Longitudinal studies of the effect of monoamine oxidase inhibitors on sleep in man

Summary Monoamine oxidase inhibitors suppressed REM sleep during longitudinal sleep studies in four subjects. While the REM suppression occurred during maximum dosages, one normal subject showed an increase in REM time during the initial phase of drug administration. One patient had a marked REM compensation after the drug was discontinued. There were no consistent changes in Non-REM sleep. Monoamine oxidase inhibition was measured by plasma and platelet studies, as well as by 24-hour urinary tryptamine levels.We wish to thank Dr. William Bunney and Dr. David Anderson for their assistance     

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-HT_1A 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-HT_1A 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-HT_1A 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.     

单胺氧化酶抑制剂及其药物相互作用研究

目的了解单胺氧化酶抑制剂(MAOIs)及其与其他药物的相互作用。方法调查本院及其他医疗机构的药品说明书,检索中英文文献数据库,对涉及MAOIs的重点记录,进行整理归纳、分析总结。结果有11种常用药品属于MAOIs,近40种药品与MAOIs存在药物相互作用。结论上述药品应尽可能避免与M AOIs合用,或合用时减少用药剂量,以避免或减轻药物不良反应。     

Use of monoamine oxidase inhibitors in chronic neurodegeneration

Introduction: Neurotransmission by biogenic monoamines is important for brain function. Biogenic amine turnover employs the enzymes catechol-O-methyltransferase and monoamine oxidase in neuronal and glial cells. Inhibition of these enzymes elevates biogenic amine levels in the synaptic cleft. Subtype selectivity of inhibition is lost during long-term use of ‘selective’ monoamine oxidase inhibitors.

Areas covered: This narrative review discusses use of monoamine oxidase inhibitors in the context with chronic neurodegeneration.

Expert opinion: Antidepressant drugs increase synaptic concentrations of biogenic amines. In the aging brain, then one of the two enzymes involved in degrading synaptic amines, catechol-O-methyl transferase, increasingly catalyzes methylation processes. Therefore, metabolism by monoamine oxidase plays an incremental, predominant role in biogenic amine turnover, leading to greater oxidative stress. In patients with chronic neurodegenerative disorders, symptoms, such as depression and apathy, are often treated with drugs that elevate biogenic amine levels. This therapeutic strategy increases biogenic amine turnover, thereby generating neurotoxic aldehydes and enhanced oxidative stress, each of which influence and accelerate the course of neurodegeneration. We propose that antidepressant therapy should be initiated first with monoamine oxidase inhibitors only. If adequate clinical response is not achieved, only then they should be supplemented with a further antidepressant.     

Recovery from amnesia induced by pre-test injections of monoamine oxidase inhibitors

Amnesia was induced in C57BL6J male mice by pre-training injections of cycloheximide (CYC) in a one-trial passive avoidance task. This amnesia was reversed by pre-testing injections of two monoamine oxidase inhibitors (MAOI's) catron and pargyline. The results of 2 non-contingent control groups indicated that mice injected with cycloheximide but given foot shock in a place different from the training apparatus did not show increased latency following treatment with catron and pargyline. This indicates that recovery is specific for training in the passive avoidance task. Depletion of norepinephrine (NE) by diethyldithiocarbamate (DEDTC), a dopamine beta hydroxylase inhibitor, resulted in an amnesia similar to that induced by CYC. DEDTC-induced amnesia was also reversed by catron and pargyline.     

Platelet monoamine oxidase activity in first-degree relatives of schizophrenic patients

Platelet monoamine oxidase (MAO) is under genetic control. A lower MAO activity in chronic schizophrenia has repeatedly been reported, and it has been suggested that reduced activity of this enzyme reflects an increased vulnerability to schizophrenia. To test this hypothesis platelet MAO was determined in 65 first-degree relatives of 22 schizophrenic index patients and in matched healthy controls. No difference in mean activity between the two samples could be detected, suggesting that reduced MAO activity in schizophrenia is more likely to be a phenomenon secondary to the disease. A significant parent-offspring correlation of MAO activities was obtained.This investigation was supported by the Deutsche Forschungsgemeinschaft     

Effects of monoamine oxidase inhibitors on performance during differential reinforcement of low response rate

The effects of three monoamine oxidase inhibitors (MAOI) on performance under a differential-reinforcement-of-low-rate 72-s schedule (DRL 72-s) for water reinforcement were determined. All three drugs (isocarboxazid, iproniazid, phenelzine) reduced response rate and increased reinforcement rate in rats performing under the DRL schedule. Drugs from other classes (alcohol, chlordiazepoxide, morphine, pentobarbital) did not produce similar effects. The ability of MAOI to increase reinforcement rate under a DRL 72-s schedule is similar to that recently reported for tricyclic antidepressants and the two atypical antidepressants mianserin and iprindole. These findings support the contention that the DRL schedule may be useful as a test for identifying new antidepressants and for elucidating the neurochemical effects of antidepressants that are responsible for their therapeutic actions.     

Molecular characteristics of human platelet monoamine oxidase

Summary The monoamine oxidase B (MAO-B) selective inhibitor J-508 (N-methyl-N-propargyl-(1-indanyl)-ammonium chloride) appears to interact with MAO-B in a manner consistent with a suicide reaction. Because of this property, J-508 could be used, under the appropriate conditions, to titrate the concentration of MAO-B active centres in the human platelet, although some non-specific binding of this compound to sites other than the active centre of this enzyme form was found, thus limiting the accuracy of the titration method. The molecular characteristics of human platelet MAO-B (K _m, V _max, approximate enzyme concentrations and molecular turnover numbers) towards three of its monoamine substrates have been estimated. The natural variation of platelet MAO-B activity from individual to individual is due to a variation in the V _max without a variation in the K _m towards benzylamine as substrate, and is based, at least in part, upon a variation in the concentration of this enzyme form.     

Lifetime monoamine oxidase inhibition and sleep

The effects of clorgyline, a type A monoamine oxidase (MAO) inhibitor, on the sleep of the rat were examined after subacute and lifetime administration. When 2 mg/kg/24 hours were given for 60 hours, type A MAO was inhibited by 92% and a significant reduction in REM sleep time was noted. When fetal rats were exposed to maternal dosage of 1 mg/kg/24 hours and then received this dose from one to 6 weeks postnatally, type A MAO was inhibited by 99%, but there were no alterations in the EEG sleep stages. In summary, subacute administration of clorgyline resulted in decreases in both Type A MAO and REM sleep; during chronic administration in a developing animal, Type A MAO was again decreased, but there was no corresponding changes in REM sleep.     

Relation between brain monoamine oxidase (MAO) activity and the firing rate of locus coeruleus neurons

Summary Utilizing a specific low substrate concentration technique, intrasynaptosomal MAO-A and MAO-B activities within the rat brain noradrenaline system were studied. It was found that mainly MAO-A was localized intrasynaptosomally, whereas MAO-B contributed with less than 15% of the total intrasynaptosomal MAO activity, a phenomenon that was also observed within the central dopamine system. It is suggested that the intrasynaptosomal pool of MAO in the noradrenaline and the dopamine systems may reflect the density of innervation of the respective system throughout the brain. In addition, the effects of various selective monoamine oxidase (MAO) inhibitors on the noradrenergic intrasynaptosomal MAO activity as well as on the neuronal firing rate of noradrenaline containing cells in the locus coeruleus (LC) were investigated. Pretreatment with the MAO-A selective inhibitors clorgyline (10 mg/kg, i.p., 1 h) or (+)-FLA 336 (1 mg/kg, i.p., 1 h) caused a significant depression (40%) of mean spontaneous firing rate of LC neurones, randomly encountered throughout the LC. The MAO-B selective inhibitor pargyline (10 mg/kg, i.p., 1 h) was found to lack effect in this regard. However, pretreatment with (–)-deprenyl (10 mg/kg, i.p., 1 h), equally a selective MAO-B inhibitor, markedly suppressed the spontaneous firing rate of LC units. This inhibition by (–)-deprenyl was blocked by pretreatment with SK&F 525 A (50 mg/kg, i.p., 30 min), an inhibitor of microsomal drug metabolizing enzymes. Thus, the depression of LC units by (–)-deprenyl seems to be executed by a metabolite, e. g. l-amphetamine. Taken together, the present electrophysiological and biochemical results show that the neuronal depression of noradrenaline neurones in the LC by MAO-inhibitors is specifically related to the inhibition of MAO-A. Furthermore, the data indicate a relationship between the activity of intrasynaptosomally located MAO-A and the neuronal activity of central noradrenaline pathways.     

Effects of co-administration of a selective serotonin reuptake inhibitor and monoamine oxidase inhibitors on 5-HT-related behavior in rats

5-hydroxytryptamine (5-HT) syndrome is a dangerous condition of 5-HT excess that can occur in the case of co-administration of a monoamine oxidase (MAO) inhibitor and a serotonin reuptake inhibitor (SSRI). The goal of the present study was to investigate the effects of acute administration of MAO inhibitors and subchronic administration of fluvoxamine on 5-HT-related behaviors (head shaking and 5-HT syndrome) in rats treated with 5-hydroxytryptophan (5-HTP). Administration of the non-selective MAO inhibitor, pargyline, and the selective MAO-A inhibitor, clorgyline, resulted in 5-HT syndrome in 5-HTP-treated rats, and subchronic co-administration of fluvoxamine intensified the syndrome. However, administration of the selective MAO-B inhibitor, selegiline, did not induce 5-HT syndrome with or without subchronic fluvoxamine co-administration. These data suggest that non-selective MAO and selective MAO-A inhibitors can induce 5-HT syndrome in humans when co-administered with SSRI. Further, the risk of 5-HT syndrome may be lower with the selective MAO-B inhibitor, selegiline.     

Inhibition of monoamine oxidase and semicarbazide-sensitive amine oxidase by mexiletine and related compounds

Summary The in vitro inhibition by mexiletine and related compounds of the activity of rat brain, heart and lung mono-amine oxidase-A (MAO-A), rat brain MAO-B, human platelet-poor plasma benzylamine oxidase and a clorgyline-resistant, semicarbazide-sensitive amine oxidase (SSAO) distinct from both MAO and benzylamine oxidase has been studied. The compounds were most active towards MAO-A and SSAO. IC₅₀ values for mexiletine towards rat heart MAO-A and SSAO were 10 mol/l and 320 mol/l, respectively. Replacement of the para-hydrogen atom in the mexiletine aromatic ring by bromine increased potency towards both MAO-A and SSAO. Replacement of the ortho-methyl group in the mexiletine aromatic ring by hydrogen increased the potency towards SSAO alone. FLA 1042, with both these substitutions, was found to be a reversible mixed-type inhibitor of both MAO-A (K _i ^slope 1.4 mol/l, K _i ^int 24 mol/l) and of SSAO (K _i ^slope 12 mol/l, K _i ^int 6 mol/l).     

Selectivity of clorgyline and pargyline as inhibitors of monoamine oxidases A and B in vivo in man

During 4 weeks of treatment with clorgyline, a selective MAO-A inhibitor, platelet monoamine oxidase (MAO) activity was unchanged. During a similar 4-week crossover treatment period with pargyline, a selective MAO-B inhibitor, platelet MAO activity was essentially completely inhibited in the same individuals. The differential effects of the two drugs on platelet MAO, which consists exclusively of the MAO-B form, suggests that the in vitro selectivity of clorgyline, and possibly of pargyline, on MAO-A and MAO-B may be maintained in vivo during long-term administration in man. Reductions in blood pressure, heart rate, and plasma amine oxidase activity were generally similar in magnitude during treatment with both drugs, however, suggesting that either these effects are nonspecific consequences of both MAO-A and MAO-B inhibition, or that pargyline also inhibited MAO-A activity.     

Carnitine and lipoate ameliorates lipofuscin accumulation and monoamine oxidase activity in aged rat heart

In this study we have focused on the levels of lipofuscin, monoamine oxidase and cholesterol phospholipid ratio in the heart muscle of young, middle aged and aged rats. In parallel, we have also investigated the levels of carnitine and lipoic acid during aging. We observed an increase in lipofuscin accumulation and monoamine oxidase activity in both middle aged and aged rats. Levels of both carnitine and lipoic acid decreased along with a decrease in cholesterol phospholipid ratio. These changes were normalized upon cosupplementation of carnitine and lipoic acid. Our results thus reveal that carnitine along with lipoic acid can be used as an effective supplement against free radical induced damage to the cardiac tissue.     

Interactions between sympathomimetic amines and a new monoamine oxidase inhibitor

A relatively safe method is described for the screening of new monoamine oxidase inhibitors with respect to their potentiation of dietary and sympathomimetic amines. Studies of such a compound, Clorgyline, and its interactions with oral tyramine and phenylephrine given by mouth to three doctor-volunteers are described. Marked potentiation of the bradycardia-inducing properties of the amines was found.     

乙型肝炎患者血清单胺氧化酶的检测

目的:探讨乙肝患者血清单胺氧化酶水平及其临床意义。方法:用快速比色法检测急性乙肝、慢性乙肝、重型乙肝、肝硬化患者血清MAO水平。结果:乙肝患者血清MAO为(46.68±20.64)u,而正常对照组MAO为(23.25±12.40)u,差异具显著性(P<0.01),且慢性乙肝、重型乙肝、肝硬化血清MAO值均高于正常对照组。急性、慢性、重型乙肝、肝硬化患者血清MAO阳性率依次为45%、50%、65%、82.5%,差异显著(P<0.01)。结论:MAO与肝纤维化密切相关,是反映肝纤维化程度及肝损害的重要指标。     

Evidence for an extraneuronal location of monoamine oxidase in renal tissues

Summary (1) Homogenates of renal cortex and renal medulla of control and 6-hydroxydopamine-denervated cat kidneys were prepared. (2) Monoamine oxidase (MAO) activity was determined with [³H]-5-hydroxytryptamine ([³H]-5HT) and [¹⁴C]--phenylethylamine ([¹⁴C]--PEA) as preferential substrates for MAO-A and MAO-B, respectively. (3) The endogenous dopamine and noradrenaline tissue contents of control and chemicallydenervated kidneys were compared with the MAO activities. (4) The results show that a 70% depletion of monoamine content by chemical denervation resulted only in a 23% reduction of MAO-A activity in the renal cortex, whereas MAO-13 was unaffected either in the cortical or the medullary zones; in the renal medulla MAO-A activity was not changed by denervation. Most of the MAO activity in the cat kidney is of the B type (74%) and is located in the renal cortex.On leave from Faculdade de Farmácia, Universidade de Coimbra, Portugal Send offprint requests to P. Soares-da-Silva at the above address