Nialamid during acute myocardial infarction.
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Acute Disease↗
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[Preliminary results of the treatment of neuroses with Nialamid].
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Depression↗
[Nialamid and its combinations with reserpine-like substances (fenoharman, reserpine) in the therapy of endogenous depressions].
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Depression↗
On spinal noradrenaline receptor supersensitivity: correlation between nerve terminal densities and flexor reflexes various times after intracisternal 6-hydroxydopamine.
The noradrenaline (NA)-dependent hindlimb flexor reflex that can be elicited by pinching the foot of acutely spinalized rats given nialamide-DOPA or clonidine was evaluated different time intervals (14 days-6 months) after intracisternal injections of 6-OH-dopamine (6-OH-DA) and correlated to the degree of bulbospinal catecholamine (CA) denervation as seen by Falck-Hillarp fluorescence histochemistry. Six and 14 days after 6-OH-DA, when almost all NA nerve terminals of the spinal cord had degenerated, the NA receptors where supersensitive to stimulation with clonidine as evidenced by an increased flexor reflex. This supersensitivity gradually disappeared as new nerve terminals were formed in the grey matter of the spinal cord during the following 3-6 months. The supersensitivity phenomenon 14 days after 6-OH-DA could also be demonstrated by L-DOPA given to animals pretreated with 100 mg/kg nialamide. Using this relatively low dose of nialamide, almost no reflex response was seen in the control group. Using a higher degree of monoaminoxidase inhibition (nialamide 200 mg/kg) also non-supersensitive, NA receptors became maximally stimulated. Therefore, 6-OH-DA treated rats now showed a weaker reflex than controls, the reflex response being directly correlated to the number of nerve terminals present that could form NA from the precursor. Using 5,6-dihydroxytryptamine, which selectively destroys 5-hydroxytryptamine (5-HT) nerves, it was shown that the flexor reflex changes were specifically related to the NA nerves and unchanged by the simultaneous presence or absence of 5-HT nerve terminals. This was further supported by the finding of a correlation between amount of nerve terminals and flexor reflex responses in individual animals, especially at longer survival times both in the clonidine and the nialamide-DOPA experiments.
Animals↗
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↗
Behavioural studies of the actions of cocaine, monoamine oxidase inhibitors and iminodibenzyl compounds on central dopamine neurones.
1. Turning behaviour after unilateral lesions of the nigro-striatal dopamine pathway in rats has been used to compare the actions of cocaine and desipramine on central dopamine-containing neurones.2. Administration of cocaine alone (5-20 mg/kg) resulted in no turning or minimal turning towards the lesioned side; the monoamine oxidase inhibitors nialamide and pargyline administered alone were also ineffective.3. After pre-treatment with nialamide (100 mg/kg) or pargyline (25 mg/kg) cocaine evoked high rates of turning towards the lesioned side.4. Desipramine (1-100 mg/kg), either alone or in combination with nialamide did not evoke turning.5. Turning evoked by the cocaine-nialamide combination was abolished by pre-treatment with alpha-methyl-p-tyrosine (150 mg/kg).6. Pre-treatment with reserpine (5 mg/kg, 24 h previously) substantially diminished turning evoked by the cocaine-nialamide combination but potentiated turning resulting from administration of methylamphetamine (5 mg/kg).7. Cocaine (20 mg/kg) administered 15 min prior to (+)-methylamphetamine (5 mg/kg) reduced the turning behaviour in the first hour after administration of the latter drug but prolonged the total duration of the effect.
Amphetamine↗
Effects of monoamine oxidase inhibitors on levels of catechols and homovanillic acid in striatum and plasma.
Levels of homovanillic acid (HVA), dihydroxyphenylacetic acid (DOPAC) and dihydroxyphenylglycol (DHPG) in plasma and the striatium were measured after inhibition of monoamine oxidase type A (MAO-A) by clorgyline (4 mg/kg i.p.), MAO-B by (-)deprenyl (1 mg/kg i.p.), both MAO-A and MAO-B by nialamide (75 mg/kg i.p.) or peripheral neuronal MAO by debrisoquin (40 mg/kg i.p.). Levels of HVA in plasma decreased by about 60% after single doses of nialamide or clorgyline, by about 80% after repeated doses of nialamide, by about 40% after a single dose of debrisoquin and by about 50% after repeated doses of debrisoquin. The administration of clorgyline, nialamide or debrisoquin significantly decreased concentrations of DOPAC and DHPG in plasma, whereas (-)deprenyl did not affect levels of DHPG or HVA. None of the MAO inhibitors produced more than about 80% depression of levels of any of the deaminated metabolites. The results suggest that most of the HVA in plasma is derived from deamination of DA by MAO-A in peripheral neurons; that DOPAC in plasma is derived from cells outside the central nervous system; that DHPG in plasma is derived virtually exclusively from the metabolism of norepinephrine in sympathetic nerve endings and that residual levels of HVA after treatment with debrisoquin provide an improved but limited indication of central dopaminergic activity.
3,4-Dihydroxyphenylacetic Acid↗
Effect of treatment of rats with antidepressants on melatonin concentrations in the pineal gland and serum.
The effect of administration of antidepressant drugs to rats on catecholamine-induced rises in the concentration of melatonin in the pineal gland and serum was studied. Increases in melatonin levels were produced by either the exogenous administration of different doses of L-isoproterenol or by exposure of rats to darkness. Repeated administration of either desmethylimipramine or nialamide reduced significantly the elevation in melatonin concentrations in the pineal gland produced by either L-isoproterenol or darkness. The rise in serum melatonin seen at night was also blunted significantly in rats treated repeatedly with these drugs. By contrast, the concentration of melatonin in either the pineal gland or serum was not reduced in rats given desmethylimipramine or nialamide acutely. In fact, daytime concentrations of melatonin both in the gland and in serum were significantly increased after either acute or repeated treatment with nialamide. The nialamide-induced increase in daytime concentrations of melatonin in the pineal gland was prevented if the rats were treated with propranolol. The diminished hormonal responsiveness produced by the repeated administration of antidepressants occurred at a time when the binding of [3H]dihydroalprenolol to pineal gland homogenates was reduced. Thus, a hormonal response to catecholamines regulated via beta adrenergic receptor activation is reduced by repeated antidepressant treatments in conjunction with the development of beta adrenergic receptor subsensitivity.
Animals↗
Interaction of bradykinin with dopaminergic receptors in the CNS.
The influence of bradykinin on the action of compounds affecting predominantly the dopaminergic receptor was studied in behavioral tests (Lat test and sterotypy) and biochemically (estimation of the level of biogenic amines--noradrenaline, dopamine and serotonin, and their metabolites--normetanephrine, homovanillic and 5-hydroxyindoleacetic acids in the brain tissue). Bradykinin potentiated the action of nialamide with L-dopa, dopamine, 1,3-dimethyl-5-aminoadamantane, apomorphine and noradrenaline. Spiroperidol abolished potentializing effect of bradykinin on the central action of nialamide with L-DOPA and of noradrenaline. In animals receiving spiroperidol with bradykinin psychostimulatory action of noradrenaline was also not observed. FLA-63--inhibitor of dopamine beta-hydroxylase--increased the potentializing effect of bradykinin on the central action of dopamine. Most significant biochemical changes between the group receiving nialamide alone and the group given nialamide together with bradykinin have been observed in corpus striatum, where the level of dopamine and its metabolite--homovanillic acid--increased. The results obtained point out that the potentiation of the central effects of catecholamines by kinins depends mainly on the interaction of this peptide with dopaminergic receptor.
Animals↗
Serotonin immunocytochemistry in the adult and developing rat brain: methodological and pharmacological considerations.
An antiserum has been raised in rabbits against serotonin (5-HT) conjugated to the invertebrate protein hemocyanin (HC). This antiserum was characterized with respect to its cross-reactivity with related compounds and its immunocytochemical staining properties in brains of adult and developing rats and in animals pretreated with various pharmacological regimens. When compared to an antiserum raised against 5-HT/bovine serum albumin (BSA) conjugates [59], the 5-HT/HC conjugate elicited a more profound immune response which resulted in the production of a specific, high titer antiserum that could be used directly for immunocytochemistry without removal of antibodies to the invertebrate carrier molecule, HC. Immunoabsorption experiments to assess the specificity of this antiserum demonstrated a small degree of cross-reactivity with dopamine (which was greater than that with norepinephrine or epinephrine). However, no staining of catecholaminergic neurons was found in untreated adult or developing animals, nor in animals pretreated with L-DOPA or L-DOPA + the MAO inhibitor nialamide, indicating that this cross-reactivity is not manifested under normal staining conditions. No cross-reactivity of the 5-HT/HC antiserum was observed for any 5-HT precursors or metabolites tested, although both this antiserum and the 5-HT/BSA antiserum did exhibit a high degree of cross-reactivity to the related indoleamines 5-methoxytryptamine (5-MT) and tryptamine. However, based on the immunocytochemical staining patterns observed, and the fact that both 5-MT and tryptamine are found in very low quantities in the normal rat brain, it appears that 5-HT is the predominant indoleamine stained by both of these antisera in the untreated rat brain. In animals pretreated with L-tryptophan + nialamide, some light staining was found in the dopaminergic A9 and A10 cell groups using either antiserum. However, since this staining was not observed in L-DOPA + nialamide treated animals it is not thought to be due to cross-reactivity with dopamine. Rather, since the staining could be inhibited by pretreatment with the catecholaminergic uptake blocker desmethylimipramine, it is postulated that this effect may be due to either (1) the non-specific uptake of 5-HT or 5-hydroxytryptophan (5-HTP) into the dopaminergic cells of A9 and A10 due to elevated levels of these substances in the dense serotonergic axonal plexus passing through this region or (2) to an increased uptake of circulating L-tryptophan by these A9 and A10 cells followed by conversion of this amino acid to tryptamine by aromatic amine decarboxylase, an enzyme common to both 5-HT and dopaminergic neurons. This latter possibility suggests that caution should be exercised when interpreting immunocytochemical staining patterns obtained in animals pretreated with L-tryptophan + nialamide using 5-HT antisera, since other cross-reactive indoleamines could be elevated by this pharmacological manipulation.
Animals↗
Serotonin and cardiac morphogenesis in the mouse embryo.
The possible involvement of the neurotransmitter serotonin (5-HT) and its binding protein (SBP) in cardiac morphogenesis was studied using mouse whole embryo culture (together with immunocytochemistry or 3H-thymidine autoradiography) and a cell migration assay. Embryos were cultured before and during the period of endocardial cushion formation, embryonic (E) days 9-12, in the presence of 5-HT, the monoamine oxidase (MAO) inhibitor nialamide, or an uptake inhibitor (fluoxetine or sertraline). For the migration assay, cells from the outflow tracts of E12 embryos were dissociated and placed in a chemotaxis chamber together with different concentrations of 5-HT. E9 embryos cultured in the presence of 10 microM 5-HT and nialamide exhibited intense 5-HT immunoreactivity (5-HT IR) throughout the myocardium. This staining was greatly diminished by fluoxetine, sertraline, or the absence of nialamide. As morphogenesis proceeded, myocardial staining in embryos exposed to 5-HT became restricted to developing endocardial cushion forming regions and was more completely blocked by uptake inhibitors. No evidence for 5-HT synthesis by myocardium was found at any age studied using the precursor L-tryptophan. SBP was present in endocardial cushions in cultured and uncultured embryos. 3H-thymidine autoradiography demonstrated that both fluoxetine and sertraline inhibited proliferation of cardiac mesenchyme, endocardium, and myocardium. These effects were most pronounced when exposure began at E9 (prior to cushion formation). Dose-dependent effects of 5-HT on migration of outflow tract cells were also observed. Taken together, these results suggest that 5-HT may play a role in cardiac morphogenesis during endocardial cushion formation.
1-Naphthylamine↗
Chronic inhibition of monoamine oxidase reduces noradrenaline release in rat vas deferens and anococcygeus muscle.
Rats were treated once (acute) or once daily for 21 days (chronic) with clorgyline (2 mg/kg) or nialamide (50 mg/kg). (-)Deprenyl (1 mg/kg) was given for 21 days. One day after the last injection, vas deferens and anococcygeus muscles were removed and noradrenaline stores labelled with 3H-noradrenaline. Efflux of total tritium following electrical field stimulation was decreased by both acute and chronic treatment with clorgyline and nialamide, as well as by chronic treatment with deprenyl. Total tritium release from anococcygeus muscle was reduced by both acute and chronic treatment with clorgyline. Fractionation of the effluent showed that release of both free noradrenaline and metabolites was decreased by MAO inhibitor treatment in vivo, but this effect was not reproduced by in vitro incubation of the vas deferens with clorgyline (1 microM). By contrast to the effect of electrical field stimulation, release of 3H-noradrenaline induced by veratrine was increased by chronic treatment with both clorgyline and nialamide. Release of total tritium by depolarising concentrations of KCl was also increased by chronic clorgyline treatment. These results could be explained by a proportionally greater release of tritium from a cytoplasmic compartment following veratrine and KCl than electrical stimulation, since MAO inhibition increases cytoplasmic noradrenaline levels. Alternatively, release by electrical stimulation may be affected to a greater extent by presynaptic alpha 2-adrenoceptors, and presynaptic receptors may be stimulated by increased synaptic levels of free noradrenaline following MAO inhibition.
Animals↗
Suppression of the hypo- and hyperthermic responses to 5-HT agonists following the repeated administration of monoamine oxidase inhibitors.
Hypo- and hyperthermic responses resulting from the activation of putative 5-HT1A and 5-HT2 receptors, respectively, were examined after the chronic treatment of rats with monoamine oxidase inhibitors. The treatment of rats for 4 or 7 days with nialamide (40 mg/kg, twice daily) resulted in a suppression of the hypothermic effect of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT, 0.05-0.25 mg/kg, SC). The decrease in body temperature elicited by a low dose of 5-methoxy-N, N-dimethyltryptamine (5MeODMT, 1 mg/kg) also was diminished in rats treated chronically with nialamide. The administration of a high dose of 5MeODMT (5 mg/kg) resulted in a hyperthermic response, which was also attenuated after the repeated administration of nialamide. The repeated administration of clorgyline (a selective inhibitor of type A MAO) or deprenyl (a selective inhibitor of type B MAO) failed to alter the hypothermic effect of 8-OH-DPAT. However, in animals treated chronically with both clorgyline and deprenyl, a suppressed response to 8-OH-DPAT was observed. In view of the concept that the hypo- and hyperthermic responses to 5-HT agonists are mediated by 5-HT1A and 5-HT2 receptor subtypes, respectively, it is concluded that the responsiveness of these 5-HT receptor subtypes involved in thermoregulatory responses is decreased following chronic treatment of rats with monoamine oxidase inhibitors. It appears that inhibition of both type A and B MAO is necessary for this desensitization process.
8-Hydroxy-2-(di-n-propylamino)tetralin↗
Influence of opioids and naloxone on rhythmic motor activity in spinal cats.
The effects of L-DOPA, naloxone, and the opioids (D-Ala2,N-Me-Phe4,Gly5-ol)-enkephalin (DAGO) and D-Ser2-Leu-enkephalin-Thr6 (DSLET) on spinal motor rhythm generation were compared in anemically decapitated high spinal cats. After premedication with nialamide, DOPA caused the well-known, slow rhythmic motor activity with a locomotor pattern. The cycle duration of the evoked rhythm was usually between 3.9 and 5.0 s. The opioids DAGO and DSLET, injected intravenously (1.2-2 mg/kg) or suffused over the lumbar spinal cord (10(-3)-10(-4) M in Ringer's solution), severely depressed the DOPA-induced rhythmic activity, sometimes completely abolishing efferent motor activity. Naloxone (0.5-1 mg/kg i.v.) exerted different rhythm-facilitating effects, depending on the experimental condition. In the acute phase after spinalization, without paralysis and without nialamide and DOPA, naloxone induced rhythmic movements with a main frequency of 1.2-2 Hz. In the same preparation with paralysis, naloxone induced a rhythmic motor activity with a distinctly higher frequency (main range 4.3-5.8 Hz). After premedication with nialamide and DOPA, naloxone facilitated or, if a rhythm was absent, induced the slow-frequency DOPA type of rhythm. Given after i.v. or topical opioid application, naloxone antagonized the rhythm-depressing action of the opioid and caused an additional facilitation of rhythmic activity. Dopa and naloxone facilitated the long-latency, segmental reflex pathways from flexor reflex afferents (FRA), while the opioids depressed them. The short-latency FRA pathways were depressed by DOPA and opioids but were facilitated by naloxone. The influence of the different drugs on spinal motor rhythm generation is discussed in relation to their influence on short- and long-latency segmental pathways from FRA. If the rhythm generation induced by DOPA is based on the release of the long-latency FRA pathways, as has been proposed before, the rhythm-depressing action of opioids may be due to the suppression of these pathways, and the particular rhythm-generating function of naloxone may be related to its facilitation of short- and long-latency FRA pathways.
Animals↗
Inhibition of 5-HT uptake into neurons and platelets in mice treated chronically with chlorimipramine and femoxetine.
A single treatment with 5-HT uptake inhibitors potentiates the hypermotility in mice produced by the MAO-inhibitor nialamide. The effect of nialamide on motility was studied in mice after 4 weeks of feeding with a normal diet and diets containing various concentrations of the 5-HT uptake inhibitors chlorimipramine and femoxetine. Chronic treatment with the two substances enhanced the motor effects of nialamide about equally, which indicates a preservation of the neuronal 5-HT uptake inhibition during such treatment. The effect of chlorimipramine and femoxetine was obtained at plasma levels equivalent to or lower than the steady-state plasma concentrations found in patients treated with two 5-HT uptake inhibitors. Determination of decreased blood 5-HT after the 4 weeks of treatment was used as an in vivo test for inhibition of 5-HT uptake into platelets. Femoxetine was a much weaker depletor of blood 5-HT than chlorimipramine. These results indicate that blockade of neuronal 5-HT uptake is obtained at lower doses of femoxetine than blockade of 5-HT uptake into platelets. In contrast, chlorimipramine presumably inhibits 5-HT uptake into neurons and platelets at about the same dose.
Animals↗
The effects of levodopa on plasma glucose in two strains of rat.
The effects of levodopa on plasma glucose were examined in two strains of rats. In fasted Wistar rats levodopa produced a dose-dependent hyperglycaemic response which was augmented by pretreatment with nialamide. This response in nialamide-treated rats was prevented by pretreatment with phentolamine and converted to a hypoglycaemic response. Phentolamine increased the plasma concentration of immunoreactive insulin (IRI). In phentolamine-pretreated rats levodopa produced a further marked increase in the plasma IRI concentration. It is suggested that the prevention of levodopa hyperglycaemia by phentolamine is due to the marked increase in the plasma IRI concentration produced by pretreatment with phentolamine. Moreover the fall in the plasma glucose concentration produced by levodopa in phentolamine-pretreated rats is likely to be due, at least in part, to the additional increase in the plasma IRI concentration produced by levodopa under these conditions. In contrast, in fasted Sprague-Dawley rats pretreated with nialamide, levodopa produced either no effect on plasma glucose, or in larger doses, a marked hypoglycaemic effect followed by death. This hypoglycaemic effect was accompanied by a decrease in the plasma IRI concentration.
Animals↗
Effects of three monoamine oxidase inhibitors on ethanol preference in mice.
These experiments investigated the effects of pargyline, N-[2-(o-Chlorophenoxy)-ethyl]-cyclopropylamine (Lilly 51641), and nialamide on voluntary ethanol consumption of C57BL/6J mice. Both pargyline and Lilly 51641 reduced ethanol preference; in contrast, nialamide did not affect preference, despite the fact that it inhibited MAO activity by more than 90%. A subsequent experiment determined that both pargyline and Lilly 51641 produced substantially greater elevations in acetaldehyde levels than did nialamide. It is suggested that increased acetaldehyde is the mechanism responsible for the reduction in ethanol preference observed with pargyline and Lilly 51641.
Acetaldehyde↗
Behavioral effects of a dimethylsulfonium analog of dopamine after injection into the nucleus accumbens and the striatum.
We have previously synthesized a chemical analog of dopamine (DA) in which the amine group has been replaced by a permanently charged dimethylsulfonium group. In the present study, we have determined whether this compound can exert DA agonist activity in the nucleus accumbens by comparing its effects with those of DA. When DA was injected into the nucleus accumbens of rats pretreated with nialamide, a monoamine oxidase inhibitor, there was marked stimulation of locomotor activity. Similarly, after intraaccumbens injection, the sulfonium analog also produced a marked stimulation of locomotor activity, and this effect was inhibited by the DA receptor antagonist, haloperidol (0.2 mg/kg, IP). However, the sulfonium analog did not stimulate locomotor activity when rats were pretreated with saline instead of nialamide. In addition, the stimulation of locomotor activity produced by the sulfonium analog in rats pretreated with nialamide was completely inhibited by the DA synthesis inhibitor, alpha-methyl-p-tyrosine. These results suggest that the stimulation of locomotor activity by the sulfonium analog is mediated indirectly through the release of DA. The sulfonium analog was able to produce marked contralateral circling after it was injected into the striatum of rats on the side of the brain in which DA nerve terminals were previously destroyed with 6-hydroxydopamine. Similarly, the sulfonium analog produced a marked stimulation of locomotor activity after it was injected into the nucleus accumbens of rats that were previously injected into this region with 6-hydroxydopamine. These results suggest that the sulfonium analog of dopamine can exert direct as well as indirect DA agonist activity.
Animals↗