THE EFFECTS OF CHRONIC REGIMENS OF CLORGYLINE A N D PARGYLTNE ON MONOAMINE METABOLISM IN THE RAT BRAIN I. C. CAMPBELL,' D. S. ROBINSON,W. LOVENBERC and D. L. MURPHY Clinical Neuropharmacology Branch, N I M H ; Hypertension-Endocrine Branch, NHLI, Bethesda, MD 20014. U.S.A.

(Received 10 February 1978. Accepted 18 J u l y 1978)

of chronic administration of clorgyline and pargyline on rat brain monoamine metabolism have been examined. The inhibitory selectivity of these drugs towards serotonin deamination ( M A 0 type A) and phenylethylamine deamination ( M A 0 type B) can be maintained over a 21-day period by proper selection of low doses of these drugs (0.5-~1.Omg/kg/24h). The results are consistent with M A 0 type A catalyzing the deamination of serotonin and norepinephrine and with M A 0 typc B having littlc effect on these monoaniines. Dopamine appears to be dcaminated in i i i ~ o principally by M A 0 type A. Clorgyline administration during a 3-week period was accompanied by persistent elevations in brain norepinephrine concentrations; serotonin levels were also increased during the first 2 weeks, but returned towards control levels by the third week of treatment. Low doses of pargyline did not increase brain monoamine concentrations, but treatment with higher doses for 3 weeks led to elevations in brain norepinephrine and 5-hydroxytryptamine; at this time significant MAO-A inhibition had developed. The changes in monoamine metabolism seen at the end of the chronic clorgyline regimen are not due to alterations in tryptophan hydroxylase activity. At this time tyrosine hydroxylasc activity was also unaffected.

Abstract- The effects

JOHNSTON

(1968) described t w o forms of M A 0 (mon0amine:oxygen oxidoreductase, deaminating; EC 1.4.3.4, M A O ) on the basis of a bimodal pattern of inhibition of tyramine deamination found with clorgyline. Later studies revealed that M A 0 type A deaminates 5 - H T a n d NE a n d is preferentially inhibited by clorgyline; M A 0 type B deaminates b-PEA a n d is preferentially inhibited by dcprenyl (KNOLL& MAGYAR, 1972) a n d pargyhne (SQUIRES, 1972). Dopam i n e a n d tyramine a r e substrates for both forms of t h e enzyme (YANG & NEFF,1974). These t w o forms of M A 0 have been extensively examined in v i m (COSTA & SANDLER, 1972; YOUDIM, 1972) a n d a recent clinical study with pargyline a n d clorgyline has attempted t o elucidate t h e possible role of the t w o enzyme forms in t h e antidepressant response t o MAO-inhibiting drugs (MURPHY et al., in press). As clorgyline a n d pargyline a r e irreversible m o n o a m i n e oxidase inhibitors, significant cumulative drug effects could occur with chronic administration such that both enzyme forms would be inhibited. T h e first p a r t of this study established whether prolonged d r u g administration leads t o continued selective inhibition of M A 0 type A a n d type B a n d the second

'

T o whom correspondence should be addressed : National Institute of Mental Health. NIH Clinical Center. Bldg. 10, Rm. 3D48. 9000 Rockville Pike, Bethcsda, M D 20014. U.S.A. Abhrrriutions used: 5-HT, 5-hydroxytryptamine: 5-HIAA, 5-hydroxyindoleacctic acid; NE, norepinephrine; PEA, phenylethylamine: MAOI, monoamine oxidase inhibitor. 49

p a r t examined the changes in aminergic systems which occur following chronic m o n o a m i n e oxidase inhibitor ( M A O I ) administration. MATERIALS A N D METHODS Sprague-Dawley rats, male and 6-12 weeks old (Taconic Farms, MD), were used. Clorgyline, pargyline and saline (in a volume of 0.2 ml) were injected intraperitoneally each morning in doses appropriate to the experiment. Animals were weighed at wcekly intervals and the doses adjusted accordingly: n o significant differences in weight gain or food intake were observed between control and drugtreated animals throughout the regimen. Drug regimens werc decided on the basis of preliminary acute dose-response studies. Both drugs were given in 2 doses: low clorgyline (0.5 mg/kg) and high clorgyline (1.0 mg/kg); low pargyline (1.0 mg/kg) and high pargyline (4.0nig/kg). The drugs were given for I , 7, 14 or 21 days and the animals were killed by decapitation, 6 h aftcr thc last dose. Amines a d 5 - H I A A . Amines and their metabolites were extracted by the methods of KWN r f a/. (1961), SCHANBERG er a!. (1968) and SHIELDS & ECCLESTON (1972). Brains were homogenized in cold 0.4 N-perchloric acid containing 2 mg/ml of ascorbic acid and 0.2% ethylenediamine tetraacetate. Following removal of denatured protein and excess perchlorate ions (using 5 N-potassium hydroxide), NE and dopamine were extracted by absorption chromatography using 'active' alumina (Woelm). 5-HT and 5-HIAA were isolated using an Amberlite CG 50 ( N H d ) resin: the amine was eluted using 1 wsulphuric acid. The recovery of 5-HT and NE was calculated using both internal and external standards. The radioactivity labelled internal standard used in the indoleamine isolation procedure ensured that

I. C. CAMPBELL, D. S. ROBINSON, W. L ~ V E N R Eand R G D. L. MURPHY

50

the 5-HIAA removed from the Amberlite resin was not contaminated by 5-HT. 5-HT and 5-HIAA were assayed using their native fluorescence in acid solution (activation 295 nm: excitation er nl., 1955; BOGDANSKI el al., 1956). 530nm) (UDENFRIEND N E and dopamine were measured fluorimetrically by a variation of the ‘trihydroxyindole’ procedure (ANSELL & BEESON,1968). Tryplophun hydroxylase and tyrosine hydroxylase. Brains were rapidly removed and chilled during dissection procedures described by BAUMFARTEN et al. (1971) and modified by VICTORet a/. (1974). Brain regions were stored in liquid nitrogen until assayed. Frozen tissues were homogenized in 0.05 M-Tris-HC1 (pH 7.4) (containing 0.02 M-dithiothreitol), in a 1:5 ratio (w/v) and centrifuged at 40,000 y for 20 min. Supernatant fractions were assayed for tyrosine hydroxylase using tyrosine M) and 6-methyl-tetrahydropterin (4.0 x M) (CICERNO et al., 1972). Tryptophan hydroxylase activity was measured by et al. (1972) as described in the method of FRIEDMAN B A ~ M G A R TetE Na / . (1973) with volumes altered to give a more sensitive microassay. Twenty pl of the supernatant fraction was incubated with 4 0 p l (12.0pmol) of Tris-HCl (pH 7.4) at 37°C for 10min: the reaction was started by adding tryptophan (IOpl: 2.0 x W ~ M ) and after 30min, was stopped by the addition of ~ N - P C A(10~1). The samples were centrifuged and 40 pl of the supernatant was added to loop1 of 3 N-HCI; the fluorescence of 5-hydroxytryptophan in the solution was measured at 540nm, using an excitation wavelength at 290 nm. 5-hydroxytryptophan standards were run concurrently. Monoatvine oxidase. Whole brain was homogenized in 10% (w/v) 0.08 M-phosphate buffer (pH 7.2) and centrifuged at 900y for 10min at 4°C. The supernatant was sonicated for approx 1 5 s to disrupt large membranous fragtnents and to prepare an even suspension of enzyme. M A 0 activity was determined by a modification of the method of ROBINSONrr a/. (1968) using PEA and 5-HT as substrates. Sonicated preparations were assayed in triplicate by incubating 50 pI aliquots (0.2-0.7 mg/protein) in 0.5 ml of 0.08 M phosphate buffer (Na,HPO,-KH,PO,) (PH 7.2) with 25 pl of radioactively-labelled substrate for 20 min at 37°C. Aliquots heated at 100°C for 10 min were assayed simultaneously to establish blank values. The final concentrations and specific activities of substrates used were 5-HT(C3H]-5-HT creatinine sulphate; 55 mCi/mmol; final concentration in assay 10- M ; New England Nuclear [NEN], Boston, MA) and PEA (phenylethylamine HCI p-[ethyl-l-’*C]); 50.98 mCi/mmol; final concentration in

TABLE1. EFFECTSOF

CLORGYLINE AND PARGYLINE ON

Day 1 Drug dosage (mg/kg/24 h) MAO-A MAO-B Clorgyline 0.5 1 .o

medium 2 x lo-’ M, NEN). Substrate concentrations were chosen such that deamination was less than 10% ovcr the reaction period. They were also in excess of the K,’s of the amines for the enzyme ( K , of PEA for M A 0 type B is 4 . 8 and ~ ~ the K , of 5-HT for M A 0 type A is 1.1 x 1 0 - 4 ~(EKSTEDT,1976; DONNELLY, 1977); thus the velocity of the reactions reflect V,,, Ascorbic acid M) and ethylenediamine tetraacetate M) were present in the phosphate buffer to prevent non-enzymatic alteration of the substrate. Following incubation, samples were placed on ice and then transferrcd t o Pasteur pipettes containing 0.5 x 2.5 cm of Amberlite resin (CG-50, 10&200 mesh, Mallinkrodt Chemical Works, St. Louis, MO), preet a/., 1976; pared as previously described (DONNELLY & MURPHY,1977). The columns were washed DONNELLY twice with one ml distilled deionized water and the entire 2.5ml collected in vials containing 17.5 ml of Aquasol (NEN). The radioactively labelled products were assayed by liquid scintillation spectrometry. Protein contenti sample was determined by the method of LOWRYet a/. (1951), using a bovine serum albumin (Sigma Chemical Co., St. Louis, M O ) standard. In figures, a bar across a point is the standard error of the mean (s.E.M.):If a bar is absent, the S.E.M.was smaller than the symbol on the diagram. Each point is the mean of 5-7 animals. Clorgyline and pargyline were gifts from May & Baker Pharmaceuticals, Dagenham, U.K. and Abbot Laboratories, Chicago, IL, respcctively. Tyrosine, tryptophan, 5-HT, NE, 5-HIAA, dopamine, dithiothreitol. 6-methyl tetrahydropterin and bovine serum albumin were obtained from Sigma Chemical Co., Ltd.

RESULTS

EfSeects on monoamine oxiduse activity

Table 1 shows t h e effects of chronic pargyline and clorgyline administration on M A 0 type A (serotonin deamination) and type B ( P E A deamination) in r a t brain. Clorgyline is a highly effective inhibitor of serotonin deamination: a single dose (0.5 mg,kg) causes an a p p r o x 55% decrease in M A 0 activity; after 14 d a y s on this regimen there is less than 10% enzyme activity remaining. At a somewhat higher d o s e (1.0 mg/kg), clorgyline causes 80% inhibition of serotonin deamination after a single treatment. T h e specificity of t h e inhibition is apparent by the fact that MAO-A

MAO-B

AND

Day 7

ACTIVITY I N THE RAT BRAIN

Day 14

MAO-A

MAO-B

MAO-A

Day 21

MAO-B

MAO-A

MAO-B

46.8 20.0

95.7 104.0

33.0 10.7

94.9 91.8

8.5 0.3

82.3

2.7 0

72.4 78.5

1.O

100.0

4.0

78.1

35.7 10.7

85.0 62.5

25.4 14.0

60.8 13.5

11.6 3.8

55.6 4.5

7.1 0

Pargyline

Values are expressed as a % of control (saline injected) animals. Each value is the mean of two brains assayed in triplicate. Results were corrected for protein content/sample before calculation of the % activity. MAO-A activity was assessed using 5-HT as substrate and MAO-B using PEA. The specific activity of M A 0 type A in control samples was 118.0nmol/mg protein/h and for M A 0 type B was 41.0nmol/mg proteinh.

51

Chronic M A 0 inhibitor administration

1

7

14

21

DAYS

FIG.1. The effects of chronic regimens of clorgyline (0.5 mg/kg) (O-), clorgyline ( I mg/kg) (O---O), pargyline ( I .O mg/kg) (A-A) and pargyline (4.0 mg/kg) (A-A) on rat brain 5HT levels. Values are expressed as p g / g brain (wet wcight) i S.E.M. and are the mean of 5-7 animals. 0-0 controls.

deamination of PEA is decreased by less than 30% even after 21 days on this higher dose regimen. Pargyline on a mg/kg basis is a slightly less potent inhibitor of M A 0 type B than is clorgyline of M A 0 type A. After 21 days of pargyline treatment at a dose of 1.0 mg/kg/24 h, monoamine oxidase B activity is reduced to less than 10% of controls. With the higher dose (4.0 mg/kg/24 h), MAO-B activity is reduced to approx 10% after a single dose. The pargyline data also show that the drug is not as specific an inhibitor of the M A 0 forms as is clorgyline. After 21 days, low pargyline dosage (1.0 mg/kg/24 h) reduces MAO-A activity by 45%: the higher dose of drug (4.0 mg/kg/24 h) reduces MAO-A activity to less than 20% of controls after 14 days and less than 5% after 21 days of treatment.

When given for 14 days, both high and low doses of clorgyline produce significant increases (approx 2-fold) in 5-HT. while the corresponding changes caused by pargyline are small. By day 21, however, the elevated 5-HT levels seen in clorgyline treated animals have decreased and are not significantly different from corresponding control values. 5-HT levels in the 21-day clorgyline-treated groups are significantly lower than the corresponding group at 1 day ( P < 0.02) and 14 days ( P < 0.01). With high dose pargyline (4.0 mg/kg/24 h) there is a significant increase (78%) in brain 5-HT after 21 days but not earlier in the regimen. 5-HT levels in the 21-day low dose pargyline (1.0 mg/kg,/24 h) treated group are significantly lower (38%) than in the corresponding control group.

Effects 011 brain 5-HT

EJTects on bruin 5 - H I A A

Single doses of clorgyline (0.5 mg/kg and 1.0 mg/kg) and pargyline (4.0 mg/kg) produce small increases in 5-HT (Fig. 1). However, the only significant increase ( P < 0.05) at this time is caused by the high dose of clorgyline and in this case the increase is only 26%.

Figure 2 shows the effects of the chronic drug schedules on brain 5-HIAA values. In all cases the changes in 5-HIAA are less than 20% of control values and throughout the regimen none of these changes is significant.

0 , 7 0 0 1 1 0.500

1

14

7

21

DAYS

FIG.2. The effects of chronic regimens of clorgyline (0.5 mg/kg) (o--o), clorgyline (1 mg/kg) (*O), pargyline (1.0mg/kg) (A-- A)and pargyline (4.0mg/kg) (A-A) on rat brain 5-HIAA levels. Values are expressed as p g / g brain (wet weight) t S.E.M. and are the mean of 5-7 animals. 0-0 controls.

1. C. CAMPBELL, D. S. ROBINSON, W. LOVENBERG and D. L. MURPHY

52

1

I

I

7

14

I

21

DAYS

FIG.3. The effects of chronic regimens of clorgyline (0.5mg/kg) (04). clorgyline ( I mg/kg) (M), pargyline (I.Omg/kg) (A--A) and pargyline (4.0mg/kg) (A-A) on rat brain NE levels. Values are expressed as pg/g brain (wet weight) & S.E.M. and are the mean of 5-7 animals. 0-0 controls. EfSects on brain N E

Effects on brain dopainine

Figure 3 shows the effects of the different regimens on brain NE. Single doses of the drugs produce at maximum an increase of 25% in NE levels. By day 7, the low clorgyline regimen has caused a 42% increase in N E and the high dose regimen an increase of 100%. Both of these increases are significant, P < 0.02 and P < 0.01 respectively. The corresponding increases caused by pargyline are 10% and 25% and these are not significantly different from controls. By day 21 the clorgyline (0.5 mg/kg)-induced increase in NE is unchanged from the 7-day value and the clorgyline (1.0 mg/kg) effect has decreased by 20%: this latter value is not significantly different from that seen after 7 days. Pargyline (1.0 mg/kg) even after 21 days of administration has no significant effect on brain NE; at this time the higher dose schedule (4.0 mg,kg) causes a significant increase (75%) ( P < 0.01); this level of amine is significantly higher than the value observed after 1 and 7 days on the regimen.

Following a single dose of either clorgyline or pargyline there are no significant increases in brain dopamine. On day 14, the only significantly raised dopamine level is in the high clorgyline (1.0 mg/kg) group: in this case the increase is by 110% (P < 0.01). After 21 days, none of the regimens cause a significant increase in brain dopamine concentrations.

TABLE 2. TYROSINE AND TRYPTOPHAN TIES AFTER

21

HYDROXYLASE DAYS OF IIRUG TREATMENT

Striatal tyrosine hydroxylase

Treatment

activity

ACTIVI-

Tegmental tryptophan hydroxylase activity

Low clorgyline

(0.5mg/kg/24 h) High clorgyline (1.0mg/kg/24 h ) Low pargyline (1.0 mg/kg/h) High pargyline (4.0 mg/kg/h)

115.4 & 17.8

106.1

12.3

108.9 i 20.3

96.9

+ 14.7

Saline

100.0 & 4.9

100.8

+ 12.1

94.3

* 3.3

79.7 & 7.4 76.7 7.4 100.0 i 9.2

Values are expressed as of controls & S.E.M.and are corrected for protein content/sample. For striatal tyrosine hydroxylase. the specific activity (SA) of control samples was 12.3 If: 0.6(5) nmol/mg protein/h and the correspond-

ing value for tegmental tryptophan hydroxylase was 16.3 & 1.5(5) nmol/mg proteinih. n = 5 per group.

Effects on tryptophan and tyrosine hydroxylase activity

Table 2 shows the effects of the various drug treatments on striatal tyrosine hydroxylase and tegmental tryptophan hydroxylase activity at 21 days. There are no significant changes in enzyme activities with chronic drug administration. With pargyline treatment there is an approx 2Cr2S% reduction in tryptophan hydroxylase activity but this does not reach statistical significance. DISCUSSION Spccijicity of clorgyline and pargyline as inhibitors of M A 0 types A and B

These results, like several previous studies (TIPTON, 1972; YOUDIM,1973; YANG & NEW, 1974; BAKHLE & YOUDIM,1976), support the concept based on in vitro studies (JOHNSTON, 1968) that two forms of M A 0 are functionally active in vivo. These results also indicate that dose selection is critical in achieving differential inhibition of the two enzyme forms during longer-term treatment with selective M A 0 inhibitors. At the doses used, clorgyline produced greater than 90% inhibition of serotonin oxidation without reducing PEA oxidation more than 2Cr30%. With pargyline, however, greater than 90% inhibition of PEA oxidation was accompanied by 4C-50X inhibition of serotonin oxidation, suggesting that the drug is a less selective inhibitor of MAO-B than is clorgyline of MAO-A : observations of lessened specificity with deprenyl, another MAO-B inhibitor, have also been reported (WALDMEIEK & FELNER, 1978). The partial loss of specificity over the 21-day study is probably

Chronic M A 0 inhibitor administration due to cumulative effects of the drugs. although ECASHIRA et al. (1976) have shown that prolonged incubation of clorgyline and deprenyl with M A 0 in uitro decreases their inhibitory specificity. Clinicallyused doses of pargyline (75-125 mg/day) are approx 1.3 times the low dose schedule studied here, and those for clorgyline (2@40 mg/day) are comparable. In patients, chronic treatment with pargyline (90 mg/ day) but not clorgyline (30 mglday) rapidly and essentially completely inhibited MAO-B activity in platelets (MURPHYet al., in press). The rapid rises in NE and 5-HT following clorgyline but not pargyline administration are in keeping with the selective M A 0 inhibitory effects observed, and are in agreement with the observations of others using larger drug doses (TOZERet al., 1966; YANG & NEFF, 1974). These selective amine changes suggest that one form of monoamine oxidase does not produce substantial deamination of the aminc which is not its preferred substrate, as 2-fold increases in brain 5-HT and NE are obtained while there is greater than 80% MAO-B activity remaining. It is surprising that marked inhibition of M A 0 A and of M A 0 A plus M A 0 B does not cause significant reductions in brain 5-HIAA. Certainly pargyline in acute higher doses has been shown to decrease 5-HIAA (TOZERet a/., 1966). Like phenelzine (MACLEANet al., 1965; MOIK,1972), pargyline and clorgyline or their metabolites might block the egress of 5-HIAA from the brain-although there is no direct evidence to suggest this possibility. An alternative explanation is that there is increased conversion of 5-IIT to 5-HIAA by transamination and decarboxylation (KIDOet d.,’ 1975). However, it may simply be that the kinetics of 5-HIAA formation and clearance, in the presence of small residual amounts of MAO-A activity, cause no changes to be visible. Recently however, it has been found (Major, L. F., Personal Communication) that 5HIAA values are lowered in CSF from clorgyline-treated patients only if the samples are analysed by a gas-chromatography mass spectrometry assay: if a fluoro-metric assay is used, no decreases are apparent, suggesting that other indoles interfere with the assay. Our results showing that increases in dopamine occur following MAO-A inhibition, but not following MAO-B inhibition, are in agreement with those of WALDMEIER et al. (1976) who showed that MAO-A is primarily responsible for dopamine deamination in the corpus striatum. In contrast, YANG& NEFF(1974) reported that acute preferential inhibition of either MAO-A or MAO-B leads to increases in rat brain dopamine: in their study, the doses used were comparable to those used here but were administered intravenously and not intraperitoneally. Furthermore, BRAESTRUP et al. (1976), while reporting that dopamine catabolism in the rat brain is by MAO-A suggested that the discrepancy between their findings and those of YANG& NEFF (1974) may be related to the latter group’s use of DL-deprenyl instead of N.< 32, I

11

53

L-deprenyl, the m-isomer being a less potent and less specific inhibitor of MAO-B (KNOLL& MAGYAR, 1972). Adaptive processes resuiting,from chronic M A 0 inhihition

We have observed apparent adaptive changes in 5-HT and possibly in dopamine and NE metabolism following chronic administration of M A 0 inhibiting drugs. The evidence is less obvious in the noradrenergic and dopaminergic systems than in the indoleamine system. With dopamine, significant increases in concentration were seen after 14 days on the clorgyline (1.0 mg/kg) regimen : that the corresponding value 7 days later has decreased towards control values may indicate an adaptive response. The late onset decreases in NE towards control levels following chronic clorgyline (1.0 mg/kg) are slight (20%)and are not accompanied by changes in tyrosine hydroxylase activity. In contrast; MANDELL(1975) showed that following chronic pargyline (1 00.0 mg/kg/day) treatment, initial increases in NE are followed by an apparent adaptation in which NE concentrations decline towards control levels and tyrosine hydroxylase activity is decreased. The differences between the two studies may be dose related. The decreases in 5-HT seen in clorgyline treated animals between 7 and 21 days suggest that adaptation has occurred in this system. Adaptation in the serotonergic system may involve a combination of modified tryptophan uptake and changes in tryptophan hydroxylase activity (KNAPP& MANDELL,1973; NECKERS et al., 1977). We found no changes in tryptophan hydroxylase activity to support this hypothesis and in this study tryptophan uptake was not examined. However, in higher doses, M A 0 inhibitors cause significant increases in tryptophan hydroxylase acet ul., 1977; ROBINSONet a/., in preptivity (CAMPBELL aration) and taken with these other findings suggest that the alterations in amine levels and the previously observed changes in tryptophan hydroxylase activity are related to altered uptake or availability of tryptophan. In this study no changes in food intake or weight gain were observed between drug-treated and control animals, and thus the changes in 5-HT levels may be related to some drug-induced alteration in tryptophan transport or metabolism. Tryptophan hydroxylase assays were done with ‘saturating’ concentrations of substrate and cofactor, and thus while changes in amounts of enzyme would be evident, changes in enzyme kinetics caused by cofactor changes might be masked. The decision to use a ‘saturating’ system was made on the premise that long-term adaptation usually involves de novo synthesis of enzyme (WEINER, 1970). The control of 5HT synthesis and catabolism continues to be a source of controversy centering around whether the rate limiting steps in the process involve primarily tryptophan availability (GRAHAME-SMITH, 1971; FERNSTROM & WURTMAN, 1972; HERYet ai., 1974), or feedback inhi-

54

I. C. CAMPBELL, D. S. ROBINSON, W. LOVENRERG and D. L. MURPHY

bition of 5-HT on tryptophan hydroxylase (MCGEER doleacetic acid (5HIAA) and homovanillic acid (HVA) & PETERS, 1969; MACONet al., 1971; HAMONet al., following probenecid in unipolar depressives treated with arnitriptyline. Psychophannacologia 23, 2 6 3 3 . 1973) or even involve M A 0 (MEEK& FUXE,1971; BRAESTRUP C., ANDERSEN H. & RANDKUP A. (1976) Thc CLARKE & SAMPATH, 1973). monoamine oxidase B inhibitor deprenyl potentiates phenylethylamine behaviour in rats without inhibition of catecholamine metabolite formation. Eur. J. Pharniac. 34, 181-187. CAMPBELL I. C. & MARSHALL E. F. (1974) Effects of chronic regimes of phenelzine, tranylcyprornine and irnipramine on rat brain and 5-hydroxytryptamine. J. Pharrnac. 5, Suppl. 2, 14. I. C.. COLBURN R. W., WALKERM. N., LOVENCAMPBELL BERG w.& MURPHYD. L. (1977) Norepinephrine and serotonin metabolism in the rat brain: Effects of chronic phenelzine administration in Proc. of X t h Congress of the C I N P (DENIKER P.. RADOUCO-THOMAS C . & VILLENEUVEA., eds.). pp. 629-640. Pergamon Press, Oxford. ClCERNO T. J., SHARPEL. G.. ROBINSE. & GROTES. s. (1972) Regional distribution of tyrosine hydroxylase in rat. 3. Neurochern. 19, 2241-2243. S. S. (1973) Studies on the funcC L - ~ R KD.E E. & SAMPATH tional role of intraneuronal monoamine oxidase. .I. Pharriiuc. exp. Ther. 187(3), 539-549. CORRODI H. & FUXE K. (1969) Decreased turnover in central 5-hydroxytryptamine nerve terminals induced by antidepressant drugs of the imipramine type. Eur. J . Pharinac. 7, 5&59. COSTAE. & SANDI.ER M. (1972) in Monoan7ine 0.uidnseN e w Vistas. Advances i n Biochentical Psychopharrnacology, Vol. 5. Raven Press. New York. DONNELLY C. H. (1977) Substrate- and inhibitor-related characteristics of monoamine oxidase. Ph.D. Thesis, Univcrsity of Maryland. DONNELLY C. H. & MURPHYD. L. (1977) Substrate- and inhibitor-related characteristics of human platelet nionoarnine oxidase. Biochein. Pharmac. 26, 853-858. DONNELLY C. 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(1972). BAKHLEY. S . & YOUDIM M. B. H. (1976) Metabolism of FRIEDMAN Partial purification and characterization of tryptophan phenylethylamine in rat isolated perfused lung: Evidence hydroxylase from rabbit hindbrain. J . b i d . Chein. 247, for monoamine oxidase ‘Type B’ in lung. Br. J . Pharmac. 41 65--4173. 56, 125-127. BAUMGARTEN H. G., BJORKLUNDA,, LACHENMAYER L., GOODWINF. K. & POSTR. M. (1974) Brain serotonin, affective illness, and antidepressant drugs: Cerebrospinal ROBINA. & STENEVl v. (1971) Long-lasting selective defluid studies with probenecid. Biochein. Psychopharinac. pletion of brain by 5,6-dihydroxytryptamine. Acta physiol. scund. Suppl. 373, 3-15. 11, 341-356. D. G. (1971) Studies in uivo on the relaBAUMGAKTEN H. G.: VICTOR s. J. & L o V E N B E R G w. (1973) GRAHAME-SMITH Effect of intraventricular injections of 5,7-dihydroxytryptionship between brain tryptophan. brain 5-HT synthesis tamine on rcgional tryptophan hydroxylase of rat brain. and hyperactivity in rats treated with a monoamine oxiJ . Neurochein. 21, 251-252. dase inhibitor and L-tryptophan. J . Neurochem. 18, 1053-1 066. BOCDANSKI D. F., PLETSCHER A,, BRODIEB. B. & UDENFRIEND s. (1956) Identification and assay of serotonin HAMONM., BOURGOIN S. & GLOWINSKI J. (1973) Feedback in brain. J. Pharmac. exp. Ther. 117, 82-88. regulation of 5HT synthesis in rat striatal slices. J . Neurochern. 20, 1727-1745. BOWERSM. B., JR. (1972) Cerebrospinal fluid S-hydroxyinW i t h psychotropic drugs in general, initial changes a r e followed by a diminution in effect if treatment is continued. SPECTOR(1963) observed increases in N E (two-fold) and 5-HT (5-fold) in rat brain stem after 4 days of treatment with iproniazid; t h e 5-HT elevation was maintained for a t least 10 days during continual drug administration, although t h e level of NE declined over days 5-9 of the regimen. VETULANI & SULSER (1975) observed increases in NE-stimulated cyclic AMP production i n t h e rat limbic forebrain following a single d o s e of pargyline; when given chronically, however, this drug produced a decrease in NE-stimulated cyclic AMP production. During chronic tranylcypromine or phenelzine administration there are initial increases in brain NE and 5-HT followed by decreases toward control levels (CAMPBELL & MARSHALL,1974; CAMPBELL et a/., 1977; ROBINSON et al., in preparation). I n three studies (COKKODI & FUXE, 1969; KNAPP& MANDELL,1975; POITOU & BOHUON, 1975), it h a s been shown t h a t initially lithium stimulates 5-HT and NE synthesis b u t after chronic administration, a m i n e synthesis decreases. C h r o n i c imipramine or amitriptyline administration t o depressed patients leads t o a decreased turnover of 5-HIAA in CSF (Bowk~s,1972; GOODWIN & POST, 1974), and changes in turnover of 5-HT have been observed following chronic imipramine administration t o animals (CORRODI & FUXE, 1969). Thus, while adaptation i n monoaminergic systems m a y b e a frequently demonstrable phenomenon, the results presented here indicate that t h e mechanisms of adaptation m a y n o t be a s simple as previously envisaged.

Chronic M A 0 inhibitor administration

55

J. (1968) Effects of drugs on human blood platelet and J. (1974) HERYR., ROUERE., KAN J. P. & GLOWINSKI plasma amine oxidase activity in vitro and in ciuo. BioThe major role of the tryptophan active transport system cheni. Pharnzac. 17, 109-119. in the diurnal variations of 5-hydroxytryptamine synROBINSON D.S., CAMPBELL I. c., WALKER M. N., L o V E N thesis in the rat brain, in Advances in Biochemical P s y BERG W. & MURPHY D. L. Erects of chronic monoamine chopharmacolo~qy, Vol. 1 I , pp. 163-168. Ravcn Press. oxidasc inhibitor treatment on biogenic amine metaboNew York. lism in rat brain. (Submitted). JOHNSTONJ . P. (1968) Some observations upon a new inSCHANBERC s. M., SCHILDKKAUT J. J.. BREESEG. R. & hibitor of monoamine oxidase in brain tissue. Biochem. KOPINI. J. (1968) Metabolism of n~rmetanephrine-[~H] Phormac. 17, 1285-1297. Y. (1975) Enzymic Kiuo R., NUGUCHI T. & MINATWAWA in rat brain. Identification of 3-methoxy-4-hydroxyphenylglycol as the major metabolite. Biochenz. 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(1972) Multiple forms of monoamine oxidase logical effects of monoamine oxidase inhibitors, in in intact mitochondria as characterized by selective inAdoances in Biocheniical Psychopharmacology (COSTAE. hibitors and thermal stability: A comparison of eight & GREENGARD P., eds.), Vol. 5, 393408. Raven Press, mammalian species, in Monoainine Oxidnse-New New York. Vistas. Aduances in Biochemical Psychopharmaco/oyy KOPINI. J.. AXELROD J. & GORDON E. (1961) The meta(COSTAE. & SANDLERM., eds.), Vol. 5, pp. 355-370. bolic fate of [jHI-epinephrine and ['4C]-metanephrine Ravcn Press, New York. in the rat. J . biol. Ckeriz. 236, 2109-2113. TIPTON K. F. (1 972) in Monoanzine Oxidase-New Vistas. LOWRY0. H., ROSERROUGHN. J., FARRA. L. & RANDALL Adcances in Biochenzical Psyohophnri~zacology(COSTAE. R. J. (1951) Protein measurement with the Folin phenol & GREENGARD P., eds.) Vol. 5, pp. 11-24. Raven Press, reagent. J . hid. Chem. 193, 265-275. New York. MACLEAN R., NICHOLSON W. J., PAREC. M. 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The effects of chronic regimens of clorgyline and pargyline on monoamine metabolism in the rat brain.

THE EFFECTS OF CHRONIC REGIMENS OF CLORGYLINE A N D PARGYLTNE ON MONOAMINE METABOLISM IN THE RAT BRAIN I. C. CAMPBELL,' D. S. ROBINSON,W. LOVENBERC an...
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