Monoamine Oxidase in Neuropsychiatry and Behavior
1999; Elsevier BV; Volume: 65; Issue: 3 Linguagem: Inglês
10.1086/302562
ISSN1537-6605
Autores Tópico(s)Parkinson's Disease Mechanisms and Treatments
ResumoMonoamine oxidase (MAO) catalyzes the oxidative deamination of a number of biogenic amines, including the key neurotransmitters serotonin (5-HT), norepinephrine (NE), and dopamine (DA) and the neuromodulator phenylethylamine (PEA). Two forms of MAO, designated "MAO A" and "MAO B," have been identified on the basis of biochemical properties and, subsequently, by cloning the relevant genes. Of the two, MAO A exhibits a higher affinity for 5-HT and NE and for the inhibitor clorgyline (Johnston Johnston, 1968Johnston JP Some observations upon a new inhibitor of monoamine oxidase in brain tissue.Biochem Pharmacol. 1968; 17: 1285-1297Crossref PubMed Scopus (1417) Google Scholar), whereas MAO B has a higher affinity for PEA, benzylamine, and the inhibitor deprenyl (Knoll and Magyar Knoll and Magyar, 1972Knoll J Magyar K Some puzzling pharmacological effects of monoamine oxidase inhibitors.Adv Biochem Psychopharmacol. 1972; 5: 393-408PubMed Google Scholar). DA is a substrate for both MAO A and MAO B. Although most tissues express both isoenzymes, human placenta and fibroblasts express predominantly MAO A, and platelets and lymphocytes express only MAO B (for review, see Shih et al. Shih et al., 1999Shih JC Chen K Ridd MJ Monoamine oxidase: from genes to behavior.Annu Rev Neurosci. 1999; 22: 197-217Crossref PubMed Scopus (932) Google Scholar). The ability of the MAOs to catabolize neurotransmitters has made these enzymes attractive candidates in the study of neurological diseases and psychiatric and behavioral traits. Indeed, even before the genes for MAO A and B were cloned, the role of MAO B in psychiatric disorders was widely studied. Platelets, which are easily obtained and lack MAO A expression, were the cell type of choice for much of this work. Low platelet MAO B activity has been associated with bipolar disorder, suicidal behavior, and alcoholism (Devor et al. Devor et al., 1993Devor EJ Cloninger CR Hoffman PL Tabakoff B Association of monoamine oxidase (MAO) activity with alcoholism and alcoholic subjects.Am J Med Genet. 1993; 48: 209-213Crossref PubMed Scopus (59) Google Scholar), as well as with sensation seeking and poor impulse control (Oreland Oreland, 1993Oreland L Monoamine oxidase in neuropsychiatric disorders.in: Yasuhara H Parvez SH Sandler M Oguchi K Nagatsu T Monoamine oxidase: basic and clinical aspects. VSP Press, Utrecht1993: 219-247Google Scholar; Holschneider and Shih Holschneider and Shih, 1998Holschneider DP Shih JC Monoamine oxidase: basic and clinical perspectives.in: Bloom FE Kupfer D Psychopharmacology: the fourth generation of progress, CD ROM edition. Lippincott Williams & Wilkins, New York1998Google Scholar). However, much of this biochemical work may need to be revisited, given the recent finding that smoking inhibits both MAO A activity and MAO B activity (Fowler et al. Fowler et al., 1996aFowler JS Volkow ND Wang GJ Pappas N Logan J MacGregor R Alexoff D et al.Inhibition of monoamine oxidase B in the brains of smokers.Nature. 1996; 379: 733-736Crossref PubMed Scopus (565) Google Scholara, Fowler et al., 1996bFowler JS Volkow ND Wang GJ Pappas N Logan J Shea C Alexoff D et al.Brain monoamine oxidase A inhibition in cigarette smokers.Proc Natl Acad Sci USA. 1996; 93: 14065-14069Crossref PubMed Scopus (368) Google Scholarb). For instance, after correcting for the effect of smoking, Simpson et al. (Simpson et al., 1999Simpson GM Shih JC Chen K Flowers C Kumazawa T Spring B Schizophrenia, monoamine oxidase activity, and cigarette smoking.Neuropsychopharmacology. 1999; 20: 392-394Crossref PubMed Scopus (22) Google Scholar) determined that MAO B activity is not significantly reduced in schizophrenics. With the successful cloning of human liver MAO A and B, Bach et al. (Bach et al., 1988Bach AW Lan NC Johnson DL Abell CW Bembenek ME Kwan SW Seeburg PH et al.cDNA cloning of human liver monoamine oxidase A and B: molecular basis of differences in enzymatic properties.Proc Natl Acad Sci USA. 1988; 85: 4934-4938Crossref PubMed Scopus (668) Google Scholar) demonstrated that MAO A and B are distinct, but closely related, X-linked genes (Shih Shih, 1991Shih JC Molecular basis of human MAO A and B.Neuropsychopharmacology. 1991; 4: 1-7PubMed Google Scholar). The MAO A and MAO B genomic sequences (Grimsby et al. Grimsby et al., 1991Grimsby J Chen K Wang LJ Lan NC Shih JC Human monoamine oxidase A and B genes exhibit identical exon-intron organization.Proc Natl Acad Sci USA. 1991; 88: 3637-3641Crossref PubMed Scopus (221) Google Scholar; Chen et al. Chen et al., 1992Chen ZY Powell JF Hsu YP Breakefield XO Craig IW Organization of the human monoamine oxidase genes and long-range physical mapping around them.Genomics. 1992; 14: 75-82Crossref PubMed Scopus (61) Google Scholar) and promoters (Zhu et al. Zhu et al., 1992Zhu QS Grimsby J Chen K Shih JC Promoter organization and activity of human monoamine oxidase (MAO) A and B genes.J Neurosci. 1992; 12: 4437-4446Crossref PubMed Google Scholar; Zhu and Shih Zhu and Shih, 1997Zhu QS Shih JC An extensive repeat structure down-regulates human monoamine oxidase A promoter activity independent of an initiator-like sequence.J Neurochem. 1997; 69: 1368-1373Crossref PubMed Scopus (30) Google Scholar) have been studied extensively in the pursuit of polymorphisms that might show these genes to be associated with psychiatric disorders and behaviors. Perhaps the most intriguing finding to emerge to date implicates MAO A in the control of aggressive behavior in humans, a finding that we and our collaborators have pursued in a knockout-mouse model. The gene for Norrie disease (ND) and the genes MAOA and MAOB are arranged in tandem on human Xp11.2-11.4 (Chen et al. Chen et al., 1995Chen ZY Denney RM Breakefield XO Norrie disease and MAO genes: nearest neighbors.Hum Mol Genet. 1995; 4: 1729-1737Crossref PubMed Scopus (66) Google Scholar). Deletion of ND is sometimes accompanied by deletion of one or both of the MAO genes and causes congenital blindness due to the disrupted development and degeneration of the neuroretina (Berger et al. Berger et al., 1992Berger W Meindl A Van de Pol TJR Cremers FPM Ropers HH Doerner C Monaco A et al.Isolation of a candidate gene for Norrie disease by positional cloning.Nat Genet. 1992; 1: 199-203Crossref PubMed Scopus (193) Google Scholar). More than one-third of ND patients also develop progressive hearing loss and manifest mental retardation or psychoses (Sims et al. Sims et al., 1989Sims KB de la Chapelle A Norio R Sankila E-M Hsu Y-PP Rinehart WB Corey TJ et al.Monoamine oxidase deficiency in males with an X chromosome deletion.Neuron. 1989; 2: 1069-1076Abstract Full Text PDF PubMed Scopus (90) Google Scholar). Two such patients, studied in detail by Sims et al. (Sims et al., 1989Sims KB de la Chapelle A Norio R Sankila E-M Hsu Y-PP Rinehart WB Corey TJ et al.Monoamine oxidase deficiency in males with an X chromosome deletion.Neuron. 1989; 2: 1069-1076Abstract Full Text PDF PubMed Scopus (90) Google Scholar) and Lenders et al. (Lenders et al., 1996Lenders JW Eisenhofer G Abeling NGGM Berger W Murphy DL Konings CH Bleeker Wagemakers LM et al.Specific genetic deficiencies of the A and B isoenzymes of monoamine oxidase are characterized by distinct neurochemical and clinical phenotypes.J Clin Invest. 1996; 97: 1010-1019Crossref PubMed Scopus (127) Google Scholar), lack detectable MAO B activity in their platelets and do not express MAO A mRNA in their fibroblasts, and they show elevated plasma and urine levels of NE, DA, 5-HT, and PEA. Two brothers with a contiguous-gene deletion encompassing ND and MAO B show an increase in urinary PEA levels, but their levels of 5-HT, NE, and DA are normal (Lenders et al. Lenders et al., 1996Lenders JW Eisenhofer G Abeling NGGM Berger W Murphy DL Konings CH Bleeker Wagemakers LM et al.Specific genetic deficiencies of the A and B isoenzymes of monoamine oxidase are characterized by distinct neurochemical and clinical phenotypes.J Clin Invest. 1996; 97: 1010-1019Crossref PubMed Scopus (127) Google Scholar). These neurochemical changes are consistent with the findings in Maoa-knockout (Cases et al. Cases et al., 1995Cases O Seif I Grimsby J Gaspar P Chen K Pournin S Muller U et al.Aggressive behavior and altered amounts of brain serotonin and norepinephrine in mice lacking MAO A.Science. 1995; 268: 1763-1766Crossref PubMed Scopus (973) Google Scholar) and Maob-knockout (Grimsby et al. Grimsby et al., 1997Grimsby J Toth M Chen K Karoum F Klaidman L Adams J Gal J et al.Increased stress response and β-phenylethylamine in MAO B-deficient mice.Nat Genet. 1997; 17: 206-210Crossref PubMed Scopus (211) Google Scholar) mice. The clearest genetic evidence that the MAOs regulate human behavior comes from the work of Brunner et al. (Brunner et al., 1993aBrunner HG Nelen M Breakefield XO Ropers HH Van Oost BA Abnormal behavior associated with a point mutation in the structural gene for monoamine oxidase A.Science. 1993; 262: 578-580Crossref PubMed Scopus (1168) Google Scholara, Brunner et al., 1993bBrunner HG Nelen MR Van Zandvoort P Abeling NGGM Van Gennip AH Wolters EC Kuiper MA et al.X-linked borderline mental retardation with prominent behavioral disturbance: phenotype, genetic localization, and evidence for disturbed monoamine metabolism.Am J Hum Genet. 1993; 52: 1032-1039PubMed Google Scholarb), who studied a Dutch family in which eight males manifest a complex behavioral syndrome that includes borderline mental retardation and impulsive aggression. Sequencing of the MAOA gene showed, at position 936, a C→T mutation that introduces a premature-termination codon and that creates a null allele in the gene. Urine samples from these affected males showed decreased levels of 5-hydroxyindolecetic acid, homovanillic acid, and 3-methoxy-4-hydroxyphenylethyleneglycol (Brunner et al. Brunner et al., 1993aBrunner HG Nelen M Breakefield XO Ropers HH Van Oost BA Abnormal behavior associated with a point mutation in the structural gene for monoamine oxidase A.Science. 1993; 262: 578-580Crossref PubMed Scopus (1168) Google Scholara, Brunner et al., 1993bBrunner HG Nelen MR Van Zandvoort P Abeling NGGM Van Gennip AH Wolters EC Kuiper MA et al.X-linked borderline mental retardation with prominent behavioral disturbance: phenotype, genetic localization, and evidence for disturbed monoamine metabolism.Am J Hum Genet. 1993; 52: 1032-1039PubMed Google Scholarb), which are the degradation products of 5-HT, DA, and NE, respectively. Further studies are required to establish the frequency of this mutation in humans, but urine analysis of 119 inmates from a prison in Taiwan showed no evidence for altered monoamine metabolism, suggesting MAO A deficiency (H. M. Hwang and J. C. Shih, unpublished data). The aggressive behavior seen in men lacking MAO A may, however, be unrelated to this genetic defect; environmental substances, stress, drugs, or, perhaps, other genetic factors in this family may increase the susceptibility of these men to aggression. However, as discussed below, the relationship between MAO A deficiency and aggression has also been confirmed in studies of MAO A–deficient mice. The MAOA and MAOB sequences have been scrutinized for the existence of polymorphisms that might be associated with other psychiatric phenotypes. Table 1 describes the MAOA polymorphisms that have been reported to be associated with such behavioral phenotypes as aggression and substance abuse (see Reich et al. Reich et al., 1999Reich T Hinrichs A Culverhouse R Bierut L Genetic studies of alcoholism and substance dependence.Am J Hum Genet. 1999; 65: 599-605Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar [in this issue]), as well as affective disorders, such as bipolar and panic disorder. As is common in such studies (see O'Donovan and Owens O'Donovan and Owens, 1999O'Donovan MC Owens MJ Candidate-gene association studies of schizophrenia.Am J Hum Genet. 1999; 65: 587-592Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar [in this issue]), associations with these phenotypes prove difficult to replicate, and both confirmatory and negative findings are presented in the table. Polymorphisms in the MAOB gene have also been identified, but no behavioral or psychiatric phenotypes have yet been associated with these variants. Most of the known MAOA polymorphisms either affect intronic sequences or introduce a silent change in the open-reading-frame polymorphisms (i.e., the EcoRV and Fnu4HI polymorphisms); these variants are unlikely to affect MAO function, although they may be in disequilibrium with other, as yet unidentified, functional variants. Recently, however, a VNTR polymorphism that affects transcriptional activity has been found in the MAOA-gene promoter (Zhu et al. Zhu et al., 1992Zhu QS Grimsby J Chen K Shih JC Promoter organization and activity of human monoamine oxidase (MAO) A and B genes.J Neurosci. 1992; 12: 4437-4446Crossref PubMed Google Scholar, Zhu et al., 1994Zhu QS Chen K Shih JC Bidirectional promoter of human monoamine oxidase A (MAO A) controlled by transcription factor Sp1.J Neurosci. 1994; 14: 7393-7403Crossref PubMed Google Scholar; Sabol et al. Sabol et al., 1998Sabol SZ Hu S Hamer D A functional polymorphism in the monoamine oxidase A gene promoter.Hum Genet. 1998; 103: 273-279Crossref PubMed Scopus (871) Google Scholar). This variant, which is associated with lower levels of MAO A activity, occurs with a higher-than-normal frequency in patients with panic disorder (Deckert et al. Deckert et al., 1999Deckert J Catalano M Syagailo YV Bosi M Okladnova O Di Bella D Nothen MM et al.Excess of high activity monoamine oxidase A gene promoter alleles in female patients with panic disorder.Hum Mol Genet. 1999; 8: 621-624Crossref PubMed Scopus (509) Google Scholar) but never occurs in patients with antisocial personality disorder (Lu et al. Lu et al., 1999Lu R-B, Lee J-F, Ko H-C, Shih JC (1999) No association of MAOA gene with antisocial personality disorder. Paper presented at the 1999 World Congress on Psychiatric Genetics, Monterey, CA, October 14-18Google Scholar).Table 1Polymorphisms of the MAO A Gene which May Be Associated with Psychiatric Disorders and BehaviorsPolymorphismDisorder/BehaviorAssociationReference(s)23-bp VNTR in intron 1Tourette syndrome and drug abuseYesGade et al. (Gade et al., 1998Gade R Muhleman D Blake H MacMurray J Johnson P Verde R Saucier G et al.Correlation of the length of VNTR alleles at the X-linked MAO A gene and phenotypic effect in Tourette syndrome and drug abuse.Mol Psychiatry. 1998; 3: 50-60Crossref PubMed Scopus (62) Google Scholar)Bipolar disorderNoCraddock et al. (Craddock et al., 1995Craddock N Daniels J Roberts E Rees M McGuffin P Owen MJ No evidence for allelic association between bipolar disorder and monoamine oxidase A gene polymorphisms.Am J Med Genet. 1995; 60: 322-324Crossref PubMed Scopus (61) Google Scholar); Lim et al. (Lim et al., 1995Lim LC Powell J Sham P Castle D Hunt N Murray R Gill M Evidence for a genetic association between alleles of monoamine oxidase A gene and bipolar affective disorder.Am J Med Genet. 1995; 60: 325-341Crossref PubMed Scopus (83) Google Scholar); Muramatsu et al. (Muramatsu et al., 1997Muramatsu T Matsushita S Kanba S Higuchi S Manki H Suzuki E Asai M Monoamine oxidase genes polymorphisms and mood disorder.Am J Med Genet. 1997; 74: 494-496Crossref PubMed Scopus (36) Google Scholar)(GT)n repeat in intron 2Bipolar disorderYesLim et al. (Lim et al., 1995Lim LC Powell J Sham P Castle D Hunt N Murray R Gill M Evidence for a genetic association between alleles of monoamine oxidase A gene and bipolar affective disorder.Am J Med Genet. 1995; 60: 325-341Crossref PubMed Scopus (83) Google Scholar)Bipolar disorderNoCraddock et al. (Craddock et al., 1995Craddock N Daniels J Roberts E Rees M McGuffin P Owen MJ No evidence for allelic association between bipolar disorder and monoamine oxidase A gene polymorphisms.Am J Med Genet. 1995; 60: 322-324Crossref PubMed Scopus (61) Google Scholar); Muramatsu et al. (Muramatsu et al., 1997Muramatsu T Matsushita S Kanba S Higuchi S Manki H Suzuki E Asai M Monoamine oxidase genes polymorphisms and mood disorder.Am J Med Genet. 1997; 74: 494-496Crossref PubMed Scopus (36) Google Scholar); Parsian and Todd (Parsian and Todd, 1997Parsian A Todd RD Genetic association between monoamine oxidase and manic-depressive illness: comparison of relative risk and haplotype risk data.Am J Med Genet. 1997; 74: 475-479Crossref PubMed Scopus (38) Google Scholar)AlcoholismYesParsian et al. (Parsian et al., 1995Parsian A Suarez BK Tabakoff B Ovchinnikova L Fisher L Cloninger CR Monoamine oxidases and alcoholism. I. Studies in unrelated alcoholics and normal controls.Am J Med Genet. 1995; 60: 409-416Crossref PubMed Scopus (42) Google Scholar); Vanyukov et al. (Vanyukov et al., 1995Vanyukov MM Moss HB Yu LM Deka R A dinucleotide repeat polymorphism at the gene for monoamine oxidase A and measures of aggressiveness.Psychiatry Res. 1995; 59: 35-41Abstract Full Text PDF PubMed Scopus (23) Google Scholar); Hsu et al. (Hsu et al., 1996Hsu Y-PP Loh EW Chen WJ Chen C-C Yu J-M Cheng ATA Association of monoamine oxidase A alleles with alcoholism among male Chinese in Taiwan.Am J Psychiatry. 1996; 153: 1209-1211PubMed Google Scholar)AggressionNoVanyukov et al. (Vanyukov et al., 1995Vanyukov MM Moss HB Yu LM Deka R A dinucleotide repeat polymorphism at the gene for monoamine oxidase A and measures of aggressiveness.Psychiatry Res. 1995; 59: 35-41Abstract Full Text PDF PubMed Scopus (23) Google Scholar)C→T mutation in exon 8AggressionYesBrunner et al. (Brunner et al., 1993aBrunner HG Nelen M Breakefield XO Ropers HH Van Oost BA Abnormal behavior associated with a point mutation in the structural gene for monoamine oxidase A.Science. 1993; 262: 578-580Crossref PubMed Scopus (1168) Google Scholara)Fnu4HI-RFLP in exon 8Bipolar disorderNoCraddock et al. (Craddock et al., 1995Craddock N Daniels J Roberts E Rees M McGuffin P Owen MJ No evidence for allelic association between bipolar disorder and monoamine oxidase A gene polymorphisms.Am J Med Genet. 1995; 60: 322-324Crossref PubMed Scopus (61) Google Scholar); Lim et al. (Lim et al., 1995Lim LC Powell J Sham P Castle D Hunt N Murray R Gill M Evidence for a genetic association between alleles of monoamine oxidase A gene and bipolar affective disorder.Am J Med Genet. 1995; 60: 325-341Crossref PubMed Scopus (83) Google Scholar); Muramatsu et al. (Muramatsu et al., 1997Muramatsu T Matsushita S Kanba S Higuchi S Manki H Suzuki E Asai M Monoamine oxidase genes polymorphisms and mood disorder.Am J Med Genet. 1997; 74: 494-496Crossref PubMed Scopus (36) Google Scholar)AlcoholismNoHsu et al. (Hsu et al., 1996Hsu Y-PP Loh EW Chen WJ Chen C-C Yu J-M Cheng ATA Association of monoamine oxidase A alleles with alcoholism among male Chinese in Taiwan.Am J Psychiatry. 1996; 153: 1209-1211PubMed Google Scholar)EcoRV polymorphism in exon 14Obsessive-compulsive disorderYesCamarena et al. (Camarena et al., 1998Camarena B Cruz C de la Fuente JR Nicolini H A higher frequency of a low activity-related allele of the MAO-A gene in females with obsessive-compulsive disorder.Psychiatr Genet. 1998; 8: 255-257Crossref PubMed Scopus (41) Google Scholar)Antisocial personality disorderNoLu et al. (Lu et al., 1999Lu R-B, Lee J-F, Ko H-C, Shih JC (1999) No association of MAOA gene with antisocial personality disorder. Paper presented at the 1999 World Congress on Psychiatric Genetics, Monterey, CA, October 14-18Google Scholar)SchizophreniaNoCoron et al. (Coron et al., 1996Coron B Campion D Thibaut F Dollfus S Preterre P Langlois S Vasse T et al.Association study between schizophrenia and monoamine oxidase A and B DNA polymorphisms.Psychiatry Res. 1996; 62: 221-226Abstract Full Text PDF PubMed Scopus (25) Google Scholar)VNTR in the promoterPanic disorderYesDeckert et al. (Deckert et al., 1999Deckert J Catalano M Syagailo YV Bosi M Okladnova O Di Bella D Nothen MM et al.Excess of high activity monoamine oxidase A gene promoter alleles in female patients with panic disorder.Hum Mol Genet. 1999; 8: 621-624Crossref PubMed Scopus (509) Google Scholar)Antisocial personality disorderNoLu et al. (Lu et al., 1999Lu R-B, Lee J-F, Ko H-C, Shih JC (1999) No association of MAOA gene with antisocial personality disorder. Paper presented at the 1999 World Congress on Psychiatric Genetics, Monterey, CA, October 14-18Google Scholar) Open table in a new tab To test the role of MAO A in behavior in a system that permits experimental manipulation, we established a line of mice with a targeted disruption of the Maoa gene (Cases et al. Cases et al., 1995Cases O Seif I Grimsby J Gaspar P Chen K Pournin S Muller U et al.Aggressive behavior and altered amounts of brain serotonin and norepinephrine in mice lacking MAO A.Science. 1995; 268: 1763-1766Crossref PubMed Scopus (973) Google Scholar). We observed that males in this strain exhibit a significant increase in brain levels of 5-HT and NE and a modest increase in DA, confirming that the substrate specificities of the mouse MAOs are similar to those in humans. Crucially, these males manifest enhanced aggression, as assessed by observation of confrontations between intruder and resident mice under standardized conditions (Cases et al. Cases et al., 1995Cases O Seif I Grimsby J Gaspar P Chen K Pournin S Muller U et al.Aggressive behavior and altered amounts of brain serotonin and norepinephrine in mice lacking MAO A.Science. 1995; 268: 1763-1766Crossref PubMed Scopus (973) Google Scholar; Shih et al. Shih et al., 1999Shih JC Chen K Ridd MJ Monoamine oxidase: from genes to behavior.Annu Rev Neurosci. 1999; 22: 197-217Crossref PubMed Scopus (932) Google Scholar). Drug studies lend further support to the notion that high CNS levels of monoamine neurotransmitters promote aggressive behavior. Ketanserin and tetrabenazine (TBZ) both act as antagonists of the vesicular monoamine transporter VMAT2 (Leysen et al. Leysen et al., 1988Leysen JE Eens A Gommeren W Van Gompel P Wynantsm J Janssen PAJ Identification of nonserotonergic [3H]ketanserin binding sites associated with nerve terminals in rat brain and with platelets: relation with release of biogenic amine metabolites induced by ketanserin- and tetrabenazine-like drugs.J Pharmacol Exp Ther. 1988; 244: 310-321PubMed Google Scholar; Roth et al. Roth et al., 1987Roth BL McLean S Zhu X-Z Chuang D-M Characterization of two [3H]ketanserin recognition sites in rat striatum.J Neurochem. 1987; 49: 1833-1838Crossref PubMed Scopus (59) Google Scholar), and ketanserin also interferes with 5-HT, by blocking 5-HT2A receptors. As shown in figure 1, both of these drugs diminish the aggressive behavior of MAO A–deficient mice in a dose-dependent manner (Shih et al., Shih et al., in pressShih JC, Ridd MJ, Chen K, Meehan WP, Kung M-P, Seif I, De Maeyer E. Ketanserin and tetrabenazine abolish aggression in mice lacking MAO A. Brain Res (in press)Google Scholar). These drugs also inhibit the behavior of wild-type mice, but the aggression is much lower in the wild-type animals when compared with the Maoa-knockout mice. Thus, untreated wild-type males exhibit aggressive behavior for 48.7 ± 18.0 s during the first 10 min after a resident and an intruder animal begin to fight; with mice of the Maoa-knockout genotype, the aggression occurs for 93.2 ± 28.9 s. The antiaggressive effect of TBZ and at least part of the effect of ketanserin may be mediated by their effects on VMAT2. MAO A–deficient mice also show more efficient emotional learning than do wild-type animals, by several measures, including the freezing-response-after-foot-shock training (Kim et al. Kim et al., 1997Kim JJ Shih JC Chen K Chen L Bao S Maren S Anagnostaras SG et al.Selective enhancement of emotional, but not motor learning in monoamine oxidase A-deficient mice.Proc Natl Acad Sci USA. 1997; 94: 5929-5933Crossref PubMed Scopus (130) Google Scholar). Evidently, fear-conditioned learning is enhanced in these mice as a result of their elevated monoamine levels. This learning phenotype is consistent both with earlier pharmacological studies, which showed that the injection of monoamines into the brains of mice increases fear-memory learning, and with subsequent work with drugs that lower the levels of monoamines, which are found to interfere with this type of learning. In addition to these behavioral differences between Maoa-knockout and wild-type mice, the phenotype of the knockout animals includes some subtle changes in neuronal structure and patterns of gene expression in the brain. The absence of MAO A activity affects the distribution throughout development of 5-HT and of factors that interact with it. Immunolabeling experiments show that 5-HT accumulates transiently at numerous atypical locations during the embryonic and postnatal development of Maoa-knockout mice, including sites within the telencephalon, the diencephalon, and the brain stem (Cases et al. Cases et al., 1998Cases O Lebrand C Giros B Vitalis T De Maeyer E Caron MG Price DJ et al.Plasma membrane transporters of serotonin, dopamine, and norepinephrine mediate serotonin accumulation in atypical locations in the developing brain of monoamine oxidase A knock-outs.J Neurosci. 1998; 18: 6914-6927Crossref PubMed Google Scholar). Interestingly, catecholaminergic cells at diverse sites, which would not be expected to express 5-HT, also display transient 5-HT immunoreactivity, perhaps as a result of 5-HT uptake via the DA or NE plasma-membrane transporter. It appears that neuron populations that form highly precise projection maps could be affected by excess 5-HT during development (Cases et al. Cases et al., 1998Cases O Lebrand C Giros B Vitalis T De Maeyer E Caron MG Price DJ et al.Plasma membrane transporters of serotonin, dopamine, and norepinephrine mediate serotonin accumulation in atypical locations in the developing brain of monoamine oxidase A knock-outs.J Neurosci. 1998; 18: 6914-6927Crossref PubMed Google Scholar), and, indeed, the increased 5-HT levels in brains from Maoa-knockout pups causes cytoarchitectural alterations in the somatosensory cortex. As Cases et al. (Cases et al., 1996Cases O Vitalis T Seif I De Maeyer E Sotelo C Gaspar P Lack of barrels in the somatosensory cortex of monoamine oxidase A-deficient mice: role of a serotonin excess during the critical period.Neuron. 1996; 16: 297-307Abstract Full Text Full Text PDF PubMed Scopus (438) Google Scholar, Cases et al., 1998Cases O Lebrand C Giros B Vitalis T De Maeyer E Caron MG Price DJ et al.Plasma membrane transporters of serotonin, dopamine, and norepinephrine mediate serotonin accumulation in atypical locations in the developing brain of monoamine oxidase A knock-outs.J Neurosci. 1998; 18: 6914-6927Crossref PubMed Google Scholar) have shown, these changes in brain structure may be related to the enhanced aggression of MAO A–deficient mice, because administration of p-chlorophenylalanine—which inhibits tryptophan hydroxylase, the rate-limiting enzyme in 5-HT biosynthesis—reverses both the structural changes and the aggressive behavior of adults (Cases et al. Cases et al., 1996Cases O Vitalis T Seif I De Maeyer E Sotelo C Gaspar P Lack of barrels in the somatosensory cortex of monoamine oxidase A-deficient mice: role of a serotonin excess during the critical period.Neuron. 1996; 16: 297-307Abstract Full Text Full Text PDF PubMed Scopus (438) Google Scholar). Further clues to the brain structures involved in aggression come from the work of Shi et al. (Shi et al., 1998Shi Y Chen K Rebrin I Shih JC Expression of MAO A cDNA in forebrain of MAO A deficient mice reduced aggressive behavior.Neuroscience. 1998; 24: 1922Google Scholar), who used a tissue-specific promoter to restore MAOA expression specifically to the forebrain of Maoa-knockout animals. The duration of aggressive behavior is reduced to normal levels in these transgenic mice, suggesting that the lack of MAO A in the forebrain of Maoa-knockout mice underlies their enhanced aggression. Radio-ligand binding and autoradiography have also shown that the numbers of sites that are positive for VMAT2, 5-HT1A, 5-HT2A, or 5-HT2C are decreased in brains of MAO A–deficient mice (Shih et al. Shih et al., in pressShih JC, Ridd MJ, Chen K, Meehan WP, Kung M-P, Seif I, De Maeyer E. Ketanserin and tetrabenazine abolish aggression in mice lacking MAO A. Brain Res (in press)Google Scholar), perhaps because the excess ligand causes these factors to be down-regulated. Interestingly, however, MAO B does not appear to be altered in its expression level in Maoa-knockout mice. The apparent absence of compensatory changes in expression may make these mutant animals valuable tools to study the distribution and function of MAO B. Brains of Maoa-knockout pups accumulate 5-HT at a concentration nine times higher than do wild-type mice at the same stage (Cases et al. Cases et al., 1995Cases O Seif I Grimsby J Gaspar P Chen K Pournin S Muller U et al.Aggressive behavior and altered amounts of brain serotonin and norepinephrine in mice lacking MAO A.Science. 1995; 268: 1763-1766Crossref PubMed Scopus (973) Google Scholar), but in adult animals the difference is only twofold. This change probably indicates that MAO B is capable of oxidation of 5-HT in vivo in the absence of MAO A, and its timing may reflect the late expression of MAO B. Thus, it is reasonable to speculate that 5-HT would be greatly enhanced in mice deficient for both MAO genes. We are currently generating Maoa/Maob–double-knockout mice, which may recapitulate some of the features of the patients with ND that have been discussed above. The development of mice lacking both MAO A and MAO B should allow us to explore the genetic interactions between Maoa and Maob in both neural development and the control of behavior. Grimsby et al. (Grimsby et al., 1997Grimsby J Toth M Chen K Karoum F Klaidman L Adams J Gal J et al.Increased stress response and β-phenylethylamine in MAO B-deficient mice.Nat Genet. 1997; 17: 206-210Crossref PubMed Scopus (211) Google Scholar) showed that the brain level of PEA is eightfold higher in Maob-knockout mice than in wild types, although 5-HT, NE, and DA levels are not altered. The effect of MAO B on PEA is consistent with findings in patients with ND who lack MAO B expression (Lenders et al. Lenders et al., 1996Lenders JW Eisenhofer G Abeling NGGM Berger W Murphy DL Konings CH Bleeker Wagemakers LM et al.Specific genetic deficiencies of the A and B isoenzymes of monoamine oxidase are characterized by distinct neurochemical and clinical phenotypes.J Clin Invest. 1996; 97: 1010-1019Crossref PubMed Scopus (127) Google Scholar) and with suggestions that this neurotransmitter may modulate mood and affect (Linnoila et al. Linnoila et al., 1983Linnoila M Karoum F Cutler NR Potter WZ Temporal association between depression dependent dyskinesias and high urinary phenylethylamine output.Biol Psychiatry. 1983; 18: 513-518PubMed Google Scholar). The role of MAO A in aggression, first identified by Brunner et al. (Brunner et al., 1993aBrunner HG Nelen M Breakefield XO Ropers HH Van Oost BA Abnormal behavior associated with a point mutation in the structural gene for monoamine oxidase A.Science. 1993; 262: 578-580Crossref PubMed Scopus (1168) Google Scholara, 1993b), has been confirmed in MAO A–deficient mice, which, like the men in the Dutch family, show increased brain levels of 5-HT, NE, and DA and manifest enhanced aggression. However, aggression is a complicated behavior, and mice that lack any of several genes also manifest altered aggression, including those for the adenosine 2a receptor (Ledent et al. Ledent et al., 1997Ledent C Vsugeois JM Schiffmann SN Pedrazzini T El Yacoubi M Vanderhaeghen JJ Costentin J et al.Aggressiveness, hypoalgesia and high blood pressure in mice lacking the adenosine A2a receptor.Nature. 1997; 388: 674-678Crossref PubMed Scopus (747) Google Scholar), estrogen receptor (Ogawa et al. Ogawa et al., 1996Ogawa S Lubahn DB Korach KS Plaff DW Aggressive behavior of transgenic estrogen-receptor knockout male mice.Ann N Y Acad Sci. 1996; 794: 384-385Crossref PubMed Scopus (23) Google Scholar), 5-HT1B receptor (Ramboz et al. Ramboz et al., 1996Ramboz S Saudou F Amara DA Belzung C Segu L Misslin R Buhot M-C et al.5-HT1B receptor knock out-behavioral consequences.Behav Brain Res. 1996; 73: 305-312Crossref PubMed Scopus (179) Google Scholar), bcr (a GTPase-activating protein for Rac [Voncken et al. Voncken et al., 1998Voncken JW Baram TZ Gonzales-Gomez I Van Schaick H Shih JC Chen K Groffen J et al.Abnormal stress response and increased fighting behavior in mice lacking the bcr gene product.Int J Mol Med. 1998; 2: 577-583PubMed Google Scholar]), CaMKIIα (Mayford et al. Mayford et al., 1996Mayford M Bach ME Huang Y-Y Wang L Hawkins RD Kandel ER Control of memory formation through regulated expression of a CaMKII transgene.Science. 1996; 274: 1678-1683Crossref PubMed Scopus (1063) Google Scholar), catechol-o-methyltransferase (Gogos et al. Gogos et al., 1998Gogos JA Morgan M Luine V Santha M Ogawa S Pfaff D Karayiorgou M Catechol-o-methyltransferase-deficient mice exhibit sexually dimorphic changes in catecholamine levels and behavior.Proc Natl Acad Sci USA. 1998; 95: 9991-9996Crossref PubMed Scopus (757) Google Scholar), nitric oxide synthase (Kriegsfeld et al. Kriegsfeld et al., 1997Kriegsfeld LJ Dawson TM Dawson VL Nelson RJ Snyder SH Aggressive behavior in male mice lacking the gene for neuronal nitric oxide synthase requires testosterone.Brain Res. 1997; 769: 66-70Crossref PubMed Scopus (57) Google Scholar), and oxytocin (DeVries et al. DeVries et al., 1997DeVries AC Young III, WS Nelson RJ Reduced aggressive behavior in mice with targeted distruption of the oxytocin gene.J Neuroendocrinol. 1997; 9: 363-368Crossref PubMed Scopus (102) Google Scholar). To date, no lesions in these genes in humans have been reported, and these mouse data have yet to be applied to the treatment of behavioral or psychiatric disorders. Most of the drugs now used to treat aggressive behavior act on brain DA, 5-HT, and α-aminobutyric acid-receptor subtypes (Miczek et al. Miczek et al., 1994Miczek KA Weerts E Haney M Tidey J Neurobiological mechanisms controlling aggression: preclinical developments for pharmacotherapeutic interventions.Neurosci Biobehav Rev. 1994; 18: 97-110Crossref PubMed Scopus (155) Google Scholar). However, these medications, including benzodiazepines and antipsychotics, treat aggression largely by sedating the patient. Doses of ketanserin and TBZ, which abolish the aggressive behavior of MAO A–deficient mice, on the other hand, do not produce sedation (Shih et al., Shih et al., in pressShih JC, Ridd MJ, Chen K, Meehan WP, Kung M-P, Seif I, De Maeyer E. Ketanserin and tetrabenazine abolish aggression in mice lacking MAO A. Brain Res (in press)Google Scholar). Therefore, ketanserin and TBZ may be developed as novel antiaggressive agents. Further studies using Maoa- and Maob-knockout mice will provide new insights into human neuropsychiatric disorders. New techniques, such as cDNA expression arrays, may help to detect new genes and polymorphisms that are associated with neuropsychiatric disorders and behaviors. We acknowledge the support of grants from the National Institute for Mental Health (R37 MH39085, MERIT Award; K05 MH00795, Research Scientist Award; and RO1 MH37020, the Boyd and Elsie Welin Professorship Award). The valuable discussion of Drs. K. Chen and M. J. Ridd is greatly appreciated. Because of page limits, a number of key references could not be included, but the electronic version of this article contains a Supplemental Reading List that includes references to many relevant articles.
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