Differential Inhibition of Neuronal and Extraneuronal Monoamine Oxidase Graeme Eisenhofer, Ph.D., Jacques W. M. Lenders, M.D., Ph.D., Judith Harvey-White, B.S., Monique Ernst, M.D., Ph.D., Alan Zametkin, M.O., Dennis L. Murphy, M.O., and Irwin J. Kopin, M.D.

Tiiis study examined wlzetlzcr tile neuronal and 1-dcprcnyl tlzan with dcbrisoquin (255'¼, compared to a cxtmneuronal sites of action of two 1110110a111i11e oxidase 27% increase). Tlze comparable decreases in plasma (MAO) inlzibitors, 1-deprenyl and debrisoq11i11, could be concentrations of DHPG indicate a similar inhibition of disti11g11islzcd by their effects 011 plasma concentrations of intmncuronal MAO by both drugs. Much larger increases cateclw/a111ine metabolites. Plas111a co11centratio11s of tlzc in 110m1ct11nephrine after 1-deprenyl than after debrisoquin i11tra11euro11al dea111inatcd metabolite of" 11orepi11eplzrine, arc consistent with a site of action of the latter drug directed diiiydroxypiienylglycol WHPG), were decreased by 77'½, at the neuronal rather than the extraneuronal compartment. after debrisoquin and by 64'½, after l-dcpm1yl ad111i11istmtio11. Thus, differential changes in deaminated and O-methylated Plasma conccntmtions of the extmneuronal O-111etlzyl11tcd 11111i11c metabolites allm:us identification of neuronal and 111etabolitc of 11orcpineplzri11e, normctaneplzrine, were extra neuronal sites of action of MAO inhibitors. incrrnsed s11bst11ntiall11 more during treatment zpitfz [Neuropsychopharmacology 15:296-301, 1996]

KEY IVORDS: Monoa111inc oxidase; Monomnine oxidase a family with an X-linked point mutation of the MAO-A inhibitors; Catec/10/11mi11es; Met11bolis111; Norcpincplzrine; gene where afflicted males exhibit impaired impulse Non11et1111cpl1ri11c control provides the most compelling evidence for a The monoamine oxidases (MAO) A and B catalyze the role of MAO in the expression of behavior (Brunner et deamination of biogenic amines and represent targets al. 1993). for therapeutic intervention in se\·eral neuropsychiatric Recognizing that MAO is differentially distributed conditions (Murphy et al. 1980; Berry et al. 1994b ). Ab­ among and within tissues and cell types (Berry et al. normal MAO acti\·ity has been implicated in alcohol­ 1994a; Lai et al. 1994; Thorpe et al. 1987) raises the pos­ ism, depression, and other psychiatric disorders (Ger­ sibility that involvement of the enzyme in different neu­ shon et al. 1979; Devor et al. 1993), but the discovery of ropsychiatric conditions might depend on regional ab­ normalities in MAO activity. Targeting therapeutic interventions to specific tissues or cell types would From the Clinical l\ieuroscie>ncl' Branch, National Institute ot therefore provide a means for tailoring treatment to the Neurological Disorders and Stroh' (CE, JH-W, lJK), Child Psychia­ try Branch (VIE, AZ). and I.aborator\' of Clinical Science (DLM) . specific neuropsychiatric condition. ."..fational Institute of Mental He,1lth, National Institutes of Health, This study examined whether differences in MAO BPtlwsda, :vL1r\'land; and DPpartnwnt of 'Vledicin<' (JW\.1L), Di\'ision activity among neuronal and extraneuronal compart­ of General Internal Medicine, St. Radboud Uni\·ersit\' Hospital, Nijrnegen, The Netherlands. ments can be distinguished using plasma concentra­ Address corrl'spondencl' to: Craenll' Eist>nhofer, Ph.D., Building tions of catecholamine metabolites. Dihydroxyphenyl­ 10, Room 'iN21-I, National Institutl's ot Health, 10 Center Driw. glycol (DHPG)r produced largely by deamination of \.1SC 1-12-1, Betht'SL"Li, .\1D 20892-1-12-1. RecL•in•d August 17. l 99~; re\ isl'd October 17, 1LJ9'i; accepted norepinephrine within sympathetic neurons (Goldstein October 18, i 'J95. et al. 1988) proYided an index of intraneuronal MAO ac-

N!:LRCll 1'.--,\l'ffl)['II \R\\.\(_l))t_)C) ]LJlJ()-\tl[. 1;, \.t).) :D 1LJ96 American Colll'ge of 1'europs\·chopharrnarnlog\' Published bv Else\·ier Science Inc. 0893-133X/96/$15 00 655 An'nut,-of the Americas, New York,;\, Y llJ()]() SSDI 0893-133X(95)00233-2 NEUROPSYCHOPHARMACOLOGY 19%-VOL. 15, 'JO.~ Intra- and Extraneuronal Monoamine Oxidase 297

tivity. Normetanephrine and metanephrine, O-methy­ Blood samples (10 ml) were collected by venipuncture lated metabolites of norepinephrine and epinephrine from a forearm vein with subjects in the semi-supine and substrates for extraneuronal MAO, were indices of position. The data presented here represent results for extraneuronal MAO activity. Other measurements of samples drawn before and during the last week during the catecholamine precursor, dihydroxyphenylalanine which subjects received 1-deprenyl. (DOPA), and of the dopamine metabolite, dihydroxy­ phenylacetic acid (DOPAC), provided indices of ty­ Processing of Blood Samples rosine hydroxylase activity and dopamine deamination. Intraneuronal MAO was inhibited with debrisoquin, a Blood samples were transferred into tubes containing drug that is concentrated in sympathetic nerves by neu­ heparin or EDTA and centrifuged to separate the ronal uptake (Giachetti and Shore 1967; Medina et al. plasma. The plasma was removed and stored at -80°C 1969; Pettinger et al. 1969). The effects of debrisoquin until assayed for concentrations of catechols and metab­ were compared with those of 1-deprenyl, administered olites. Plasma concentrations of norepinephrine, epi­ at a dose sufficient to cause inhibition of both MAO-A nephrine, DHPG, DOPA, and DOPAC were estimated and MAO-B. by liquid chromatography with electrochemical detec­ tion after alumina extraction (Eisenhofer et al. 1986). Plasma concentrations of normetanephrine and meta­ METHODS nephrine were also estimated using liquid chromatog­ Subjects raphy with electrochemical detection following extrac­ tion on solid-phase ion-exchange columns (Lenders et The study population included 26 healthy volunteers al. 1993). Plasma concentrations of sulfate-conjugated (mean ::+:: SD, age 45 ::+:: 24 years) and 14 patients with at­ normetanephrine and metanephrine were estimated tention-deficit hyperacti\·ity disorder (mean ::+:: SD, age similarly after incubation of 200-µl samples of plasma 36 ::+:: 7 years). Subjects included 34 males and 6 females. with sulfatase (Sigma Chemical Co., St Louis, MO) at Women of childbearing potential were excluded. Exper­ 37°C for 30 minutes. imental protocols were approved by the intramural re­ view boards of the two institutes involved in the study Statistical Methods and subjects gave written informed consent to participate. Differences in plasma concentrations of catecholamines, Procedures DOPA, and metabolites before and during treatment with MAO inhibitors were assessed using the Student's Debrisoquin was obtained as a gift from Hoffman-La paired t-test. Differences in changes in concentrations Roche (Nutley, I\J) and formulated for administration during treatment with 1-deprenyl versus debrisoquin as tablets in the National Institutes of Health pharmacy. were assessed by two-way analysis of variance (ANOVA). The drug was administered to 26 normal volunteers at Because of the nature of the within-subjects study de­ graded doses over a 9-day inpatient stay at the Clinical sign, variances in changes in concentrations before and Center, National Institutes of Health. During the first 3 during MAO inhibitor treatment are shown using stan­ days, subjects were administered placebo tablets. On dard errors of the differences. the fourth and fifth days, subjects were administered 10 mg of debrisoquin daily. The dose was increased to 20 mg a day lWer the next 2 days and to 40 mg a day dur­ RESULTS ing the last 2 days. Total daily doses were divided into four equal doses deli\·ered 6 hours apart. Blood samples Plasma concentrations of norepinephrine were de­ (10 ml) were collected by venipuncture from a forearm creased by 20'½, to 26% during treatment with debriso­ vein with subjects in the supine position. The data pre­ quin (p < .001) or 1-deprenyl (p < .05), whereas plasma sented here represent results for samples drawn on the concentrations of epinephrine were unaffected (Table third and the last day on which subjects received de­ 1 ). Plasma concentrations of the catecholamine precur­ brisoquin. sor DOPA were decreased by 47% during treatment L-deprenyl (Selegiline hydrochloride, Eldepryl) was with debrisoquin (p < .001) and by 21 °/4, with 1-deprenyl provided by Somerset Pharmaceuticals Inc (Tampa, FL). (p < .002). Plasma concentrations of the deaminated The drug was administered orally to 14 subjects at a dopamine metabolite DOPAC were decreased similarly dose of 60 mg per day for 6 weeks, a dose previously es­ by 53'\, to 55'¾, during treatment with debrisoquin (p < tablished to cause inhibition of both MAO-A and MAO-B .001) or 1-deprenyl (p < .001), whereas concentrations of (Sunderland et al. 1985). Subjects received 1-deprenyl on DHPG, the deaminated metabolite of norepinephrine an outpatient basis but returned to the clinical center for and epinephrine, were decreased by 77°/o with debriso­ periodic clinical evaluation, including sampling of blood. quin (p < .001) and by 63'1/c, with 1-deprenyl (p < .001). 298 G. Eisenhofer et al. NEUROPSYCHOPHARMACOLOCY 1996-VOL. 15, NO. 3

Table 1. Plasma Concentrations of Catecholamines, DOPA, u DHPG DOPAC and Catecholamine Metabolites before and during < 0

Treatment with Debrisoquin or L-deprenyl 0 Q.. 0 -20 11 Baseline Treatment SED i::. :i::: Norepinephrine Q -40 OS Debrisoquin 20 1.1() 0.81 0.08* 5 L-deprenvl H '-,L.:J.:.. 2.01 0.22* 'i5. -60 Epinephrine .5 Debrisoquin 10 ll.10 0.09 0.02 .. Debrisoquin C L-deprenvl 12 0.3') ll.33 ll.ll5 ""OS .c -80 • Deprenyl DOPA "' Debrisoquin llJ 7.ll-t -t.36 0.26* t-!i L-deprenvl 1-t 8.22 6.-15 ll 63* DOPAC z 300

Debrboquin 20 7.6H 3.ll-t 0.5h* z L-deprem·l 1-t 10.32 -thlJ l.32* -0

DHPG .""::,..., 200 Debrisoquin 20 -+.28 0.97 0.2W C: 0 L-depreml 1-t :1.S2 1.89 0.12* ..."' 0 Normetanephrine ] Debrisoquin 16 (1.32 0.35 0.03t 100 L-depn:n, I 13 0.2lJ 0.91 ll.2lt .5

Metanephrine C OS Debrisoquin 16 0.1-t 0.17 ll.Olt .c L-deprenvl 1-t 0.1-t 0.18 (].()]t " 0 freeNMN conjugated NMN Normetanephrine-sulfate Debrisoquin 15 7 3; 13.76 0.52t L-deprenvl n 7.61 25.28 2.79t z 300 Metanephrine-sulfate ::; -0 Debrisoquin 15 317 -t.-12 ll.37t OS L-deprem·I H -1.02 LJ.81 32-tt ::, .""..., 200 C: 0 Results are rnt:'an concentratitll1~ (nn1ol/L) \Yith \ c1rj.1nce an1Png ..<.; p<1ired data ,hnwn lw stancfard error, of tlw difference (SEO). 11 num­ 0

1 .. ber of ubsen ation~. "'d~notes .1 dL'CrL~asL' {1 • _()~), wherL'clS tdenutt'~ ,111 .::.. incrt',1,e I/'· ..ll,) during tre.itnwnt. 100 ·="' ""C: .cOS MAO-inhibition-induced decreases in plasma con­ '-' 0 centrations of dearninated metabclites contrasted with free MN conjugated MN increases (p < .05) in the O-methylated metabolites, Figure 1. Percentage changes in plasma concentrations of normetanephrine, and metanephrine (Table 1). De­ DHPG and DOPA (lop) and plasma concentrations of free creases in deaminated metabolites did not differ signifi­ and sulfate conjugated normetanephrine (111idd/f) and of cantly during treatment with l-deprenyl and debriso­ metanephrine (bottom) during treatment with debrisoquin quin, whereas there were strikingly smaller increases in (diagonal liars) or deprenyl (solid lmrs). plasma concentrations of normetanephrine (F = 19.2, p < .001) and normetanephrine sulfate (F = 11.3, p < .005) during treatment with debrisoquin than with 1-depre­ creases in sulfate-conjugated metanephrine tended to nyl (Figure 1). During treatment \Vith 1-deprenyl plasma be larger after MAO inhibition than those in unconju­ concentrations of free normetanephrine increased by gated metanephrine and larger with 1-deprenyl than 255°0, whereas with debrisoquin, there was only a 27°o with debrisoquin. increase. Similarly, normetanephrine sulfate increased by 260'\, after 1-deprenyl, but only by 100'\, after de­ brisoquin. Debrisoquin caused larger (p < .001) increases in sulfate-conjugated than -unconjugated normeta­ DISCUSSION nephrine. The MAO-inhibition-induced increases in plasma Considering how MAO is compartmentalized among metanephrine were smaller ( <25"o increases) than and within tissues provides a basis for understanding those for normetanephrine and did not differ during how regional abnormalities in MAO activity may be in­ treatment with 1-deprenyl or debrisoquin (Figure 1 ). In- volved in specific neuropsychiatric disorders and how NEUROPSYCHOl'H.\RMACOLOCY 19%-VtlL. l:i, NO. 3 Intra- and Extraneuronal Monoamine Oxidase 299

targeting particular cell types may offer a useful ap­ and Osswald 1985) could also explain the differential proach for therapeutic intervention. The differential effects of the two drugs. However, other findings in rats changes in deaminated and O-methylated catechola­ that plasma normetanephrine is increased by selective mine metabolites after 1-deprenyl and debrisoquin ad­ inhibition of MAO-A, but not of MAO-B, indicate that ministration illustrate how measurements of biogenic normetanephrine is not a substrate for the latter isoen­ amine metabolites can be used to distinguish the activ­ zyme (Eisenhofer and Finberg 1994). The selectivity of ity of MAO in different cellular compartments. MAO-A for deamination of normetanephrine has been DHPG in plasma is predominantly produced by the confirmed in humans by findings that specific genetic deamination of norepinephrine within sympathetic deficiencies of MAO-B do not result in increased nerves (Goldstein et al. 1988). Thus, the large decreases plasma concentrations of normetanephrine, whereas in plasma DHPG after debrisoquin and 1-deprenyl indi­ deficiencies of MAO-A cause similar increases to those cate that both drugs are effective inhibitors of intraneu­ found in patients with deficiencies of both isoenzymes ronal MAO. In contrast, normetanephrine and meta­ (Lenders et al. 1996). nephrine are produced by extraneuronal O-methylation Smaller increases in plasma concentrations of meta­ of norepinephrine and epinephrine (Graefe and Hensel­ nephrine than of normetanephrine after inhibition of ing 1983). Thus, MAO-inhibition-induced increases in MAO are consistent with findings in rats where inhibi­ plasma normetanephrine and metanephrine result from tion of MAO-A caused fourfold increases in normeta­ inhibition of their deamination in extraneuronal com­ nephrine and only twofold increases in metanephrine partments. MAO-inhibition-induced increases in plasma (Eisenhofer and Finberg 1994). In addition, patients normetanephrine and metanephrine are also secondary with X-linked deletion of the genes for MAO-A and B to the resulting increased a\·ailability of precursor cate­ show smaller increases above normal in plasma meta­ cholamines for O-methylation. nephrine than in normetanephrine (Eisenhofer et al. The large 250'\, increase in plasma concentrations of 1995). Smaller MAO-inhibition-induced increases in free normetanephrine after deprenyl is similar in mag­ plasma metanephrine than normetanephrine are ex­ nitude to MAO-inhibition-induced increases in plasma plained by differences in their sites of formation. Over normetanephrine in rats (Eisenhofer and Finberg 1994) 90'1/o of plasma metanephrine is derived from metabo­ or increases in urinary excretion of norrnetanephrine in lism of epinephrine within the adrenal gland where humans (Linnoila et al. 1982; Koulu et al. 1989; Berlin et O-methylation, not deamination, is the primary path­ al. 1990). The increase is also consistent with the sev­ \vay of metabolism (Eisenhofer et al. 1995). Although eral-fold higher than normal plasma concentrations of significant amounts of normetanephrine are also pro­ normetanephrine in patients with X-linked deletion of duced within the adrenals, most is formed in extraneu­ the genes for .\1AO-A and B (Eisenhofer et al. 1995). ronal and extraadrenal tissues from norepinephrine re­ The minimal increases in plasma normetanephrine leased by sympathetic nef\'es. after debrisoquin agree with previous findings of little Small, but significant, decreases in plasma norepi­ change in the urinary excretion of normetanephrine af­ nephrine after administration of both MAO inhibitors ter 6 to 8 weeks of treatment with debrisoquin (Silas et suggest decreases in norepinephrine release, as a result al. 1979). Much smaller increases in plasma normeta­ of either decreased sympathetic outflow or of replace­ nephrine after debrisoquin than after 1-deprenyl-despite ment of norepinephrine by octopamine. The sym­ a similar magnitude of inhibition of intraneuronal patholytic effects of debrisoquin are well established MAO by both drugs-indicate less effective inhibition of and provided the basis for the initial introduction of the extraneuronal MAO after debrisoquin than after 1-depre­ drug as an antihypertensive (Giachetti and Shore 1967). nyl administration. The selectivity of debrisoquin for in­ A similar action of 1-deprenyl is not established, but is hibition of neuronal over extraneuronal MAO is consis­ consistent with findings of sympathoinhibitory actions tent with the primary intraneuronal actions of the drug of other MAO inhibitors (Lavian et al. 1994). The study that result from its active uptake and concentration by design, where there were differences in duration of sympathetic nerves (Giachetti and Shore 1967; Medina drug treatment and no controls for temporal influences et al. 1969; Pettinger et al. 1969). The results show that or possible changes in plasma catecholamine clearance differences in MAO activity among neuronal and extra­ precludes definitive interpretation of the changes in neuronal compartments may be distinguished by com­ plasma norepinephrine. These factors and differences in parisons of plasma concentrations of the intraneuronal subject groups (i.e., outpatients versus hospitalized nor­ deaminated metabolite of norepinephrine DHPG with mal volunteers) or posture at time of blood sampling those of the extraneuronal metabolite normetanephrine. may also account for differences in baseline variables; At low doses (5-10 mg/ day in humans), 1-deprenyl, however, they are unlikely to be responsible for the dif­ is a more selective inhibitor of MAO-B than of MAO-A. ferential changes in plasma concentrations of O-methy­ Thus, previous findings in canine saphenous vein that lated and deaminated metabolites during treatment normetanephrine is deaminated by MAO-B (Caramona with the two MAO inhibitors. 300 G. Eisenhofer et al. NEUROPSYCHOPHARM:\COLOGY 1996-VOL. 15, NO. 3

The decreases in plasma DOPA after MAO inhibition chromatographic determination of 3,4-dihydroxy-phe­ are consistent with previous findings (Eisenhofer et al. nylglycol, catecholamines, and 3,4-dihydroxyphenylala­ 1986, 1988), where these changes reflect feedback inhibi­ nine in plasma, and their responses to inhibition of monoamine oxidase. Clin Chem 32:2030-2033 tion of tyrosine hydroxylase by increased axoplasmic concentrations of norepinephrine. Because MAO-A is Eisenhofer G, Goldstein DS, Ropchak TG, Kopin IJ (1988): Source and physiological the predominant form of the enzyme in sympathetic significance of plasma 3,4- dihydroxyphenylalanine in the rat. J Neurochem 51: neurons, the decrease in plasma DOPA indicates that 1204-1213 both drugs inhibit the enzyme. This finding is also con­ Eisenhofer G, Friberg P, Pacak K, Goldstein DS, Murphy DL, sistent with lowered plasma concentrations of DOPA in Tsigos C, Quyyumi AA, Brunner HG, Lender JWM patients with X-linked deficiencies of MAO-A, but not (1995): Plasma metadrenalines: Do they provide useful in those with absent MAO-B (Lenders et al. 1996). information about sympatho-adrenal function and cate­ DiYergent changes in plasma concentrations of cholamine metabolism. Clin Sci 88:533-542 O-methylated and deaminated catecholamine metabo­ Gershon ES, Targun SD, Leckman JF (1979): Platelet lites proYide a sensitive approach to detect generalized monoamine oxidase (MAO) acti\'ity and genetic vulner­ disorders or drug-associated changes of biogenic amine ability to bipolar (BP) affective illness. Psychopharmacol Bull 15:27-30 metabolism. 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