Effects Of Monoamine Oxidase Inhibitors Research Articles

Effect of R-(-)-deprenyl and harmaline on dopamine- and peroxynitrite-induced membrane permeability transition in brain mitochondria.

The present study examined the effect of MAO inhibitors, deprenyl and harmaline, on the membrane permeability transition in brain mitochondria. Deprenyl, harmaline, and antioxidant enzymes (SOD and catalase) attenuated alteration of the swelling, membrane potential, cytochrome c release, and Ca2+ transport in mitochondria treated with dopamine. In contrast, deprenyl and harmaline did not reduce the peroxynitrite-induced change in membrane permeability. Deprenyl and harmaline inhibited the decrease in thioredoxin reductase activity and the thiol oxidation in mitochondria treated with dopamine but did not decrease the effect of peroxynitrite. Deprenyl and harmaline significantly decreased the formation of melanin from dopamine. The results suggest that deprenyl and harmaline may protect brain mitochondria against the toxic action of dopamine oxidation by the maintenance of thioredoxin reductase activity, inhibition of thiol oxidation, and inhibition of dopamine oxidation product formation. In contrast, MAO inhibitors may not defend brain mitochondria against damaging action of peroxynitrite.

Neurotoxicity of MPTP.

After the discovery of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), we acquired a good animal model of Parkinson's disease. The extraordinary recent growth in knowledge using MPTP parkinsonism has fostered increased understanding of Parkinson's disease. In the present paper, the discovery of MPTP and the biochemical, pathological, and clinical findings of MPTP parkinsonism are first reviewed briefly. Next, using MPTP parkinsonism, unresolved issuses such as the apoptosis of MPTP, levodopa toxicity, and neuroprotective effects of monoamine oxidase inhibitors or dopamine agonists are discussed. Finally, environmental factors such as the etiology of Parkinson's disease are examined. Some genetic factors that lead to familial Parkinson's disease have recently been reported, but most cases of Parkinson's disease are sporadic. Recent epidemiological evidence emphasizes an etiological relation of 18th and 19th century industrialization to Parkinson's disease. Man-made toxins, such as industrial chemicals and herbicides/pesticides, have been suggested to increase the risk of developing Parkinson's disease. I would like to highlight the significance of re-examination of environmental factors in the etiology of Parkinson's disease.

Region-dependent effects of acute and chronic tranylcypromine in vivo on [ 3H]2-BFI binding to brain imidazoline I 2 sites

An imidazoline I 2 site has been localised to monoamine oxidase. However, in vitro studies of the effect of monoamine oxidase inhibitors on imidazoline I 2-site radioligand binding have produced conflicting findings. Using the technique of autoradiography, we examined the effect of in vivo administration of the irreversible monoamine oxidase inhibitor tranylcypromine on binding of the imidazoline I 2 site-specific ligand [ 3H]2-(-2-benzofuranyl)-2-imidazoline ([ 3H]2-BFI) in four rat brain nuclei which are known to possess a high density of imidazoline I 2 sites, together with cerebral cortex and cerebellum which show weaker binding. A single acute pre-treatment with tranylcypromine significantly increased imidazoline I 2 site-specific binding in four regions: arcuate nucleus, interpeduncular nucleus, pineal gland and area postrema, but effects in cortical areas and cerebellum were not significant. The extent of the increase was proportional to the control binding in each region. In contrast, five daily treatments with the same dose of tranylcypromine significantly reduced [ 3H]2-BFI binding in these same areas. The potential role of monoamine oxidase isoforms in these changes is discussed.

Effects of MAO inhibitors upon MPTP mice chronically treated with suprathreshold doses of L-dopa.

Groups of mice were administered either saline or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (2 X 40 mg / kg, s.c., separated by a 24-hour interval) 4-6 weeks prior to behavioural testing. At testing, all the MPTP-injected mice were repeatedly administered L-dopa (20 mg / kg, s.c., five times each week, Monday-Friday), by applying a procedure that induced a severe reduction of motor activity parameters from Day 1 to Day 25. Control (uninjected mice) received only saline and were retained only for neurochemical analysis. In each of three experiments, following the reduction of the activity-stimulating effects of L-dopa by repeated administration, a restorative effect of different monoamine oxidase (MAO) inhibitors was tested by co-administration of the test compounds (irreversible MAO-B inhibitor, reversible MAO-A inhibitors, or irreversible MAO-A / mixed MAO inhibitors) with L-dopa (20 mg / kg). In each case the MAO inhibitor was injected 60 min prior to L-dopa. L-Deprenyl (3 or 10 mg / kg, s.c.), in combination with L-dopa, reinstated locomotion and total activity, but not rearing, dose-dependently, in L-dopa-tolerant mice. The reversible MAO-A inhibitors, amiflamine and alpha-ethyltryptamine, in combination with L-dopa, reinstated locomotion and total activity, leaving rearing unaffected; Ro 41-1049 (3 mg / kg, s.c.) restored all three parameters of activity; locomotor activity was restored by all three doses (1, 3, and 10 mg / kg, s.c.). On the other hand, neither the irreversible MAO-A inhibitor, clorgyline, nor the mixed MAO inhibitor, phenelzine, produced any directly effective restorative increments. Neurochemical analysis confirmed the severe striatal dopamine depletion of MPTP-treated mice. These results demonstrate a synergistic and restorative action of combining certain MAO inhibitors, namely the reversible MAO-A inhibitors, with the suprathreshold dose of L-dopa in MPTP-treated, L-dopa-tolerant mice.

Monoamine oxidase inhibitors reduce conditioned fear stress-induced freezing behavior in rats

The present study examined the acute anxiolytic effects of monoamine oxidase inhibitors on freezing behavior, a putative index of anxiety induced by conditioned fear stress. The selective serotonin 1A receptor agonist tandospirone (0.1–10 mg/kg) inhibited freezing dose dependently. The irreversible, non-selective monoamine oxidase inhibitors tranylcypromine (3 and 15 mg/kg) and phenelzine (30 and 80 mg/kg) reduced freezing significantly. Clorgyline (10 mg/kg, irreversible selective monoamine oxidase A inhibitor), N-(2-aminoethyl)-5-( m-fluorophenyl)-4-thiazole carboxamide (Ro 41-1049) (30 mg/kg, reversible selective monoamine oxidase A inhibitor), selegiline (3 mg/kg, irreversible selective monoamine oxidase B inhibitor) and lazabemide (10 mg/kg, reversible selective monoamine oxidase B inhibitor) had no effect on freezing behavior. However, combined administration of clorgyline (10 mg/kg) and selegiline (3 mg/kg) reduced freezing significantly, as well as combined administration of clorgyline (10 mg/kg) and lazabemide (10 mg/kg), Ro 41-1049 (30 mg/kg) and selegiline (3 mg/kg), or Ro 41-1049 (30 mg/kg) and lazabemide (10 mg/kg). These effects of monoamine oxidase inhibitors on freezing were not due to non-specific motor effects. These results suggest that acute inhibition of both monoamine oxidase A and B reduced anxiety or fear, while inhibition of monoamine oxidase A or B alone failed to reduce anxiety or fear.

Comparison of neurochemical effects of the monoamine oxidase inhibitors phenelzine, moclobemide and brofaromine in the rat after short- and long-term administration

Background: Chronic administration of several irreversible monoamine oxidase (MAO) inhibitors induces a down-regulation of tryptamine and 5-hydroxytryptamine 2 receptors in rat brain, but there is a paucity of information available on the effects of reversible MAO-A inhibitors on these receptors. Methods: Acute and chronic experiments were conducted in rats and the effects of the irreversible monoamine oxidase inhibitor, phenelzine and the reversible MAO type-A inhibitors, moclobemide and brofaromine, on tryptamine and 5-hydroxytryptamine 2 receptors were analysed using radioligand binding techniques. In addition, activities of MAO-A and -B were determined radiochemically and brain and/or urine levels of tryptamine, 5-hydroxytryptamine, 3-methoxy-4-hydroxyphenylglycol (MHPG), β-phenylethylamine, brofaromine and moclobemide were determined by chromatographic procedures. Results: After 30 days of administration, moclobemide and brofaromine selectively inhibited brain MAO-A activity and phenelzine inhibited MAO-A and -B to equal extents. All three drugs caused a significant down-regulation of tryptamine receptors, whereas only phenelzine significantly down-regulated 5-hydroxytryptamine 2 receptors. In a comparison of phenelzine and brofaromine, both caused marked elevations of urinary tryptamine and decreases of urinary MHPG levels, while only phenelzine increased β-phenylethylamine levels. After 14 days of administration, phenelzine, but not moclobemide or brofaromine, significantly increased levels of tryptamine in brain; all three drugs significantly increased 5-HT levels. Limitations: 24-h urine samples were not collected for moclobemide-treated animals and brain levels of tryptamine were not measured after 30-day administration. Conclusions: These studies revealed marked neurochemical differences among phenelzine, moclobemide and brofaromine which could contribute to their actions in the clinical setting.

Evidence that the neuronal nitric oxide synthase inhibitor 7-nitroindazole inhibits monoamine oxidase in the rat: in vivo effects on extracellular striatal dopamine and 3,4-dihydroxyphenylacetic acid

The present study investigated in vivo the kinetic of the changes in rat striatal extracellular concentrations of dopamine (DA), and its monoamine oxidase (MAO)-derived metabolite 3,4-dihydroxyphenylacetic acid (DOPAC), following administration either of nitric oxide (NO) synthase (NOS) inhibitors 7-nitroindazole (7-NI) and N ω -nitro- l-arginine methyl ester (L-NAME) or of the widely used MAO inhibitor pargyline. DA and DOPAC concentrations were determined every 4 min by microdialysis combined with capillary zone electrophoresis coupled with laser-induced fluorescence detection (CZE-LIFD) and by differential normal pulse voltammetry (DNPV), respectively. Administration of 7-NI, both systemic (30 mg/kg, intraperitoneally, i.p.) or intrastriatal (1 mM through the microdialysis probe), as well as administration of pargyline (75 mg/kg, i.p.), induced simultaneously in the striatum a significant increase in extracellular DA and a significant decrease in extracellular DOPAC. However, administration of L-NAME (200 mg/kg, i.p.) produced a significant increase in striatal extracellular DA without changes in extracellular DOPAC. These data suggest a possible MAO inhibitory effect of 7-NI which seems to be restricted to this NOS inhibitor. These results may be of special interest for the studies on functional role of NO in the brain, particularly in dopaminergic transmission.

Evidence that the neuronal nitric oxide synthase inhibitor 7 -nitroindazole inhibits monoamine oxidase in the rat: in vivo effects on extracellular striatal dopamine and 3,4-dihydroxyphenylacetic acid

The present study investigated in vivo the kinetics of the changes in rat striatal extracellular concentrations of dopamine (DA), and its monoamine oxidase (MAO)-derived metabolite 3,4-dihydroxyphenylacetic acid (DOPAC), following administration either of nitric oxide (NO) synthase inhibitors 7-nitroindazole (7-NI) and N ω -nitro- l-arginine methyl ester ( l-NAME) or of the widely used MAO inhibitor pargyline. DA and DOPAC concentrations were determined every 4 min by microdialysis combined with capillary zone electrophoresis coupled with laser-induced fluorescence detection (CZE-LIFD) and by differential normal pulse voltammetry (DNPV), respectively. Administration of 7-NI, both systemic (30 mg/kg, i.p.) or intrastriatal (1 mM through the microdialysis probe), as well as administration of pargyline (75 mg/kg, i.p.), induced simultaneously in the striatum a significant increase in extracellular DA and a significant decrease in extracellular DOPAC. On the other hand, administration of l-NAME (200 mg/kg, i.p.) produced a significant increase in striatal extracellular DA without changes in extracellular DOPAC. These data suggest a possible MAO inhibitory effect of 7-NI which seems to be restricted to this NOS inhibitor. These results may be of special interest for the studies on the functional role of NO in the brain, particularly in dopaminergic transmission.

MAO inhibitory side effects of neuroleptics and platelet serotonin content in schizophrenic patients.

In order to study the putative monoamine oxidase (MAO) inhibitory side effect of neuroleptics and simultaneous changes in platelet serotonin content both MAO-B activity and serotonin (5-HT) content in platelets of 30 healthy volunteers and 50 schizophrenic patients treated with neuroleptics were investigated. Our results have shown significantly lower MAO-B activity (15.26 +/- 6.81 S.D. vs. 8.63 +/- 3.82 mmol/hour/10(9) platelets) and higher platelet 5-HT content (906.19 +/- 285.33 vs. 1,727.85 +/- 947.40 ng/10(9) platelets) in the schizophrenic group. Platelet MAO-B activity was considerably lower in paranoid and residual schizophrenics compared with other patients, however, no difference was found in platelet 5-HT content between different subtypes of schizophrenia. Various neuroleptic treatments did not produce different effects either on platelet serotonin content or platelet MAO-B activity.

Increase of 5HT and VIP immunoreactivity within the hamster ( Mesocricetus auratus) SCN during chronic MAOI treatment

The effects of chronic treatment with the monoamine oxidase inhibitor (MAOI), clorgyline (CLG; 2 mg/kg per day) on serotonin (5HT) and vasoactive intestinal peptide (VIP) immunoreactivity (IR) within the hamster suprachiasmatic nucleus (SCN) were examined. Optical densities of 5HT IR and VIP IR were increased by MAOI treatment. VIP IR was increased in both the ventrolateral and dorsal regions of the SCN, suggesting that VIP content was increased within both perikarya and terminals of VIP neurons. The results suggest that previously described effects of MAOIs on the mammalian circadian system may be mediated in part, by their effects on serotonergic input to VIP neurons within the SCN.

In vivo hydroxylation of the neurotoxin, 1-methyl-4-phenylpyridinium, and the effect of monoamine oxidase inhibitors: electrospray-MS analysis of intra-striatal microdialysates.

The neurotoxin 1-methyl-4-phenylpyridinium (MPP+) has been shown to increase hydroxyl radical formation in the striatum. The production of hydroxyl radicals correlates with the MPP(+)-driven dopamine release which presumably leads to increased metabolism via monoamine oxidase or increased dopamine autoxidation. Both processes result in enhanced production of hydrogen peroxide, which in the presence of iron(II) ions decomposes to the hydroxyl radical. Monoamine oxidase inhibitors decrease the production of hydroxyl radicals as measured by salicylate and 4-hydroxybenzoate trapping. As both MPP+ and monoamine oxidase inhibitors, such as deprenyl and MDL-72,974A, possess aromatic rings, hydroxyl radical adduct formation was investigated in vitro in defined Fenton systems and also in vivo using intra-striatal microdialysis to infuse MPP+ to rats pretreated systemically with either deprenyl or MDL-72,974A. Electrospray mass spectrometric analysis, using full-scan, fragment ion and constant neutral loss spectra, demonstrated ring hydroxylation of all three compounds in the Fenton systems. Spectral comparison of microdialysis samples with spectra from the Fenton reactions indicated the in vivo hydroxyl radical adduct attachment to MPP+, deprenyl and possibly MDL-72,974A.

Electrophysiological effects of monoamine oxidase inhibition on rat midbrain dopaminergic neurones: an in vitro study.

1 The effects of the inhibition of monoamine oxidase (MAO) type A and B have been evaluated on the spontaneous firing activity of the dopaminergic (principal) neurones of the rat midbrain intracellularly recorded from a slice preparation. 2 The non-specific MAO inhibitor, pargyline, superfused at a concentration of 10-100 microM, decreased or abolished the spontaneous firing discharge of the principal neurons in the subtantia nigra pars compacta and ventral tegmental area. This effect had a slow onset and appeared to be sustained. 3 The administration of the dopamine D2/3 receptor antagonist, sulpiride (100-300 nM), antagonized the pargyline-induced effect, while the superfusion of the dopamine D1 receptor antagonist, SCH 23390 (1-3 microM) did not counteract the induced inhibition of the firing rate. 4 The inhibitor for the MAO A, clorgyline (30-100 microM), reduced the firing rate of the dopaminergic neurones. A similar depressant effect was also observed when a MAO B inhibitor, deprenyl (30-100 microM), was applied. Lower concentrations of both drugs (300 nM-10 microM) did not produce consistent effects on neuronal discharge. 5 Our data suggest that only the blockade of both types of MAO enzymes favours the inhibitory action of endogenous dopamine on somato-dendritic D2/3 autoreceptors.

A Turnover Study of Hypothalamic Monoamine Oxidase (MAO) and Effects of MAO Inhibition on Gonadotropin Secretion in the Female Catfish, Heteropneustes fossilis

In the present study, the rate constants of degradation ( k) and synthesis (S) and half-life of hypothalamic monoamine oxidase were determined to explain annual variations and biphasic effects of the enzyme to low and high doses of estradiol-17β (E 2) in 3-week ovariectomized Heteropneustes fossilis . In the preparatory phase, the half-life ( t 1/2) of the enzyme was the longest (21.16 days) with low k (0.03275 days -1) and S (0.000845 Units/day) values, suggesting a low turnover of the enzyme. In the prespawning phase the t 1/2 was the shortest (11.65 days) with high k (0.0595 days -1) and S (0.011 Units/day) values. The low and high turnovers of the enzyme, respectively, in these two seasons could be correlated to low and high profiles of plasma E 2 levels. In the resting phase, the values were in between ( t 1/2 = 18.83 days, k = 0.0368 days -1, S = 0.00211 Units/day) but the plasma E 2 level was undetectable. Three weeks of ovariectomy increased the t 1/2 (19.04 days) compared to that of the control (11.61 days) with decreases in both k and S values. The administration of a low dose of E 2 (0.1 μg/g BW) further increased the t 1/2 (19.63 days) over that of the ovariectomized fish with a significant rise in the S value. However, a high dose of E 2 (1.0 μg/g BW) decreased it (13.33 days) by reducing the S and elevating the k values. These results suggest that the stimulatory effect of low doses of E 2 on the enzyme activity is produced by elevating its synthesis rate and the inhibitory effect of high doses of E 2 by simultaneously decreasing the synthesis and increasing the degradation rates of the enzyme. The administration of a single dose (75 mg/kg BW) of pargyline has elevated plasma gonadotropin (GTH) level after 3 and 6 hr and 7 days in the sham-ovariectomized (control), ovariectomized, and ovariectomized low-E 2-dose groups; the peak increase was found at 6 hr. On the contrary, in the ovariectomized high-E 2 group the GTH level was inhibited at 3 and 6 hr postinjection. These changes in the GTH level could be correlated with changes in the profiles of hypothalamic monoamines. The data show that E 2 exerts its feedback regulation of GTH by modifying monoaminergic activity at the level of oxidative deamination.

Responses of forebrain neurons to the MAO-B blocker l-deprenyl

Despite the large amount of neuropharmacological data concerning catecholamine (CA) mechanisms of the mammalian brain, little is known yet about the effects of MAO-inhibitors on single neurons. The present series of experiments aim to elucidate these specific neurochemical attributes of forebrain cells. Single neuron activity was recorded by means of multibarreled microelectrodes in the caudate nucleus, globus pallidus, and amygdala of both anesthetized rats and anesthetized or alert monkeys during microelectrophoretic application of the MAO-B blocker L-deprenyl (DEPR). CAs (dopamine and noradrenaline), glutamate, GABA, and acetylcholine were also applied. Nearly the half (46%) of all forebrain neurons tested responded, exclusively with inhibition, to DEPR, and the CA-sensitive cells were especially responsive to the MAO-B inhibitor. The time course of DEPR-induced neuronal suppression was short. In some cases, amphetamine (AMPH) and clorgyline (CLOR) were also applied microelectrophoreticaly. AMPH elicited similar activity changes to those seen after DEPR administrations, whereas CLOR applications were less effective. Our results provide evidence that DEPR can effectively modulate the activity of CA-sensitive neurons in the three different forebrain regions of two different species. On the basis of this data, the possible neurochemical mechanisms of DEPR action are discussed.

Thyroid iodide transport is reduced by administration of monoamine oxidase A inhibitors to rats.

The present work was addressed to study a possible relationship between monoamine oxidase (MAO) and the thyroid iodide transport mechanism. Normal rats treated with clorgyline (a selective MAO-A inhibitor) or tranylcypromine (a non-selective MAO inhibitor) showed a significantly diminished thyroid MAO activity, while deprenyl and pargyline (MAO-B inhibitors) did not modify the thyroidal enzyme activity with respect to the control group. Under these conditions, in vivo iodide transport was reduced both by clorgyline and tranylcypromine administration whereas it remained unchanged after treatment with MAO-B inhibitors. The effect of MAO inhibitors on thyroid MAO activity and in vivo iodide transport was also evaluated in rats treated with exogenous thyrotrophin (TSH) after endogenous TSH secretion blockade produced by T4 administration. In this condition, thyroid MAO activity was significantly lowered by clorgyline and was not modified by deprenyl. In contrast to the results observed in normal rats, in vivo iodide transport in TSH-treated rats remained unaltered after treatment either with clorgyline or deprenyl. MAO activity evaluated in bovine thyroid follicles in primary culture was highly sensitive to low concentrations of clorgyline (< 10 nmol/l) and relatively insensitive to deprenyl, a finding that indicates a predominance of the MAO-A isoform in the follicular cells in culture. When clorgyline (0.1 and 1 mumol/l) or deprenyl (1 mumol/l) were added to the culture medium, no modifications in the active transport of iodide were observed. These results indicate the absence of a direct linkage between thyroid MAO activity and the active iodide transport.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of monoamine oxidase inhibitors and dopamine agonists on the behavior of mammal- and frog-eating snakes

Skin mucus of the frog, Xenopus laevis, induces climbing and attenuates tongue flicking in Nerodia sipedon; these effects are induced alone and are potentiated by l-deprenyl, a monoamine oxidase type B inhibitor (MAO-B i), but not by clorgyline, an MAO type A inhibitor (MAO-A i). Both MAO-A and MAO-B metabolize dopamine, with MAO-B having the higher affinity; MAO-A selectively metabolizes serotonin and norepinephrine and MAO-B is selective for phenylethylamine. It was hypothesized that clorgyline and l-deprenyl would differentially modulate tongue flicking and climbing in frog-eating ( Nerodia erythrogaster) and mammaphagous ( Elaphe o. obsoleta) snakes, based on physiological differences between the species. l-Deprenyl caused a decrease in tongue flicking and climbing by Elaphe and an increase in climbing by Nerodia, whereas clorgyline did not alter tongue flicking, climbing, or locomotor activity in either species. To further assess the role of dopamine, hybrid black/gray rat snakes, E. o. spiloides, were administered the D 1 and D 2 dopamine receptor agonists SKF 77434 (SKF 38393, N-allyl) and quinpirole, respectively. SKF 77434 and quinpirole attenuated climbing, but only SKF 77434 attenuated tongue flicking in Experiment 3; neither drug affected locomotor activity. Results suggest that dopaminergic stimulation by MAO-B i and dopamine agonists modulates tongue flicking and climbing behaviors in snakes, and that the contrasting climbing reactions induced by MAO-B i between Elaphe and Nerodia may be linked to quantitative differences in endogenous catecholamine levels and/or to the numbers and sensitivity of receptors.

Monoamine oxidase inhibitory effects of some 4-aminophenethylamine derivatives

The in vitro and ex vivo monoamine oxidase (MAO) inhibitory effects of (±)4-dimethylamino-α-methyl-phenethylamine 4-DMAA) and (±)4-methylamino-α-methyl-phenethylamine (4-MAA) were reassessed, in comparison with the previously unstudied achiral parent compound, 4-dimethyl-aminophenethylamine (4-DMAPEA) and with a salt of 4-DMAA enriched in the levo isomer, (“−”)-4-DMAA, using amiflamine [ S-(+)-4-dimethylamino- α,2-dimethylphenethylamine] as positive control. The in vitro studies confirmed that 4-amino-α-methylphenethylamine derivatives are highly selective and reversible MAO-A inhibitors. Furthermore, (“−”)-4DMAA was less active than the racemic mixture. The side chain-unsubstituted compound, 4-DMAPEA, proved to be a nonselective and reversible MAO inhibitor. The ex vivo results, in which catecholamines, serotonin (5-HT) and their metabolites were measured in two brain regions after i.p. administration, confirmed the results obtained in vitro. These results are consistent with the suggestion that the 4-amino group contributes to MAO inhibitory effects of α-methyl-phenethylamines, and show that the presence and orientation of an α-methyl side chain substituent may be important when determining the potency and selectivity of these compounds. All compounds tested could be quantified by HPLC with electrochemical detection.

Monoamine oxidase inhibitors inhibit [ 3H]quinpirole binding in rat striatal membranes

This study describes interactions of monoamine oxidase inhibitors at binding sites labeled by [ 3H]quinpirole, a putatively selective ligand for dopamine D 2-like receptors, in in vitro binding assays in rat brain. Monoamine oxidase inhibitors potently and competitively inhibited equilibrium binding of [ 3H]quinpirole in homogenate binding assays with the following rank order of potencies: clorgyline ⩾ Ro 41-1049 > pargyline > (−)-deprenyl > (+)-deprenyl > Ro 16-6491 > iproniazid. This rank order of potencies does not correlate with the potencies of these drugs at monoamine oxidase-A or monoamine oxidase-B, σ site(s) or dopamine receptors. Monoamine oxidase inhibitors did not alter the ability of quinpirole to compete for [ 3H]spiperone binding. Quinpirole did not inhibit monoamine oxidase-A or monoamine oxidase-B activity and had low affinity (200 nM) for σ site(s). These data suggest a potential novel binding site for [ 3H]quinpirole in rat brain and/or an alternative site of action for the antidepressant effects of monoamine oxidase inhibitors.

Effects of monoamine oxidase inhibitors on the acid metabolites of some trace amines and of dopamine in the rat striatum

The effects of the administration of selective and non-selective inhibitors of monoamine oxidase (MAO) on the concentrations of three trace acid metabolites [phenylacetic acid (PAA); m-hydroxyphenylacetic acid (mHPAA); and p-hydroxyphenylacetic acid (pHPAA)] and of an acid metabolite of dopamine [3,4-dihydroxyphenylacetic acid (DOPAC)] in the rat striatum were determined. Administration of brofaromine (1−100 mg/kg, s.c.) a type AMAO inhibitor, dose-dependently decreased DOPAC and mHPAA levels. pHPAA levels were decreased by 100 mg/kg brofaromine, but PAA levels were unaffected. Doses of deprenyl of less than 100 mg/kg, i.p., had no effect on any of the acids, while 100 mg/kg decreased DOPAC, mHPAA and pHPAA but not PAA levels. Clorgyline, pargyline and tranylcypromine treatment decreased the levels of DOPAC, mHPAA and pHPAA but not PAA. Administration of α-monofluoromethyldopa, an inhibitor of aromatic amino acid decarboxylase, decreased the levels of all four acids. It was concluded that deamination of the respective parent amine by type A MAO is primarily responsible for the synthesis of DOPAC and mHPAA, but that another pathway contributes to pHPAA synthesis. It appears that either PAA arises predominantly independently from the actions of MAO or that its removal via transport or further metabolism regulates its concentration.

Modulation of capsaicin induced airway reflexes in humans: effect of monoamine oxidase inhibition.

1. In animal studies monoamine oxidase (MAO) inhibition has been shown to reduce the cough response through elevation of 5-HT in the central nervous system. In this study the effect of selective inhibition of the two subtypes of MAO (MAO-A and MAO-B) was studied on human airway reflexes. 2. Capsaicin-induced cough and reflex increase in respiratory resistance were measured in nine normal volunteers before and after MDL 72394 (MAO-A inhibitor) 16 mg or MDL 72974A (MAO-B inhibitor) 12 mg. 3. Neither inhibitor altered capsaicin-induced cough. Following treatment with MDL 72394, however, the capsaicin-induced reflex increase in resistance was enhanced, by 5.97 +/- 2.1 fold of the placebo value at 1 h. 4. Thus, neurotransmitters in the central nervous system which are substrate for MAO-A (i.e. noradrenaline, 5-HT) may be involved in the control of capsaicin-induced reflex bronchoconstriction.