Monoamine Oxidase: Basic and Clinical Perspectives

D.P. Holschneider, M.D. and J.C. Shih, Ph.D.

Monoamine oxidase (MAO) is a flavin-adenosine-dinucleotide (FAD)-containing enzyme which converts biogenic amines to their corresponding aldehydes. The enzymatic reaction requires molecular oxygen and produces aldehyde and hydrogen peroxide according to the overall equation R-CH2-NH2 + O2 + H2O R-CHO + NH3 + H2O2. Subsequently, the aldehyde intermediate is rapidly metabolized, usually by oxidation via the enzyme aldehyde dehydrogenase to the corresponding acid, or in some circumstances to the alcohol or glycol by the enzyme aldehyde reductase.

Johnston first demonstrated the existence in the brain of two forms of MAO, termed MAO-A and MAO-B, which differed on the basis of their substrate affinities and inhibitor sensitivities (67). The primary substrates of MAO in the brain are neurotransmitters such as epinephrine (EP), norepinephrine (NE), dopamine (DA), serotonin (5-HT), and b-phenylethylamine (PEA). Other amines, such as tyramine (precursor to DA) are also catabolized by MAO after being absorbed from the gastrointestinal tract or after being generated as a result of bacterial metabolic transformations. These substrates are deaminated by both forms of the enzyme, albeit with differing kinetic parameters. Kinetic parameters describing the relative participation of the two forms depend on the concentration, affinity and turnover rate of the substrate. Under normal physiologic conditions, NE and 5-HT are the preferred substrates of MAO-A, and PEA is the preferred substrate of MAO-B. Both forms of the enzyme metabolize tyramine, octopamine, tryptamine, and DA, though DA in human brain has a higher affinity for MAO-B (Table 1).

It has been hypothesized that cellular compartmentation of MAO may also be a contributing factor in determining substrate specificity (149). Hence, in dopaminergic neurons which contain little—if any—MAO-B, the metabolism of catecholamines such as NE or DA will be determined largely by MAO-A. Conversely, extraneuronally, where MAO-B is found in abundance in astrocytes, the proportion of catecholamines deaminated by MAO-A decreases.

Stereoselectivity of MAO also may contribute to the enzyme's affinity for a specific substrate. This is underscored by the fact that l-deprenyl is a more potent inhibitor of MAO-B than is d-deprenyl. Stereoselectivity has been demonstrated for both MAO-A and -B with stereospecifically deuterated tyramine and DA (161). A review of stereochemical aspects of the active site of MAO and its interaction with substrates and inhibitors of MAO can be found elsewhere (38).

In addition to its central role in the catabolism of monoaminergic neurotransmitters, MAO plays a part in the conversion of a number of pharmacological agents from inactive to active states. Deamination of the pro-anticonvulsant milacemide by MAO-B yields glycine, an inhibitory neurotransmitter whose actions may limit the spread of synchronous, epileptiform discharges. Deamination of 2-propylpentylglycemide yields glycine and 2-propyl-l-pentyaldehyde, a precursor to the anticonvulsant valproic acid (162). Conversion by MAO-B of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to the neurotoxic pyridinium metabolite 1-methyl-4-phenylpyridinium (MPP+) produces a neurological syndrome in humans virtually indistinguishable from Parkinson's disease (80).

Intracellularly, both forms of MAO are found tightly associated with the outer membrane of the mitochondria, where they are inserted by means of the polypeptide ubiquitin, with energy provided by adenosine triphosphate (165, 166).

MAO is widely distributed in virtually all mammalian cell types (Table 2), with the notable exception of the erythrocyte (11). MAO activity can be measured in cultured human skin fibroblasts, which predominantly express MAO-A, and from platelets or lymphocytes, which predominantly express MAO-B (13,40). In the adult, the highest levels of MAO-A are found in the placenta, liver, and intestine. MAO-B is proportionately found in greatest abundance in brain tissue, although the relative contributions of the two forms of the enzyme may depend on age (54).

Within the central nervous system, MAO-A is localized primarily in cell bodies and dendrites of catecholamine cell groups (e.g., cells of the substantia nigra, locus coeruleus, nucleus subcoeruleus, and the periventricular region of the hypothalamus). MAO-B is localized in 5-HT cell groups (e.g., cells of the nucleus raphe dorsalis, nucleus centralis superior), in glial astrocytes (154), as well as to a lesser extent in histaminergic cells of the posterior hypothalamus (72). Dopaminergic neurons have no MAO-B and only small amounts of MAO-A (74,154). Neurons of the locus coeruleus and hypothalamus show both MAO-A and MAO-B activity, indicating that the same cell can express both forms (128,154). The capacities of various human and rat tissues to bind the radioligands of MAO-A and -B show a high correlation with their corresponding enzyme activities (119). Both positive and negative mismatches, however, have been reported between studies employing in situ hybridization or ligand binding, suggesting the possibility of posttranslational transport of the protein after synthesis (65,119). Alternatively, these differences may reflect different sensitivities of the techniques employed or the absence of translation of MAO mRNA under certain conditions into protein. Comparison across species should be done with caution, as significant species differences in the cellular localization of the isoenzymes have been reported (69,119).

MAO-A has been demonstrated in the endothelial cells lining cerebral blood vessels and the ependymal cells lining the ventricle. MAO-B has been localized within the end-feet of astrocytes contacting the endothelial cells (69, 152,155). Thus, MAO may constitute an important functional aspect of the blood-brain barrier.

The primary role of MAO lies in the metabolism of amines and in the regulation of neurotransmitter levels and intracellular amine stores. In the gastrointestinal system, the circulatory system and the liver, MAO serves a protective function by regulating levels of exogenous, dietary amines—many of which would otherwise exert potent pressor effects. A similar role can be attributed to MAO in the blood-brain barrier, where it is thought to prevent the entry of potentially toxic 'false neurotransmitters'.

Within neurons, MAO appears to regulate the levels of neurotransmitters released upon synaptic firing. Termination of the action of these neurotransmitters is determined by a number of factors, including their reuptake into nerve terminals, their dilution by diffusion out of the junctional cleft, as well as their metabolic transformation, specifically of catecholamines by catechol-O-methyltransferase (COMT). The uptake of neurotransmitters by glial cells and their subsequent metabolism by MAO-B may further serve to adjust levels of neurotransmitters within the extraneuronal compartment. It has been hypothesized that the existence of the two forms of MAO (A and B) may play a role in maintaining the specificity of function of catecholaminergic and serotonergic neurons. Thus, MAO-A is found in both dopaminergic, as well as noradrenergic neurons and may help eliminate 5-HT in these neurons. Similarly, MAO-B found in serotonergic neurons may protect these cells from the entry of DA and PEA, for which MAO-B shows a preferred affinity. MAO's role in limiting the presence of these neurotransmitters following their release may secondarily result in altering the release of hormones from cells sensitive to biogenic amines. Thus, MAO may function indirectly as a regulator of neuroendocrine function.

The catabolism of bioamines by MAO results in the production of the potentially toxic compounds hydrogen peroxide, ammonia, and aldehyde. Hydrogen peroxide, in particular, in the presence of iron (II) can give rise to the highly cytotoxic hydroxyl radical (•OH). Hypothetically, an increase in catecholamine turnover, as may be seen in certain pathological conditions, will increase production of such free radical intermediates. It has been suggested that increased MAO levels may represent a risk factor for a cell's potential to sustain oxidative injury (59,151).

Full understanding of the multiple physiologic functions of MAO remains a current focus of research. The role MAO plays during development of the central nervous system (CNS) is just beginning to be explored. Monoamines, including 5-HT, DA, and NE, play important roles as guiding molecules in the development of the mammalian brain. Preliminary results in rodents suggest that inhibition of MAO-A and -B during gestation results in changes of 5-HT terminal density in the cortex and caudate, as well as behavioral abnormalities, including impulsivity, stereotypic grooming, and seizures (156).

During development, MAO changes in response to cellular differentiation, as well in response to shifts in the relative proportions of cell types within a tissue. In most tissues of humans, rats, and mice, MAO-A appears before MAO-B. At birth, MAO-A is present in brain at near-adult levels, undergoing a 1.5–2-fold increase in the early postnatal period (83,140). Thereafter, MAO-A declines by approximately 50% by age 2, largely as a result of rapidly declining neuronal density (75). During adult life, MAO-A remains relatively stable, with no change or small increases noted during senescence. MAO-B, in contrast, increases several fold in most tissues after birth. In brain, a 2–5-fold increase is attributable largely to the extensive postnatal proliferation of astrocytes, which contain the majority of MAO-B of the brain (82,153). During adult life, MAO-B in the brain remains relatively unchanged until approximately the sixth decade, after which it shows a marked, progressive increase. The increase in MAO-B in late life has been attributed to the glial proliferation that accompanies neuronal loss, although other factors—genetic, environmental or hormonal—may also play a role.

Different brain regions show differences in the degree of MAO-B increase with age. The nigrostriatal system (caudate, putamen, substantia nigra), the hypothalamus, thalamus and limbic system (hippocampus, amygdala) show the largest age-dependent increases in MAO-B; lesser changes are seen in frontal cortex, prefrontal cortex, and the cingulum (43,101). MAO-B increases in senescence occur at a time when levels of many of the biosynthetic enzymes for catecholamines are decreasing. These observations may help explain the age-related decreases in NE and DA.

The cloning of human liver MAO-A and MAO-B demonstrated that the two forms of the enzyme are made of different polypeptides and are coded for by different genes residing on the X chromosome (Xp11.23) (79,126). Expression of functional enzymes by transient transfection of the cDNAs has provided unequivocal evidence that the different catalytic activities of MAO-A and -B reside in their primary amino acid sequences (78), which show approximately 70% identity and similar hydrophobicity indices. The genes for human MAO-A and -B are complex, having 15 exons with identical intron-exon organization (Figure 1).  Exon 12 codes for the covalent FAD-binding site and is the most conserved exon, sharing 94% amino acid identity between both forms of the enzyme. These results suggest that MAO-A and -B are derived from a common ancestral gene (53).

The MAO-A and -B promoters are distinctly different, even though they share 60% sequence identity. The promoter regions of human MAO-A and B genes have been characterized using a series of 5' flanking sequences linked to a human growth hormone reporter gene and transfected into human neuroblastoma cells (SHSY-5Y), mouse fibroblasts (NIH3T3) and virally transformed African green monkey kidney cells (COS 7). The maximal promoter activity for MAO-A was found in a 0.14 kb PvuII/DraII fragment (A 0.14) and in a 0.15 kb Pstl/Nael fragment (B 0.15). Both fragments are GC-rich, share approximately 60% sequence identity, and contain potential Sp1 binding sites. The organization of the transcription elements, however, is distinctly different in these two promoters (164). MAO-A is a 0.14 fragment that lacks a TATA box, consists of three Sp1 elements, and exhibits bidirectional promoter activity (163). The MAO-B core promoter fragment B 0.15 consists of two clusters of overlapping Sp1 sites separated by a CACCC element. Differences in the promoter organization of the MAO-A and B genes are important factors in determining the tissue- and cell-specific expression of the enzyme.

The availability of cDNA has made possible study of the structure and function of MAO-A and -B. The active sites and the domains conferring the substrate and inhibitor selectivity of both MAO forms have been studied using site-directed mutagenesis and chimeric enzymes. There are nine cysteine residues in the deduced amino acid sequences of both MAO-A and -B in human liver. The role of these cysteine residues in catalytic activities of MAO-A and -B was studied by site-directed mutagenesis. The catalytic activities and kinetic parameters of seven MAO-A mutants and six MAO-B mutants were similar to those of the wild-type enzymes, indicating that these cysteines are not necessary for enzymatic activity (158). However, serine substitution of the cysteine residues Cys-374 and 406 of MAO-A or residues Cys-156, 365, and 397 of MAO-B resulted in complete loss of catalytic activity. Loss of catalytic activity after serine substitution of Cys-406 of MAO-A and Cys-397 of MAO-B is probably due to inability of the enzyme to bind to the FAD cofactor, which is necessary for catalytic activity. Cysteine residues Cys-374 of MAO-A and Cys-156 and 365 for MAO-B are a requirement for the catalytic activity of the enzyme. Whether their role lies in the formation of the active site or in maintaining the appropriate conformation of the enzyme remains to be studied (158).

The construction of chimeric MAOs has allowed examination of which regions of the enzyme confer the substrate and inhibitor selectivities. Reciprocal exchange of the corresponding N-terminals and C-terminals of MAO-A and -B have shown that the C-terminal of MAO-B (but not of MAO-A) is critical for maintaining catalytic activity of the enzyme (24). Substrate specificity of MAO-A appears to be determined by amino acids 161-375, insofar as replacement of these amino acids with those of the corresponding region of MAO-B termed AB(161-375)A converts MAO-A catalytic properties to MAO-B-like ones (56). Recently, using human MAO cDNA as a probe, a novel type of MAO has been cloned from trout liver. This enzyme displays substrate and inhibitor selectivities that are dissimilar to either MAO-A or -B (22). The structure of trout MAO should provide further insights into the substrate and inhibitor selectivities of the MAOs.

Examination of animals and humans with deletions of the MAO-A and -B genes has begun to provide insight into the linkage of genes and behavior. A line of transgenic mice in which an interferon (INF-) transgene was integrated into the location of MAO-A gene resulted in MAO-A deficient mice (20). Interestingly, 5-HT concentrations in MAO-A deficient pup brains were increased up to 9-fold, compared to the wild-type. In adult brains, the 5-HT levels were only increased 2-fold when compared to the wild type, due to the appearance of MAO-B, which was not present in pups. In pup and adult brains, NE as well as DA levels were increased. Adult mice manifested a distinct behavioral syndrome, including enhanced aggression in males. Aggression has also been reported to be a behavioral feature in humans suffering from Norrie's disease, an X-linked recessive disease in males. A subset of patients with Norrie's disease demonstrate chromosomal deletions encompassing both the Norrie gene, as well as the neighboring genes for MAO (25,148). These patients are characterized by seizures, hypotonic crises, poor growth, deafness, severe mental retardation, psychosis and aggression. Interestingly, some of these patients have lived to be over 20 years of age, indicating that deletions of the MAO-A and -B genes—though they may engender changes in neurotransmitter levels, brain development and behavioral abnormalities—are not in themselves incompatible with life.

Gender may contribute to differences in MAO activity, insofar as males bear only a single copy for each gene, whereas females bear two alleles, one of which randomly undergoes inactivation. Thus, MAO activity in female tissues represents the average of the activity levels encoded by each allele. Gender may also indirectly affect enzyme levels, insofar as hormonal status appears important in determining MAO activity. This is suggested by the observation that the intensity of staining for MAO in the human fallopian tube, as well as MAO levels in platelets, correlates with the phases of the menstrual cycle; the lowest levels are seen during the ovulatory phase (36,107).

Inhibitors of MAO (MAOIs) are distinguished on the basis of their specificity for MAO-A and -B, as well as the reversibility of their inhibition (Table 3). The MAOIs currently in clinical use in the United States are all irreversible ('suicide') inhibitors characterized by site-specific covalent binding of MAO. Phenelzine and the putative active metabolite of isocarboxazid are derivatives of hydrazine, whereas pargyline and deprenyl are acetylenic agents. Both the hydrazine and the acetylenic agents bind to the flavin prosthetic group of MAO following their oxidation to reactive intermediates. The mechanism of action of the cyclopropylamine tranylcypromine is less certain but may involve initial formation of an imine by MAO, followed by reaction of a sulfhydryl group in the active center of the enzyme. Except for deprenyl, MAOIs currently in clinical use are nonselective with regard to both forms of the enzyme. Deprenyl, at doses up to 10 mg/day, selectively inhibits MAO-B; higher doses also inhibit MAO-A. Irreversible selective inhibitors of MAO-A, such as clorgyline, appear efficacious in the treatment of depression but are currently used only experimentally.

Oral absorption of the MAOIs is rapid. Inhibition is maximal within a few days, though antidepressant effects may be delayed by 2–3 weeks. Following withdrawal of the drug, the half-life of the disappearance of MAO inhibition is estimated in the rodent brain at 11–12 days for phenelzine and pargyline and 2.5 days for tranylcypromine. The half-life in human brain is likely to be longer. Studies using positron emission tomography (PET) and radiolabeled deprenyl estimated the half-life of MAO-B in human brain at 40 days (44). For clinical purposes, recovery of enzymatic activity and restoration of amine metabolism generally requires up to two weeks, presumably because the enzyme must be replaced by synthesis.

An immediate consequence of MAO inhibition is an elevation in the intracellular concentration of catecholamines, including 5-HT and other biogenic amines (tyramine, tryptophan, octopamine and PEA). Within a period of hours following amine accumulation, a decrease of neuronal firing can be demonstrated in serotonergic and noradrenergic neurons. The antidepressant response, however, may be delayed by 2–3 weeks and may depend not on the increase in neuronal amine content per se but rather on certain secondary and tertiary adaptive changes. Increases in intracellular amine levels result, via feedback inhibition, in a reduction in amine synthesis. Amines accumulating in the cytoplasm begin to enter amine storage vesicles. From there, they may either displace endogenous amines or be released as co-transmitters or partial transmitters. Clinical improvement in affective symptoms correlates best with a down regulation of b-adrenergic, a2-adrenergic, and 5-HT2 receptors seen after two weeks. This effect is observed with nonselective MAOIs and selective MAO-A inhibitors, but only with high (nonselective) dosages of the MAO-B inhibitor deprenyl (28,76). Indeed, low-dose deprenyl produces only a marginal antidepressant response (88). This suggests a more central role for MAO-A (rather than MAO-B) in the treatment of depression.

Many of the effects of the MAOIs may be unrelated to MAO inhibition, though these have been less well studied. The MAOIs also inhibit other enzymes, including dopamine b-hydroxylase, 5-HT decarboxylase, choline dehydrogenase, succinic dehydrogenase and diamine oxidase. MAOIs may also directly inhibit the transport of amines; tranylcypromine appears to block both 5-HT and catecholamine uptake. The extent to which these actions contribute to the antidepressant effect of MAOIs is unclear. Even less clear is the role that changes in the levels of trace amines (e.g., PEA) play in the pathophysiology of mental illness.

Some of the actions and side effects of deprenyl and tranylcypromine may be due in part to their direct, amphetamine-like sympathetic stimulation (70). Clinical lore has it that these nonhydrazine agents have a faster onset of action than the substituted hydrazines and may help 'energize' patients. It has been suggested that the cyclized amphetamine structure of tranylcypromine can be opened to produce amphetamine. Although amphetamine has been detected in the blood after MAOI overdose (159), it is not usually found at therapeutic doses.

The recent discovery of reversible inhibitors of MAO-A (RIMAs) has promised an increased margin of safety for use of these agents. Moclobemide and brofaromine, both soon to be introduced in the United States, demonstrate transient inhibition of the substrate binding site of MAO-A as well as competitive displacement from this site by bioamines. Compared to the irreversible MAOIs, the half-lives of the RIMAs are measured in hours rather than days or weeks (6 hours and 12 hours for moclobemide and brofaromine, respectively, in rat brain). Hence, these drugs pose significantly less risk for potentiating the pressor effects of tyramine and other ingested, indirect sympathomimetics. Absence of a significant interaction with a number of neurotransmitter receptors, including a-adrenergic, serotonergic, dopaminergic, histaminergic, cholinergic, opioid and GABAergic receptors, further improved the side-effect profile of the RIMAs.

Although they both inhibit MAO-A, moclobemide and brofaromine show a number of distinctive pharmacologic and pharmacokinetic differences. Brofaromine's inhibition of MAO-A is more than 100-fold greater than moclobemide's. In addition, brofaromine inhibits 5-HT reuptake. Moclobemide, unlike brofaromine, is itself a substrate for MAO and is converted by the enzyme to a more potent active species. Metabolites of moclobemide, unlike those of brofaromine, also inhibit to a small extent the MAO-B found in platelets (51). These differences may well affect the eventual clinical roles of these RIMAs in the therapy of depression and anxiety.

The concern has been voiced that greater reversibility of MAO inhibition, though it may achieve greater safety with regards to hypertensive reactions, may potentially impact the ability of these agents to facilitate monoaminergic transmission and hence lower clinical efficacy. Recent trials, however, have demonstrated the efficacy of both brofaromine and moclobemide in the treatment of symptoms of major depression, panic and phobia.

Orthostatic hypotension is a common side effect of the irreversible MAOIs, particularly phenelzine (Table 4). Clinically, the development of orthostatic symptoms is gradual and appears generally after 2–3 weeks of treatment. The relationship of the time course of this response to the etiology of orthostasis remains unclear. Some have suggested it may represent a compensatory down-regulation of peripheral ganglionic effects in response to central sympathetic stimulation. Others have proposed that inhibition of amine metabolism results in an artificial, supraphysiologic elevation of amines with few or no pressor effects and the resultant replacement of amines with greater pressor effects from intracellular amine stores. Gradual accumulation of octopamine in adrenergic neurons, for instance, may be the result of MAO inhibition and resultant alternate hydroxylation of tyramine to octopamine. It has been suggested that octopamine may replace NE from intra-axonal storage granules. Octopamine released upon sympathetic stimulation may act as a 'false neurotransmitter' with minimal activity at a- or b-adrenergic receptors. The result is a functional block of sympathetic neurotransmission, accompanied by decreased ability to regulate blood pressure in response to postural changes.

The onset of orthostatic hypotension correlates with peak plasma MAOI levels. Indeed, minimizing peak levels by more frequent administration of smaller doses, particularly in the case of tranylcypromine, may be effective in attenuating the orthostatic response. Hypotension related to the hydrazine MAOIs (e.g., phenelzine) is less amenable to changes in the dosing interval. Interventions targeted at maintaining intravascular volume (e.g., encouraging fluid intake, increasing dietary salt, administration of salt-retaining corticosteroids such as florinef, or the use of support stockings) may be helpful. The occurrence of hypotension with the RIMAs is significantly less than with the irreversible MAOIs.

Under normal physiologic conditions, tyramine is largely absorbed from the intestine, where it is deaminated to p-hydroxyphenylacetic acid by MAO-A and, to a lesser extent, MAO-B. The remaining tyramine is deaminated by MAO in the liver and lung (29). Inhibition of MAO prevents the metabolism of tyramine and hence increases its levels in the systemic circulation. When tyramine is taken up and concentrated by adrenergic neurons, it causes the release of stored NE, leading to a sympathomimetic hypertensive response.

Although most increases in blood pressure are mild, a hypertensive crisis, also called the 'cheese reaction', may result from the consumption of foods rich in tyramine and other amines (10) (Table 5). Symptoms characterizing a hypertensive crisis are severe hypertension, headache, tachycardia, diaphoresis, and vomiting. Though rare, fatal intracranial hemorrhage, cerebral infarction, myocardial arrhythmias or infarction have been reported.

The actual morbidity associated with administration of the irreversible MAOIs is difficult to determine. However, it has been estimated that, of the 3.5 million patients that had used tranylcypromine by 1970, about 50 persons reportedly had cerebrovascular accidents and 15 of these individuals died (58). Extensive dietary restrictions help to minimize the risk of a hypertensive response, but these conditions have also been deterrents to the use of MAOIs. Guidelines concerning foods to avoid and foods considered 'safe' have varied; aged cheeses, concentrated yeast extracts, pickled fish, sauerkraut, and broad bean pods are most clearly contraindicated (127). Difficulties in evaluating patient risk have come not only from differences in compliance with dietary restrictions but also because the tyramine content of many foods and beverages can be extremely variable. It is estimated that the tyramine content of beef liver may vary as much as 50-fold, depending on the method and period of storage; the tyramine content of certain cheeses depends on their state of ripeness (29,37). Hence, a patient ingesting certain foods may experience no adverse effects, only to witness the appearance of a hypertensive response upon ingesting a tyramine-rich sample at a later time.

In addition to tyramine, hypertensive responses have been reported particularly with over-the-counter sympathomimetics such as ephedrine, pseudoephedrine and phenylpropanolamine, which are present in many decongestants and cough medicines (35). Hypertension also may arise when MAOIs are combined with L-dopa, methylphenidate, dextroamphetamine, reserpine, guanethidine, or tetrabenazine. Deprenyl, a specific MAO-B inhibitor at low doses (10 mg/day), can be administered safely with dietary tyramine, L-dopa, or L-dopa plus a decarboxylase inhibitor (94).

For clinicians, the differentiation of true hypertensive crises from rebound headaches caused by MAOI-induced postural hypotension is important in order to avoid unnecessary treatment of patients with agents normally used to lower blood pressure during a hypertensive crisis (e.g., nifedipine, a calcium channel blocker or phentolamine, an alpha adrenergic blocker).

Because tyramine competitively displaces moclobemide, brofaromine, and other RIMAs from their inhibiting site on MAO-A, the use of this newer generation of MAOIs promises greater safety. Because they are reversible, if the RIMAs must be stopped their clinical effect is reversed within 24–48 hours. Indeed, heavy oral loading with tyramine results in a 7–10-fold increase in pressor sensitivity for moclobemide and brofaromine, compared to 54-, 13-, and 5-fold increases for tranylcypromine, phenelzine and deprenyl, respectively (7,63).

Concurrent administration of an MAOI with agents that increase serotonin availability may, in rare instances, result in a specific toxic reaction termed the 'serotonin syndrome.' The serotonin syndrome is characterized by a constellation of at least three of the following symptoms present in the setting of a recent addition or increase in dosage of a serotonergic agent: mental status changes, agitation, myoclonus, hyperreflexia, fever, shivering, diaphoresis, ataxia and diarrhea (131,133). Hypertension need not occur. In rare, severe cases, a progression to seizures, hyperthermia (>40.5oC, 104oF), rhabdomyolysis, ventricular arrhythmia, respiratory arrest and death can be seen.

Most case reports of the serotonin syndrome have come from patients who received a simultaneous combination of an MAOI with a specific serotonin reuptake inhibitor (SSRI) or tricyclic antidepressant (TCA). The combination of inhibition of MAO with inhibition of reuptake may result in a flood of 5-HT and NE into the synapse, exceeding its capacity for enzymatic catabolism. The only effective route of catabolism for excess 5-HT is through MAO; catecholamines, on the other hand, can be catabolized also by catechol-o-methyl transferase (COMT). Thus, when combined with inhibition of MAO, the blockade of 5-HT reuptake may have greater potential for CNS toxicity than the blockade of catecholamine reuptake. Accentuation of serotonergic neurotransmission has been implicated in this syndrome, possibly as a result of activation or modification of the 5-HT1A receptor in the brainstem and spinal cord. The importance of 5-HT in the serotonin syndrome is underscored by the fact that in animals this syndrome can be blocked by pretreatment with p-chlorophenylalanine, an inhibitor of 5-HT synthesis, and by methysergide, a 5-HT receptor antagonist.

Toxicity is seen more often when TCAs and SSRIs are added to MAOIs rather than vice versa, although reactions may occur at any time, as well as when switching between MAOIs. To avoid potentiation, most manufacturers recommend a drug-free period when switching a patient either from a TCA or SSRI to an MAOI or vice versa. The duration of this drug free period is determined by considerations of the half-life of the drug and how long it takes the body to regenerate an adequate supply of the enzyme. Thus, 4–5 weeks are recommended when initiating an MAOI in a patient who previously received fluoxetine. The active metabolite of fluoxetine, norfluoxetine, has a half-life of seven days. For other SSRIs or TCAs with shorter half lives, a 1–2 week washout may be adequate.

Concomitant administration of TCAs and MAOIs has been safely used in the past. At present, however, there is insufficient evidence documenting a clear clinical advantage of combining these drugs over using them separately to justify the additional risk. TCA/MAOI or SSRI/MAOI combinations are not recommended, except in severely refractory patients in a monitored inpatient setting. Although the RIMAs may present a lower risk, moclobemide has been implicated in eliciting the serotonin syndrome in two patients receiving concomitant TCAs, as well as in patients receiving SSRIs (16,96,130). Selegiline in rare instances has been reported to cause the serotonin syndrome in combination with SSRIs (66,134). In subjects receiving serotonergic agents, caution is advised in dispensing doses of selegiline greater than 10 mg/day, above which it begins to lose its selectivity for MAO-B.

Other agents with serotonin-potentiating properties have been implicated, as well, in the serotonin syndrome, including meperidine, other phenyl-piperidine analgesics, pentazocine, dextromethorphan, buspirone, clomipramine, lithium, tryptophan, fenfluramine, and methylenedioxymethamphetamine (MDMA, 'ecstasy'). Administration of meperidine to a patient receiving MAOIs is absolutely contraindicated. Plant-derived narcotics such as codeine or morphine may elicit fewer adverse reactions than meperidine and may be initiated if agents such as acetaminophen, aspirin or nonsteroidal anti-inflammatory drugs fail. Dosage reduction of these narcotics is advisable, since MAOIs often magnify their effects, including analgesia.

Most cases of the serotonin syndrome are mild and resolve within 6–24 hours. Nevertheless, hospitalization of the patient for observation is prudent. Optimal treatment generally is conservative and entails discontinuation of the suspected medication and providing supportive measures when necessary. Hyperreflexia and myoclonus may respond to benzodiazepines and possibly propranolol. Patients who develop hyperthermia unresponsive to acetaminophen should be treated aggressively with external cooling and paralysis, which may diminish the risk of complications (rhabdomyolysis and disseminated intravascular coagulation) developing later. Other agents, such as methysergide and cyproheptadine, both nonspecific 5-HT1 and 5-HT2 receptor antagonists, are useful adjuncts in treating the serotonin syndrome.

Other side effects have been reported, including dizziness (often, though not always, related to orthostatic hypotension), headaches, inhibition of ejaculation, and skin rashes (Table 4). Difficulty in urination, weakness, fatigue, dry mouth, blurred vision and constipation can be observed, but the cause is unknown. Phenelzine seems especially likely to cause such effects, particularly at higher doses, even though significant antimuscarinic activity has not been detected in vitro.

In contrast, the RIMAs moclobemide and brofaromine have few interactions with a number of neurotransmitter receptors, including a-adrenergic, serotonergic, dopaminergic, histaminergic, cholinergic, opioid and GABAergic receptors. Moclobemide lacks the anticholinergic and sedative effects associated with the TCAs, making it a particularly useful option in the elderly. Compared with the SSRIs, moclobemide has a similar overall tolerability, although it tends to cause fewer gastrointestinal effects and has not been reported to interfere with sexual function.

Both the irreversible MAOIs and the RIMAs rarely cause cardiac effects and at therapeutic doses have little effect on seizure threshold. Hepatotoxicity (e.g., progressive, necrotizing, hepatocellular damage) has occurred in some patients receiving MAOIs of the hydrazine type (e.g., phenelzine) making it advisable to check liver function periodically in patients receiving high doses and in those receiving prolonged therapy with these drugs. Risk of hepatotoxicity with the non-hydrazine MAOIs (e.g., tranylcypromine, pargyline, selegiline) and the RIMAs (e.g., moclobemide, brofaromine) is absent or minimal.

If an MAOI is discontinued abruptly rather than in progressive steps symptoms of agitation, irritability, pressured speech, insomnia or drowsiness, psychosis and delirium may result (125,141). Overlap of these symptoms with those seen in amphetamine withdrawal suggests that the downregulation of sympathomimetic autoreceptors may be responsible (141).

Controlled trials of patients with endogenous depression receiving therapeutic doses of MAOIs for a minimum duration of four weeks in an outpatient setting demonstrated a response rate of 70%, an efficacy similar to that of heterocyclic antidepressants (31,50,71). In the treatment of severely depressed hospital inpatients, evidence to date most strongly supports tranylcypromine, whose efficacy appears comparable to that of electroconvulsive treatment, imipramine and amitriptyline (111!popup(ch46ref111)). Phenelzine appears efficacious, as well, provided it is given at adequate doses for a minimum of four weeks (15,32). Few controlled studies have examined the treatment response in patients previously refractory to TCAs, although treatment responses of approximately 50% have been reported with MAOI monotherapy (90,97). MAOIs, like TCAs, are effective in preventing relapse (49,114). Continuation and maintenance doses should be kept at acute dosing levels for a minimum of four months, with longer term prophylaxis for those with more frequent recurrence of their illness.

Recent trials show the RIMAs to be effective in the treatment of patients with endogenous depression (27,81). Moclobemide and brofaromine have demonstrated efficacy equivalent to amitriptyline, imipramine, clomipramine and fluvoxamine (2,14,57,147). Long-term studies have demonstrated that moclobemide maintains its antidepressant activity for 6–12 months. Moclobemide, given alone or in combination with another antidepressant, is effective in elderly patients and in patients with refractory depression (95,116,132). Absence of diet restrictions, a lesser degree of medication interactions, greater tolerability and improved safety in overdose should allow greater applicability of the RIMAs, compared with the conventional MAOIs, in the treatment of depressive disorders.

Another subtype of depressive disorder has been referred to as 'nonendogenous,' 'neurotic,' or 'atypical.' These patients often report symptoms opposite to those encountered in a typical endogenous depression. While the depressed mood in patients with 'endogenous' depression is largely unresponsive to external influences, 'atypical' depression may show temporary improvement to a euthymic state in response to positive environmental events ('mood reactivity'). 'Atypical' depressions may be precipitated by interpersonal or social rejection ('rejection sensitivity'), and patients may report hypersomnia and hyperphagia rather than the insomnia and anorexia seen in 'endogenous' depression. In the past, the hydrazine MAOIs have become more associated with the treatment of atypical depressive syndromes, characterized by prominent anxiety, including panic. The non-hydrazine MAOIs, because of their amphetamine-like, energizing properties, are more frequently recommended in atypical depressions characterized by reversed vegetative signs (e.g., hyperphagia, hypersomnia). Though past studies have supported a role for MAOIs in the treatment of atypical depression (85,108), further work is needed to assess whether MAOIs (hydrazine or non-hydrazine) or the RIMAs have greater specificity for various subtypes of depression.

It appears that inhibition of MAO-A activity is required for antidepressant effect, insofar as studies with deprenyl suggest that it is an inferior antidepressant at selective dosages. Nevertheless, inhibition of MAO-B activity on platelets correlates with treatment response. This correlation has been studied principally with phenelzine. Maximal platelet MAO inhibition reportedly occurs within 2–4 weeks of starting treatment (48,115). Both MAO-B inhibition and treatment response are dose-dependent, with the best responses in patients who demonstrate greater than 80% inhibition. MAO-B activity in platelets correlates poorly with MAO-B and MAO-A activities in cerebral cortex (160), suggesting that inhibition of MAO in platelets may simply reflect drug absorption or drug compliance. Successful inhibition by itself does not guarantee successful treatment of depression, and the best predictor of response remains dose and duration of treatment.

MAOIs have prominent effects on sleep and sleep architecture, including a decrease in total sleep time and suppression of REM (rapid eye movement) sleep. The occurrence of REM sleep suppression has been associated temporally with an improvement in mood (39). In fact, REM suppression is a property shared by most effective antidepressants, including TCAs, lithium, and serotonin reuptake inhibitors. The extent to which the REM suppression caused by MAOIs contributes to the antidepressant effect itself remains unclear (42). Tentatively, both changes in sleep patterns and antidepressant responses have been linked to alterations in 5-HT regulation. Of the RIMAs, brofaromine has similar effects on sleep as the irreversible agents, whereas moclobemide does not have a striking REM sleep suppressant effect (42,109).

Past studies have demonstrated the efficacy of MAOIs in panic disorder with and without agoraphobia, as well as in other phobic states. Open trials and placebo-controlled studies revealed a high efficacy for phenelzine in the treatment of panic symptoms, although residual phobic anxiety and avoidance may remain in 25–40% of subjects and require additional behavior therapy (18,124,144). There is some evidence that MAOIs may be more efficacious than TCAs in patients with panic attacks (124), particularly if these are found in association with a depressive syndrome (30,71,85). Recent trials using the safer and better tolerated RIMAs suggest an efficacy of brofaromine and moclobemide comparable to that of phenelzine or clomipramine (3,143,146).

In the treatment of social phobia, characterized by an exaggerated fear of exposing oneself to the scrutiny of others, the response rate of phenelzine is 60–70% (142,145). Moclobemide has similar efficacy (146). The phenelzine response is superior to that of atenolol or placebo at eight and 16 weeks (86).

The biological mechanism of antipanic and antiphobic action remains unclear. MAOIs have potent effects on noradrenergic as well as serotonergic function, both of which have been implicated in the etiology of panic symptoms (21,98,135). In support of an antipanic effect mediated by noradrenergic mechanisms, MAOIs have been shown to diminish the output of central and peripheral noradrenergic metabolites. MAOIs downregulate b1, a1 and a2 receptors and suppress neuronal firing in the locus coeruleus (21,93). In support of a serotonergic mechanism of an antipanic effect, MAOIs have been shown to increase brain 5-HT levels (12), decrease cerebrospinal fluid (CSF) levels of 5-hydroxyindoleacetic acid (5-HIAA), downregulate 5-HT1 and 5-HT2 receptors, and decrease the firing rate of serotonergic neurons in the raphe nucleus (93). To what extent these observations are mere associations versus direct causations of the antipanic effects of MAOIs remains to be clarified.

The apparent advantage of MAOIs over TCAs in the treatment of panic and phobic symptoms has prompted speculation that anxiolysis may be related to differences in the pharmacological effects of these agents. Antipanic and antiphobic effects have been linked to changes in dopaminergic function, insofar as administration of MAOIs results in a moderate reduction of dopamine metabolites, whereas TCAs have little or no effect (64). Others have suggested that the antipanic effects may be linked to changes in PEA, whose levels are sensitive to the nonspecific MAOIs but not the TCAs (85)). Alternatively, the ability of phenelzine to increase brain levels of g-aminobutyric acid (GABA) may contribute to the anxiolytic effects of the MAOIs (1). More research is needed to evaluate these hypotheses.

Buchsbaum et al. proposed 20 years ago that reduced MAO levels, reported previously in patients with affective disorders and chronic schizophrenia, may predict a vulnerability to psychiatric disorder (17). These individuals show a tendency to demonstrate personality traits that increase their vulnerability to, for example, drug-abuse and social maladaptation (102). Since that time, the relationship between low levels of platelet MAO and personality characteristics such as sensation-seeking, impulsiveness, monotony avoidance and aggression has been repeatedly demonstrated in both human and animal studies. Alcoholics, particularly alcoholics with a strongly inherited disposition (type 2), have low platelet MAO, as well as sensation seeking-related personality traits (100,157). This finding has been confirmed and extended by Devor et al., who reported low platelet MAO activity in first-order relatives of alcoholics (33). It must be noted, however, that complete inhibition of MAO-B with deprenyl does not result in significant personality changes. This observation highlights the complexity of the perhaps multiple physiologic parameters that underlie the personality characteristics associated with low platelet MAO activity.

Human brain MAO-B activity is increased in a number of brain degenerative disorders such as Parkinson's disease (PD) [121], Alzheimer's disease (AD) [68,120] and Huntington's disease (HD) [89]. The extent to which these changes reflect increased gliosis, gene regulation or the influence of other, possibly hormonal, factors is unclear.

Deprenyl was first introduced in the treatment of PD by Birkmayer (9). Patients with PD show motor impairment resulting from the dramatic loss of dopaminergic neurons in the pars compacta of the substantia nigra. Birkmayer posited that inhibition of MAO-B in these patients would slow the catabolism of DA and thus improve their symptoms. Indeed, deprenyl at a dosage of 10 mg/day did potentiate the effects of L-dopa, although the symptomatic relief decrease after one or two years. Because of its effectiveness and relative lack of side effects, deprenyl has become widely prescribed to PD patients.

Subsequently, in a retrospective, unblinded study, Birkmayer found that Parkinson's disease patients receiving combinations of deprenyl 10 mg/day and L-dopa lived longer than those who did not receive deprenyl (8). This implied that deprenyl delayed the progression of PD and supported earlier findings by Knoll, who demonstrated that deprenyl extended the life span of laboratory rats by about 50% (73). Findings from Birkmayer's study were greeted initially with skepticism but were reexamined when it was discovered that deprenyl, by inhibiting MAO-B, prevented the development of MPTP-induced parkinsonism (26,60).

It had been known since the 1950s that MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) could produce toxic, parkinsonian-like symptoms in monkeys. Interest in MPTP was rekindled by case reports of parkinsonian symptoms seen in drug addicts after their self-administration of MPTP, an accidental by-product of the black market synthesis of the pain-killer meperidine (80). Later it was noted that the neurotoxicity of MPTP appears to depend on its deamination to MPP+ (1-methyl-4-phenylpyridinium) by MAO-B. MPP+ enters the dopaminergic neuron via the nerve terminal uptake carrier, damaging the neuron by inhibiting cellular respiration, probably at the level of NADH CoQ1 reductase (complex I) in the respiratory chain (110). Neurotoxicity can be dramatically attenuated by specific inhibition of MAO-B with deprenyl, whereas specific inhibitors of MAO-A show little effect (60). Likewise, transgenic mice lacking the gene for MAO-B appear resistant to MPTP toxicity (55).

Two prospective studies reexamined the clinical utility of deprenyl in newly diagnosed PD patients not yet receiving L-dopa (103,138). Indeed, patients receiving deprenyl at 10 mg/day showed a significant delay in the rate of symptom development and the need for treatment with L-dopa, compared with patients receiving placebo. Several other studies followed examining the role of deprenyl as monotherapy in PD. The large, multicenter DATATOP study of 800 patients with PD showed that deprenyl significantly delayed the development of disability, compared with results in the placebo and antioxidant a-tocopherol (vitamin E; 104) groups (Figure 2).  Recent evidence, however, suggests that these improvements may not be sustained at long term follow-up (105).

The current concept of the importance of MAO in the development of neurodegenerative disease includes not only its putative role in converting an exogenous protoxin to a toxin but also its role in the formation of peroxides generated from the oxidative metabolism of DA. The catabolism of biogenic amines by MAO produces hydrogen peroxide. Hydrogen peroxide, unless it is detoxified by glutathione peroxidase, can be converted by iron-mediated Fenton reactions to toxic hydroxyl radicals ( ·OH) that induce lipid peroxidation and cell death. Consistent with this hypothesis are findings of increased levels of basal lipid peroxidation, MAO-B, ferritin, and iron (III), as well as decreased levels of reduced glutathione, in the substantia nigra of PD subjects (34,112,129). Recent evidence suggests that hereditary variation, particularly of MAO-A haplotypes, may be one of the factors that influence the susceptibility of individuals to PD (62).

Considerable uncertainty remains regarding whether improvements observed with deprenyl in clinical trials are due to symptomatic or protective mechanisms. Symptomatic effects of deprenyl might be the result of an increase either of striatal DA or of deprenyl's amphetamine metabolite. In addition, symptomatic relief might result from an unsuspected antidepressant effect or from dopaminergic modulation due to increases in the trace amine PEA. Alternatively, deprenyl may engender a neuroprotective effect by inhibiting the oxidation of a putative protoxin, or by interfering with the production of free radicals generated during the catabolism of biogenic amines. Analyses of deprenyl wash-in and wash-out indicate that the drug has a symptomatic effect that is more pronounced than previously appreciated. Furthermore, a survival curve similar to that observed with deprenyl can also be obtained by modeling a theoretical drug whose effects are mediated through alleviation of symptoms rather than neuroprotection (123). Deprenyl, however, appears to be able to delay the appearance of disability independent of whether a symptomatic effect was experienced initially. These observations raise the possibility that additional neuroprotective mechanisms may exist. This is supported by an autopsy study showing that the number of medial nigral neurons is greater and the number of Lewy bodies is fewer in PD patients who have been treated with selegiline in combination with L-dopa, compared with patients who received L-dopa alone (113).

Recent studies suggest that deprenyl might prevent or reverse neuronal destruction in nondopaminergic neurons through 'neurotrophic-like' mechanisms unrelated to its MAO inhibitory activity (137). Further work is needed to evaluate this third hypothesis.

Patients with AD show an increase in brain MAO-B levels above those observed as a result of normal aging. Increases up to 3-fold are seen in temporal, frontal, and parietal cortex, with overall increases greater in white than in grey matter (68,120). A number of short-term clinical trials have found that 10 mg/day of deprenyl improved performance of AD subjects on selected neuropsychological tests (19,41, 52,87,92,122,136). Additionally, behavioral improvements have been noted, as well as improvements on neuropsychological scales of mood, anxiety, physical tension, and agitation.

Whether symptomatic or neuroprotective mechanisms are responsible for these effects remains unclear. One explanation posits an improvement in attention span or mood in these patients resulting from increases in catecholamine levels or the presence of an amphetamine metabolite. However, dosages of deprenyl selective for MAO-B inhibition produced only small increases in levels of homovanillic acid (HVA) and no changes in NE or other monoamines in cerebrospinal fluid. Furthermore, (-) methamphetamine and (-) amphetamine, both metabolites of deprenyl (70), are only weakly active, and a 10-mg/day dose of deprenyl is felt to provide insufficient levels of these to account for improvements noted in attention or mood. The role of elevated levels of trace amines such as PEA, which may function to indirectly facilitate activation of striatal DA receptors remains unclear. Other hypotheses proposed that deprenyl prevents neuronal oxidative damage through inhibition of the production of oxidative radicals or by increasing tissue concentrations of the free radical scavenger enzymes, such as superoxide dismutase or catalase (117).

Recently, the efficacy of selegiline and a-tocopherol has been evaluated in a double-blind, placebo-controlled, randomized trial evaluating the rate of disease progression in patients with AD of moderate severity (118). In this study, selegiline appeared to slow the progression of disease over a two-year period, as measured by a composite score reflecting four different markers: death, institutionalization, loss of the ability to perform at least two of three basic activities of daily living, or an increase of a grade in the Clinical Dementia Rating. Subjects treated with either selegiline, a-tocopherol, or combination treatment reached the measured functional endpoint an average of 3–4 months later than those treated with placebo. Significance, however, was achieved only after statistical adjustment for differences in base-line scores on the Mini-Mental State Examination. Of note, selegiline showed no effect on MMSE scores. The authors point out that an outcome of improved function despite the absence of improved cognition raises the possibility that the effects observed may be a nonspecific health benefit attributable to antioxidants rather than an effect on the underlying disease process of AD itself. How well this study's composite end point reflects the degenerative process in Alzheimer's disease remains an issue of controversy.

Subjects with AD have significantly increased platelet MAO-B, compared with age-matched controls. An association has been found between MAO-B measured in platelets and severity of dementia, measured by Folstein score (MMSE), in patients with nonfamilial AD. Although the deduced amino acid sequences of human platelet and frontal cortex monoamine oxidase B are identical (23), the relationship of peripheral measures of MAO to central measures remains to be clarified. Because of the wide variability in platelet MAO levels, differences measured between groups of AD subjects and elderly controls cannot be used for diagnosis of individual patients.

Current research on MAO is proceeding on several exciting frontiers. The question of whether MAOIs, particularly the newer generation of RIMAs, have greater specificity for subtypes of mood or anxiety disorders has not yet been answered decisively. Double-blind, placebo-controlled studies will need to examine potential clinical applications of the MAOIs in disorders such as post-traumatic stress disorder, attention deficit disorder, bulimia, borderline personality disorder, as well as migraine headaches—in which preliminary reports have suggested efficacy (47,91,106,139,150). Further work is needed to characterize the role deprenyl should play in the treatment of neurodegenerative diseases such as PD, AD, HD and vascular dementia. Clarification is needed specifically concerning the extent to which deprenyl's actions are attributable to symptomatic versus neuroprotective/neurotrophic mechanisms.

Recent evidence has shown a decrease in the activities of both forms of MAO in heavy dependent smokers. Decreases have been reported in platelet MAO-B activity and plasma concentrations of catecholamine metabolites (6), as well as in brain MAO, by PET using radiolabeled [11C]iodoclorgyline or [11C] deuterium-deprenyl (45,46). An initial, double-blind, placebo-controlled trial suggested that moclobemide may facilitate smoking cessation in heavy smokers (5). Because of the strong association between depression and smoking, it has been suggested that some smokers may use their habit to self-medicate themselves for depression. Further investigations regarding this hypothesis, as well as the importance of the RIMAs in the treatment of smoking cessation, are needed.

Radionuclide-labeled MAOIs such as [125I]-iodoclorgyline or [11C]-deuterium-deprenyl may serve as useful radiopharmaceuticals for the in vivo quantitative analysis of MAO in brain using single photon emission computed tomography (SPECT) or PET (61). PET studies with [11C]-deuterium-deprenyl have begun to show promise in the differentiation of pituitary adenomas from meningiomas based on their different levels of MAO-B (4). Furthermore, the increased concentration of MAO-B found in glial cells may allow [11C]-deuterium-deprenyl PET imaging to become a useful tool for identifying areas of local gliosis that are associated with epileptogenic foci in certain seizure disorders (77).

Recombinant DNA technology has greatly furthered the study of the structure and functional relationships of MAO-A and -B in recent years. The active sites and the domains conferring substrate and inhibitor selectivity can be delineated if large quantities of solubilized pure enzymes can be obtained and their structures elucidated by X-ray crystallography. Such structural information will be essential for designing MAO-A and -B specific inhibitors which may act as antidepressants with fewer side effects.

Knowledge concerning the promoters which regulate the expression of MAO-A and -B genes is in its infancy. The variation in cis-elements and transcriptional factors may explain some of the large variation in MAO activity in human subjects. Mutations in the promoters may be linked to psychiatric and neurodegenerative diseases. This area has not yet been explored. MAO-A and -B are key isoenzymes that degrade 5-HT, DA, NE, and PEA. MAO-A knock-out mice show increased levels of 5-HT, DA and NE, as well as aggressive behavior. These mice represent an animal model to study the molecular mechanisms of aggression and may help us develop novel drugs for the treatment of aggressive behavior. It is exciting that with tissue-specific, gene knock-out techniques, it is now possible to delete the MAO-A and -B genes within specific brain regions instead of in the whole animal. Such techniques should help us understand the in vivo role of monoamine neurotransmitters in specific brain areas, as well as their roles in behavior. This will provide fundamental information for developing new drugs targeted to specific brain regions, a process that may reduce unwanted side effects.

This work was supported by a Mentored Clinical Science Development Program Award K12-AG-00521 (Dr. Holschneider), a Merit Award R37 NH39085 (Dr. Shih), a Research Scientist Award K05 MH 00796 and R01 MH 37020 from the National Institute of Mental Health (Dr. Shih). Support from the Boyd and Elsie Welin Professorship (Dr. Shih) is also greatly appreciated.

published 2000