Effects Of Monoamine Oxidase Inhibitors Research Articles

Study of the acute effect of MAO inhibitors on learned helplessness paradigm

Study of the acute effect of MAO inhibitors on learned helplessness paradigm

A Comparative Study of the Electrocardiographic Effects of Phenelzine, Tricyclic Antidepressants, Mianserin, and Placebo

Although the electrocardiographic effects of the tricyclic antidepressants have been extensively investigated, there are fewer data on the effects of monoamine oxidase inhibitors and tetracyclics on cardiac conduction. This study used high speed recordings of the electrocardiogram to investigate the cardiographic effects of phenelzine and mianserin and to compare these to the effects of imipramine, amitriptyline, and placebo. Phenelzine caused significant slowing of the heart rate, while mianserin showed little effect on heart rate compared to the increases in rate seen with tricyclics. In clinically effective doses, neither phenelzine nor mianserin caused changes in conduction, while both tricyclics studied caused the expected prolongation of conduction. These data suggest that phenelzine and mianserin deserve further study in patients with disease of the cardiac system as they may be less likely to cause heart block in these patients.

The concentration ofp- andm-tyramine in the rat mesolimbic system: its regional distribution and effect of monoamine oxidase inhibition

The concentrations ofp-tyramine andm-tyramine have been determined in 6 brain areas from the mesolimbic system by a specific and sensitive mass spectrometric technique.p- andm-Tyramine are unevenly distributed amongst these nuclei. The highest concentrations ofp-tyramine were measured in the olfactory tubercle followed by the nucleus accumbens and septal nuclei while form-tyramine the concentrations decreased in the following order: olfactory tubercle, nucleus accumbens, amygdala, septal nuclei and nucleus tractus diagonalis.

Effects of different monoamine oxidase inhibitors on the metabolism of L-dopa in the rat brain

The influence of monoamine oxidases A and B on the metabolism of dopamine or the expanded dopamine pool following L-dopa administration remains unclear. This study found that treatment of Sprague-Dawley rats with monoamine oxidase inhibitors strongly affected L-dopa metabolism in the brain, but the influence varied with each individual inhibitor. In animals pretreated with pargyline or clorgyline, L-dopa administration led to huge accumulations of dopamine and significantly raised central norepinephrine concentrations. In contrast, similar L-dopa injections in deprenyl-pretreated rats caused only a moderate rise in dopamine and no change in norepinephrine. There seems to be little relationship between the degree of monoamine oxidase inhibition and the accumulation of catecholamines and their metabolites in the rat brain. The effects of monoamine oxidase inhibitors on dopamine accumulation appeared to occur outside the catecholaminergic neurons since in the animals pretreated with 6-hydroxydopamine, which decreased significantly the content of brain catecholamines, dopamine accumulation following L-dopa administration still remained considerable. On the other hand, the influence of monoamine oxidase inhibitors on brain norepinephrine concentrations seemed to originate in the noradrenergic neurons because norepinephrine increase was greatly reduced in rats treated with 6-hydroxydopamine but was restored when the treatment with 6-hydroxydopamine was accompanied by desimipramine which specifically protects noradrenergic stores.

The effect of monoamine oxidase inhibitors compared with classical tricyclic antidepressants on learned helplessness paradigm

Martin Patrick, Philippe Soubrié and Pierre Simon. The effect of monoamine oxidase inhibitors compared with classical tricyclic antidepressants on learned helplessness paradigm. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1987, 11 : 1–7. 1. 1. The present study investigated the effect of monoamine oxidase inhibitors, nialamide which is a non specific monoamine oxidase inhibitor (MAOI), toloxatone which is a A type MAOI and L-deprenyl which is a B type MAOI compared with classical tricyclic antidepressants (clomipramine, desipramine and imipramine), on the escape deficit induced by inescapable shocks (learned helplessness paradigm). 2. 2. Rats were first exposed to inescapable shock pretreatment (60 shocks, 15 sec duration, 0,8 mA, every minute + 15 sec) and 48 h later, shuttle box training (30 trials/day, 15 min.) was initiated in order to evaluate interference effect. 3. 3. Rats with inescapable shocks exhibited escape and avoidance deficits when tested for subsequent responding in a shuttle-box. Daily i.p. injections of nialamide (8 and 16 mg/kg), toloxatone (16 and 32 mg/kg), L-deprenyl (32 and 64 mg/kg) and tricyclic antidepressants (clomipramine: 16 and 32 mg/kg, desipramine: 16 and 24 mg/kg, imipramine: 16 and 32 mg/kg) eliminated escape deficits. 4. 4. In rat exposed to inescapable shocks and treated with L-deprenyl (16 mg/kg/day), nialamide (32 mg/kg/day) or toloxatone (64 mg/kg/day), avoidance responses are significantly increased as compared with non drugged rats preexposed to inescapable shocks. 5. 5. These data extend previous results bearing on the similarity of action of MAOI and tricyclic antidepressants in learned helplessness paradigm (Sherman et al., 1982) and are in agreement with data obtained in other animal models of depression.

The regional distribution of p-tyramine and m-tyramine in the rat corpus striatum and the effect of monoamine oxidase inhibition

These experiments show that in the rat corpus striatum the highest concentrations of p -and m -tyramine were found in the caudate nucleus while somewhat lower values were observed in the putamen and globus pallidus. Inhibition of monoamine oxidase by pargyline produced an increase in the concentration of both tyramines in the three areas. The effect of pargyline is more marked with p -tyramine, however, the regional distribution of both — and m -tyramine are preserved after monoamine oxidase inhibition. In addition, the pargyline treatment produced a significant reduction in corpus striatum p -tyrosine while no changes were observed in the tryptophan concentrations.

Presynaptic dopamine receptors in the cardiovascular system.

Stimulation by agonists of presynaptic dopamine receptors on nerve terminals of peripheral sympathetic neurons results in inhibition of norepinephrine release and a concomitant reduction of end organ responses to sympathetic nerve stimulation. These presynaptic dopamine receptors are of the DA-2 subtype and can be blocked selectively by the antagonist S-sulpiride. Presynaptic DA-2 receptors are the target of action of agonists with potential antihypertensive and bradycardic effects. Under control conditions exposure to S-sulpiride on its own does not enhance norepinephrine release. Following chronic treatment of cats with pargyline, S-sulpiride produced a small but significant increase in the electrically-evoked release of 3H-norepinephrine from perfused atrial slices. The possible involvement of peripheral presynaptic DA-2 receptors in the antihypertensive effects of monoamine oxidase inhibitors is discussed.

The effects of monoamine oxidase inhibitors on the ejaculatory response induced by 5-methoxy-N,N-dimethyltryptamine in the rat.

The ejaculatory response and other components of the 5-hydroxytryptamine (5-HT) behavioural syndrome induced by 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) (3 mg kg-1, i.p.) were studied following single and repeated treatment of rats with eight different monoamine oxidase (MAO) inhibitors. Single and repeated treatment with the 5-HT agonist 5-MeODMT, and with low doses of the potent releaser of 5-HT, p-chloroamphetamine (PCA) were also included in the study. Repeated but not single treatment with 5-MeODMT reduced strongly but reversibly the ejaculatory response and the behavioural responses. Repeated but not single treatment with the nonselective and irreversible MAO inhibitors nialamide and pargyline reduced markedly the ejaculatory response but only slightly the 5-HT behavioural responses. Repeated treatment with the irreversible MAO-B inhibitor (-)-deprenyl, with the irreversible MAO-A inhibitor, clorgyline, with the reversible MAO-A inhibitor moclobemide, and with low doses of PCA did not affect either of the responses. Repeated but not single combined treatment with clorgyline plus PCA caused an almost complete blockade of all the four responses. The selective and reversible MAO-A inhibitors (as well as 5-HT releasers) amiflamine, alpha-ethyltryptamine, and alpha-methyltryptamine reduced markedly the ejaculatory response after both single and repeated treatments. The behavioural responses were blocked only after repeated treatment. It is concluded that single and repeated treatments of rats with different MAO inhibitors do not produce a common alteration in 5-HT2 receptor functions. Repeated treatment with 5-MeODMT caused a blockade of 75-95% of the ejaculatory response and 5-HT behavioural responses. A similar strong blockade was only produced by the combined effect of MAO-A inhibition and 5-HT release.

The newcastle anxiety depression diagnostic index in relationship to the effects of monoamine oxidase inhibitors and tricyclic antidepressants

The Newcastle Anxiety Depression Diagnostic Index (NADDI) was applied to 151 patients who received a monoamine oxidase inhibitor (MAOI) or a tricyclic antidepressant (TCA) drug. The pretreatment presence of a physical stressor and absence of agoraphobia were associated with superior MAOI effects. In women nine of the 13 NADDI items were associated with superior response to the MAOI drugs: these items comprised the absence of childhood anxiety, agoraphobia, compulsive symptoms, early awaking, and retardation, and the presence of dependent traits, neuroticism, physical stress, and panic attacks. In men the absence of suicidal tendencies and retardation, and the presence of dependent traits and panic attacks were associated with superior TCA effects. A within-treatment analysis indicated that depressed men responded better to MAOI than did anxious men.

Forms of atypical depression and their response to antidepressant drugs

Three definitions of atypical depression are evaluated with respect to the effects of monoamine oxidase inhibitors (MAOIs) and tricylic antidepressants (TCAs) on the basis of pooled data from several double-blind studies. Those three definitions of atypical depression are (1) depression with associated panic, (2) depression secondary to a diagnosis of anxiety, and (3) depression with reversed vegetative change. In none of these forms was a drug difference observed. However, when gender was taken into account, MAOIs were superior to TCAs in depressed women with panic attacks, whereas TCAs were superior to MAOIs in depressed men with panic attacks.

The oxidation of adrenaline and noradrenaline by the two forms of monoamine oxidase from human and rat brain

The selective monoamine oxidase inhibitors clorgyline and (?)-deprenyl were used to study the distribution of monoamine oxidase-A and -B (MAO-A, MAO-B) activities towards (?)-noradrenaline and (+),(?)-adrenaline in homogenates from seven different regions of human brain. The activities towards 5-hydroxytryptamine and 2-phenethylamine, which are essentially specific substrates for the A- and B-forms, respectively, under the conditions used in this work, were also determined. Noradreanline and adrenaline were substrates for both forms of the enzyme in all regions studied. The total MAO activity was found to be highest in the hypothalamus and lowest in the cerebellar cortex. Use of the selective MAO inhibitors clorgyline and (?)-deprenyl also showed adrenaline and noradrenaline to be substrates for both forms of the enzyme in rat brain. In human cerebral cortex and rat brain the two forms were found to have similar K(m)-values and maximum velocities towards adrenaline. These values for the two forms were also found to be similar in human cerebral cortex when noradrenaline was used as the substrate. In contrast MAO-A showed a significantly lower K(m) and a higher maximum velocity towards noradrenaline in rat brain. These results suggest that the rat may not provide a close model of the human for studies on the effects of MAO inhibitors on brain noradrenaline metabolism.

Serotoninergic but not noradrenergic neurons in rat central nervous system adapt to long-term treatment with monoamine oxidase inhibitors

Repeated administration of monoamine oxidase inhibitors induces a transient decrease in the firing rate of serotoninergic neurons followed by complete recovery, whereas it results in a persistent reduction of the firing rate of noradrenergic neurons. Under these conditions, serotoninergic, but not noradrenergic, neurons undergo a desensitization of their somatic autoreceptors. Serotoninergic neurons therefore show the capacity to free themselves from their autoregulatory control, a property which noradrenergic neurons appear to be lacking. The time course of the recovery in the firing rate of the serotoninergic neurons is consistent with the delayed antidepressant effect of monoamine oxidase inhibitors.

14C]-beta-phenethylamine, its distribution after administration by various routes to cats, and the effects of monoamine oxidase inhibitors.

[14C]-beta-phenethylamine [( 14C]-PEA) was instilled intragastrically, intraduodenally (i.d.) or infused into the portal vein or femoral artery of cats, anaesthetized with chloralose, to investigate its distribution in the body. [14C]-PEA and phenylacetic acid (PAA) accounted for approximately 85% of radioactivity recovered in blood from control cats or those pretreated with deprenyl or mebanazine. Progressively greater portal venous (PV), cranial mesenteric arterial (CMA) and PV-CMA concentrations of PEA and PAA were observed with increase in amount of PEA instilled intraduodenally (i.d.); PAA predominated over PEA, more so in CMA than PV blood. Radioactivity was not recovered from blood following intragastric instillation of PEA. When histamine 1.7 mumol kg-1, i.d., was combined with PEA 1.7 mumol kg-1, i.d., or tyramine 8.5 mumol kg-1, i.d., was combined with PEA 8.5 mumol kg-1, i.d., PV-CMA values for PEA were significantly augmented. Arterial concentrations of PEA were increased 3.5 to 5 fold compared to controls by pretreatment with mebanazine or deprenyl plus clorgyline; arterial concentrations of PAA were reduced. PEA blood concentrations were not significantly altered by clorgyline or deprenyl pretreatment. Infusion of PEA 680, 1020 or 1360 nmol kg-1 min-1 for 20 min into the portal vein raised blood pressure 60 to 100 mmHg (at a PEA concentration of ca, 2 nmol ml-1) but lacked effect on the nictitating membrane despite peak arterial PEA concentrations of 20 nmol ml-1; in cats pretreated with mebanazine or clorgyline plus deprenyl, half-maximum contraction of the nictitating membrane occurred with arterial PEA concentrations of 4.8 to 9 nmol ml-1. In cats pretreated with mebanazine or deprenyl plus clorgyline, half maximum contraction of the nictitating membrane was elicited also by intraduodenal PEA 8.5 mumol kg-1 at arterial PEA concentrations of ca. 2 nmol ml-1, despite lack of effect of PEA 17 mumol kg-1, i.d., in control cats with a peak arterial PEA concentration of 1.8 nmol ml-1. [14C]-PEA and PAA were recovered from liver, kidney, distal small intestine, lung, arterial vessel walls, skeletal muscle, brain, foetus and amniotic liquor, after PEA instilled i.d., overall concentration of PEA exceeding that of PAA except in the kidney. The combined amount of PEA and PAA in kidney was 7 to 20 fold that in other tissues. PEA content of tissues was significantly elevated and that of PAA diminished by pretreatment with deprenyl plus clorgyline, and to a lesser extent after mebanazine.

Inhibition of monoamine oxidase selectively in brain monoamine nerves using the bioprecursor (E)-beta-fluoromethylene-m-tyrosine (MDL 72394), a substrate for aromatic L-amino acid decarboxylase.

(E)-beta-Fluoromethylene-m-tyrosine (FMMT) is a dual-enzyme-activated inhibitor of monoamine oxidase (MAO). The compound is not an inhibitor per se but is decarboxylated by aromatic L-amino acid decarboxylase (AADC) to yield a potent enzyme-activated irreversible inhibitor of MAO, (E)-beta-fluoromethylene-m-tyramine, which shows some selectivity for inhibition of MAO type A. Decarboxylation of FMMT was demonstrated in vitro using hog kidney AADC and in vivo in rats by the ability of alpha-monofluoromethyldopa (MFMD), a potent inhibitor of AADC, to prevent MAO inhibition produced by FMMT. In isolated synaptosomes, FMMT was decarboxylated by AADC, and, furthermore, the compound was actively transported into these isolated nerve endings. An active transport into the CNS has also been demonstrated in vivo by performing competition experiments with leucine. To demonstrate that FMMT is preferentially decarboxylated within monoamine nerves of the CNS, the nigrostriatal 3,4-dihydroxyphenylethylamine (dopamine) pathway of rats was unilaterally lesioned with 6-hydroxydopamine or infused with MFMD. Under these conditions, MAO inhibition produced by orally administered FMMT in the striatum ipsilateral to the lesion or infusion was markedly attenuated. Combination of FMMT with an inhibitor of extracerebral AADC, such as carbidopa, protected peripheral organs against the MAO inhibitory effects and concomitantly enhanced MAO inhibition in the CNS. Such combinations had a greatly reduced propensity to augment the cardiovascular effects of intraduodenally administered tyramine, when compared with FMMT given alone or with clorgyline, a selective inhibitor of MAO type A. The results obtained with FMMT suggest the possibility of achieving selective inhibition of MAO within monoamine nerves of the CNS and, further, suggest that combination of FMMT with an inhibitor of extracerebral AADC will reduce the propensity of this inhibitor to produce adverse interactions with tyramine.

Unit activity in the dorsal raphe in freely-moving cats: Effects of monoamine oxidase inhibitors

Two commonly used monoamine oxidase inhibitors, tranylcypromine and pargyline, produced dose-dependent decreases in the activity of serotonin-containing neurons in the dorsal raphe in awake, freely-moving cats. The onset of the suppression of unit activity occurred within 15–20 min after administration of drug and persisted for 6–16 hr, depending upon dose. Parallel neurochemical studies revealed that serotonin in the brain was significantly increased following inhibition of monoamine oxidase, and that concentrations of serotonin were still significantly elevated after unit activity in the raphe had returned to baseline levels. These data suggest that autoreceptors on neurons of the dorsal raphe may become tolerant following prolonged exposure to large concentrations of serotonin.

Acute Psychosis Following Phenelzine Discontinuation

Most concern over the untoward effects of monoamine oxidase inhibitors (MAOIs) has concentrated on the hypertensive crises and recently on orthostatic hypotension, hypomania, and sexual dysfunction. However, little has been written about withdrawal effects when MAOIs are discontinued. This article reports an acute organic psychosis marked by visual, auditory, and tactile hallucinations after abrupt discontinuation of phenelzine in two young women without previous history of psychotic symptoms.

The differential observation of type A and B MAO-containing terminal fibers in the cerebral cortex of the rat

The selective monoamine oxidase inhibitors clorgyline and (−)-deprenyl were used to study the distribution of monoamine oxidase-A and -B (MAO-A, MAO-B) activities towards (−)-noradrenaline and (+),(−)-adrenaline in homogenates from seven different regions of human brain. The activities towards 5-hydroxytryptamine and 2-phenethylamine, which are essentially specific substrates for the A- and B-forms, respectively, under the conditions used in this work, were also determined. Noradreanline and adrenaline were substrates for both forms of the enzyme in all regions studied. The total MAO activity was found to be highest in the hypothalamus and lowest in the cerebellar cortex. Use of the selective MAO inhibitors clorgyline and (−)-deprenyl also showed adrenaline and noradrenaline to be substrates for both forms of the enzyme in rat brain. In human cerebral cortex and rat brain the two forms were found to have similar Km-values and maximum velocities towards adrenaline. These values for the two forms were also found to be similar in human cerebral cortex when noradrenaline was used as the substrate. In contrast MAO-A showed a significantly lower Km and a higher maximum velocity towards noradrenaline in rat brain. These results suggest that the rat may not provide a close model of the human for studies on the effects of MAO inhibitors on brain noradrenaline metabolism.

Diethylpropion-induced psychosis reprecipitated by an MAO inhibitor

A case of diethylpropion-induced psychosis in a 26-year-old woman is reported. The patient's psychosis recurred while she was receiving phenelzine. It is postulated that chronic stimulant use leads to increased sensitivity to the psychosis-inducing effects of monoamine oxidase inhibitors. Language: en

O-54) - The effect of MAO inhibitors on pre-systemic deamination of tyramine in the dog intestine

O-54) - The effect of MAO inhibitors on pre-systemic deamination of tyramine in the dog intestine

Negative feedback control of serotonin release in vivo: Comparison of 5-hydroxyindolacetic acid levels measured by voltammetry in conscious rats and by biochemical techniques

All evidence that serotonin release from central neurones is controlled by a negative feedback mechanism comes from in vitro studies 4, 7, 16, 21, 23 To study this problem in vivo we performed differential pulse voltammetry 8 in conscious rats, in which carbon fibre electrodes had been implanted 2–15 weeks previously. The effects of monoamine oxidase inhibition (which decreases the amount of 5-hydroxyindoleacetic acid), as well as that of probenecid (which increases 5-hydroxyindoleacetic acid), suggests that 5-hydroxyindoleacetic acid rather than serotonin is measured. Blockade of the presynaptic serotoninergic autoreceptors by methiothepin, metergoline or quipazine led to an increase in differential current of the peak attributed to 5-hydroxyindoleacetic acid in hippocampus, hypothalamus and striatum. Stimulation of these receptors by m-chlorophenylpiperazine, MK-212 or LSD decreased the signal attributed to 5-hydroxyindoleacetic acid. A decrease in the signal was also seen with cinanserin. Stimulation of presynaptic α 2-adrenoreceptors by clonidine decreased the signal. Metergoline, quipazine and cinanserin showed biphasic effects, and no effect was observed with methysergide. In general, a reasonable agreement with the results of Baumann & Waldmeier 4 obtained in vitro with electrically stimulated [ 3H]serotonin prelabelled cortex slices was achieved with differential pulse voltammetry. Only partial agreement with the results of voltammetry was obtained if 5-hydroxyindoleacetic acid was determined biochemically under comparable conditions. Qualitatively, the effects observed with methiothepin, m-chlorophenylpiperazine, clonidine and LSD were in good agreement with those measured with voltammetry as well as with the in vitro effects obtained in electrically stimulated cortex slices. No, or only partial correlation with the results obtained with voltammetry was found with MK 212, cinanserin, metergoline and quipazine. It is concluded that voltammetry preferentially measures extraneuronal 5-hydroxyindoleacetic acid rather than overall changes of this metabolite.