramine.

Animals↗

PubMed1991

Corticosterone and prolactin response to TFMPP in rats during repeated antidepressant administration.

The corticosterone and prolactin response to acute administration of the 5-HT agonist 1-(m-trifluoromethylphenyl) piperazine (TFMPP) (10 mg kg-1) was assessed in rats treated for 10 days with either saline, amitriptyline (20 mg kg-1 day-1) or nialamide (40 mg kg-1 day-1). For all groups, TFMPP significantly increased both serum corticosterone and prolactin concentrations compared with control animals challenged with saline. However, the corticosterone response to TFMPP was attenuated significantly by nialamide pretreatment, while the prolactin response to TFMPP was enhanced significantly by amitriptyline pretreatment. These results support previous reports that antidepressants differentially affect 5-HT-ergic systems involved in the regulation of corticosterone and prolactin secretion.

Amitriptyline↗

PubMed1975

Accumulation of norepinephrine (NE) by rat organs in vivo.

In anesthetized rats intravenously infused, norepinephrine (NE) was accumulated by the heart, the spleen and the lung in a dose-related manner. With the lower dose of NE (2.5 mg/kg) the organ/blood ratios were more than unity and were generally greater than with higher doses (5 and 10 mg/kg), indicating that accumulation occurred by active uptake. Nialamide and pyrogallol treatment increased accumulation in the three organs. In animals receiving nialamide and pyrogallol treatment, normetanephrine (uptake2 inhibitor) and desmethylimipramine (uptake1 inhibitor) inhibited accumulation in all the organs and the entire accumulation of NE could be ascribed to uptake1 and uptake2 processes. In these animals, phenoxybenzamine and bilateral adrenalectomy inhibited and enhanced, respectively, the accumulation in the heart and the spleen only. NE accumulated in hearts of animals in vivo could be partly washed out by perfusion with NE-free medium in vitro. Washout was prevented by normetanephrine, indicating that this effect was not a passive diffusional leakage.

Adrenal Glands↗

PubMed1983

Catecholaminergic control of alpha-melanocyte-stimulating hormone (alpha MSH) release by frog neurointermediate lobe in vitro: evidence for direct stimulation of alpha MSH release by thyrotropin-releasing hormone.

The role of dopaminergic and adrenergic innervation of the intermediate lobe of amphibian pituitary in the release of alpha MSH has been studied in vitro. Neurointermediate lobes of frog (Rana ridibunda Pallas) have been perifused in amphibian culture medium (ACM) for 5-7 h. alpha MSH released in the effluent perifusate was measured by means of a sensitive and specific RIA. No significant morphological alteration of neurointermediate lobe cells was observed during the perifusion experiment, even at the electron microscopic level. The existence of dopaminergic receptors, responsible for an inhibition of frog melanotrophs, was shown using the dopaminergic agonists apomorphine (10(-6) M) and bromo-2-ergocryptine (10(-8) and 10(-7) M), which initiated a marked reduction of alpha MSH secretion. The effect of apomorphine was obliterated by the dopaminergic antagonist haloperidol. Haloperidol itself induced a dose-related stimulation, and the monoamine oxidase inhibitor nialamide (4 x 10(-3) M) inhibited alpha MSH secretion. In addition, haloperidol led to a complete reversal of the inhibitory effect of nialamide on alpha MSH secretion. These results demonstrate the existence, in the parenchyme of the intermediate lobe, of dopaminergic nerve fibers that are functionally active. The beta-adrenergic agonist isoproterenol was responsible for a dose-related stimulation of alpha MSH secretion; the stimulatory effect was reversed by the beta-adrenergic antagonist propranolol. TRH is a potent stimulator of alpha MSH secretion in amphibians. Since haloperidol and propranolol did not abolish the stimulation of alpha MSH release induced by TRH, it appeared that TRH action was not mediated via an inhibition of dopamine release or via a stimulation of adrenergic nerve fibers.

Animals↗

PubMed1975

The effects of drugs on accumulation and release of catecholamines in rat brain slices.

Pretreatment of rats with reserpine decreased the uptake and release of labelled NE and DA in rat slices. MAO inhibition with nialamide partially antagonized the effects of reserpine, but nialamide itself decreased the release of labelled DA. Treatment of brain slices in vitro with phenoxybenzamine or desmethylimipramine inhibited uptake of catecholamines, and affected spontaneous and electrically-stimulated release in a manner consistent with the existence of an alpha-receptor-mediated feedback regulation of release at both NE and DA nerve terminals. The effect of phenoxybenzamine on stimulated release was observed to be dependent on stimulation rate.

Animals↗

PubMed1977

[Brain monoamines and circadian rhythm of spontaneous motor activity of rats].

The effect of three drugs, parachlorophenylalanine, nialamide and disulfiram, drugs known by their action on the two sleep phases, slow wave sleep and I-REM-sleep, have been studied and tested by their effect on the motor circadian rhythm : PCPA and disulfiram reduce the amplitude of the rhythm by two opposed mechanisms : PCPA increases the motor activity, especially the day-time activity, disulfiram reduces the motor activity, especially the night-time activity. The former reduces the serotonine content, the latter the noradrenaline content of the central nervous system. Nialamide (5 or 10 mg/1000 g) is without any action of the rhythm. Both doses increase very much the motor activity ; but the central excitatory state undergoes the normal circadian rhythm. This monoaminoxydase inhibitor is without any action on the circadian rhythm.

Animals↗

PubMed1975

Activity of some enzymes which synthesize and metabolize catecholamines in the brain and peripheral organs in developing rats.

Activities of monoamine oxidase (MAO), DOPA-decarboxylase (DD), phenoletha-nolamine-N-methyltransferase (PNMT) and phosphodiesterase (PDE) were studied in the brain and its parts, heart, kidneys, adrenals and liver in developing rats. In vitro, the action of nialamid on MAO activity in the liver, RO-4-4602 on DD activity in the liver, and D(-) INPEA on PNMT activity in the adrenals was investigated. The influence of 6-hydroxydopamine (6-OHDA), 200 mg/kg i. p., on MAO activity in the liver of developing rats was also studied. Irregular changes in activities of examined enzymes during development were observed. 6-OHDA, nialamid and RO-4-4602 inhibited enzyme activities in young rats more strongly than in adult animals.

Adrenal Glands↗

PubMed1989

Heart-transplant and mono-amine oxidase inhibitors.

A case of anesthesia for a heart-transplant operation on a patient on mono-amine oxidase inhibitors (M.A.O.I.) is reported. This 63-year-old farmer was in end-stage cardiac failure due to familial cardiomyopathy. For 24 hours before surgery, he was on a dobutamine infusion (3 mcg/kg/min). He had been taking nialamide (100 mg/day) for 8 years for reactional depression and had not stopped it, despite advice. Anesthesia was induced with etomidate and succinylcholine, and maintained with fentanyl (25 mcg/kg/min) and pancuronium. Cardio-vascular stability was maintained during induction and first stage of surgery, up to cardectomy. Graft ischemia was 188 minutes. Successful defibrillation occurred after verapamil 3 mg. Weaning from C.P.B. was easy with dopamine (5 mcg/kg/min) and isoprenaline (0.01 mcg/kg/min). Post-operatively, on day 1, hypertension appeared and needed a nitroprusside infusion. On day 3, the patient needed another anesthetic for removal of pericardial clots, without problems. He remained very confused and disorientated during all his stay in hospital, but improved greatly with a neuroleptic. He left the hospital on day 28 in a good shape, with an anxiolytic, captopril and immunosuppressors. One month later, he was back on nialamide. The pharmacology of the M.A.O.I. is reviewed and their interactions with anesthesia are discussed as well as the use of inotropes. In this case, the denervated heart-graft, free from M.A.O. inhibition, behaved normally when transplanted in a chronically M.A.O.I. treated recipient.

Adjustment Disorders↗

PubMed1981

Experimental ultrastructural modifications of the content of serotoninergic supra-ependymal nerve fibres in the rat.

1. In this study, evidence is presented that the electron-dense dot observed in the synaptic vesicles of axonal varicosities belonging to the supra-ependymal nerve fibres (SEF) of rats is related to the serotonin content of these vesicles. 2. The size of the dense dot and the relative number of small granular vesicles (SGV) were markedly increased by intraventricular administration of serotonin as well as by acute or chronic treatment with inhibitors of monoamine oxidases. 3. Conversely, the administration of reserpine diminished the percentage of SGV, as compared to untreated animals, and prevented the formation of granules in synaptic vesicles of chronic nialamide-treated rats. 4. With respect to large granular vesicles (LGV), it was found that chronic inhibition of MAO increased their number within the varicosities, whereas reserpine administration in untreated rats resulted in their disappearance. 5. Our results strongly imply that serotonin is present in both SGV and LGV of the SEF varicosities. This conclusion is supported by some radioautographic pictures obtained after intraventricular administration of 3H-5-HT which show silver grains over both populations of vesicles. Further support was obtained by the use of the Tranzer's cytochemical method in either untreated or nialamide treated rats. This method demonstrates that the reaction specific of monoamines occurs in both types of vesicles with either treatment but that larger stores of 5 HT (larger granules) are demonstrated after inhibition of MAO. 6. It is concluded that both SGV and LGV may represent storage organelles for exogenous and endogenous 5-HT.

Animals↗