Monoamine oxidase activity and serotoninergic turnover in human brain

PnqNeum-Psychophamac.

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Vol. 2, pp.225230. 1978. Printed in Great Britain

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MONOAMINE OXIDASE ACTIVITY AND SEROTONINERGIC TURNOVER IN HUMAN BRAIN R. ADOLFSSON', C-G. GOTTFRIES3 L. ORELANDI, B-E. ROOS4, A. WIBERGl and B. W;NBLAD2 Departments of Pharmacologyl, Pathology' and Psychiatry' University of Umed, Umed and Department of Psychiatry, University of Uppsala4, Uppsala, Sweden (Final

form,

March 1978)

Abstract 1. Serotonin (5-HT), its metabolite 5-hydroxyindol acetic acid (5-HIAA) and monoamine oxidase (MAO) activity have been estimated in various parts of the brains from patients without known history of neurologic or psychic disease. It was found that there were strong correlations between the concentrations of 5-HT and 5-HIAA in the various parts of the brain, indicating that synthesis and release of serotonin are proportional but may occur at different rates in the different parts. 2. MAO activities were highly intercorrelated between different parts of the brain in each individual and were also weakly correlated both to concentrations of 5-HT and of 5-HIAA. Those findings may indicate that MAO activity reflects the serotoninergic turnover in the brain. 3. Since there are indirect evidences that platelet and brain MAO activities are positively correlated to each other, the low platelet MAO activities found in patients with suicidal behaviour and/or disposition for alcohol abuse thus seems to indicate a low serotoninergic activity in those patients. Keywords:

brain,

monoamine

oxidase,

serotonin,

S-hydroxyindol

acetic

acid

Introduction Changes in the rate of the turnover of monoamine transmitters are assumed to be of importance in the pathogenesis of some psychiatric disorders. Thus low levels of 5-HIAA (Dencker et-al., 1966; Asberg et al., 1976a) and low increases in the concentrations of S-HIAA and homovanillic acid (HVA) after probenecid loading (Roes and Sjgstrijm, 1969) have been found in the cerebrospinal fluid (CSF) of patients with depressive disorders or subgroups of this disorder. In post mortem investigations on brain tissue low levels of 5-hydroxytryptamine (5-HT) and 5-HIAA have been found in suicides (Shaw et al., 1967; Bourne et al., 1968; Pare et al., 1969; Lloyd et al., 1974). In no signs of disturbed metabolism of 5-HT a recent investigation, however, in suicides has been found (Beskow et al., 1976). Beside estimations of concentrations of biogenic amines and their metabolites studies on the activities of enzyme systems involved in the synthesis or metabolism of those amines may also give valuable information. The activity of MAO (EC 1.4.3.4) which oxidatively deaminates the monoamine transmitter substances has thus been found to be lowered in brain tissue from suicides with a previous history of alcohol abuse (Gottfries et al., 1975) as well as in platelets from alcoholics (Wiberg et al., 19771, and bipolar reports of depressives (Murphy and Weiss, 1972). There are also several low platelet MAO activities in schizophrenics (Murphy et al., 1974). This however, has not been confirmed in some recent studies (Brockingresult, 1976; Belmaker et al., 1976; Eckert et al., in preparation). ton et al., An important

question

for

the

interpretation 225

of the

changed

MAO acti-

226

R. Adolfsson

et al.

vities mentioned above is whether, and if so, what kind of correlations there are between brain monoaminergic activities and the MAO activities. In the present investigation we have studied the correlations between concentrations of 5-HT, 5-HIAA, and MAO activities in the human brain. Materials

the

and Methods

The brain tissue used in the present investigation was, as regards estimation of 5-HT and 5-HIAA concentrations, obtained from 45 patients - male and female - with a mean age of 56.9 + 19.2 years (variance 18 - 95 years) In 20 of these cases (mean age 51.0 + 17.5 years, variance 23 - 86 years) MAO activity was also determined. Pa?ients with neurologic or psychiatric conditions in the anamnesis were excluded. The cause of death was heart infarction or malignant disease. At autopsy different parts of the brain were macroscopically dissected out and stored at -80° until analyses. Methodological aspect of the dissection technique and other experimental conditions have been discussed in detail elsewhere (Gottfries et al., 1975). 5-HT was estimated according to the method of And& and Magnusson (1967), 5-HIAA according to the method of Jonsson and Levander (1970) and MAO activity according to the method of Wurtman and Axelrod (1963) with tryptamine as substrate as described earlier (Gottfries et al., 1975). All analyses could not be done in every dissected part of the brain therefore the numbers of cases vary. The parts of brain investigated the number of cases are given in the tables. The time elapsed between and autopsy varied in our material between 6-148 hs. During this time was no decrease in the levels of 5-HT or in the activities of MAO. As the 5-HIAA values, however, they were corrected for the decrease due time elapsed between death and autopsy by calculation from a regression line. The product-moment between the variables.

method was used for the analyses One-tailed test of significance

and and death there regard! to the

of the correlations was used.

Results Table 1 shows that there was a positive correlation between the concentrations of 5-HT and 5-HIAA. Thus in all the 9 nuclei investigated the correlation coefficients were positive and showed significant levels in 5. Table Product-moment concentrations acid Part

coefficients (r) for the correlations between of 5-hydroxy-tryptamine and 5-hydroxyindolacetic in different areas of the human brain

of the

brain

Hypothalamus (n=21) Nucleus caudatus (n=41) Putamen (n=41) Pallidus (n=20) Thalamus (n=45) Mesencephalon (n=25) Pons (n=24) Medulla oblongata (n=20) Hippocampus (n=21) *

q p
1

r 0.36; 0 -22*** 0.43 0.22, 0.25 0.22, 0.35 0.04 0.24

the

227

MAOand 5-HT in human brain

The MAO activity was estimated in 9 different nuclei of the human brain. A covariation between the MAO activities in all the different parts of the brain is shown in Table 2. The correlation coefficients varied between 0.31 and 0.90 and 35 out of the 36 analyses were on significant levels (pcO.05). Table Product-moment (tryptamine Part 1 2 3 4 5 6 7 8 9 *

of the brain

Hypothalamus Nucleus caudatus Putamen Pallidus Thalamus Mesencephalon Pons Medulla oblongata Hippocampus

2

correlation coefficients for MAO activities oxidizing) between pifferent areas of the human brain

(n=20)

2

3

4

5

6

7

8

9

0.68

0.31 0.69

0.70 0.82 0.49

0.73 0.84 0.60 0.74

0.67 0.85 0.56 0.70 0.65

0.67 0.76 0.47 0.85 0.64 0.75

0.79 0.88 0.36 0.88 0.70 0.81 0.90

0.67 0.83 0.49 0.82 0.80 0.76 0.83 0.80

All correlations except for and Putamen are on significant

that

between the MAO activity level (p
in Hypothalamus

In three parts of the brains (N. Caudatus, Putamen and Thalamus), activity as well as concentration of 5-HT were estimated. Statistical analyses of the correlations between levels of 5-HT and MAO activities resulted in positive correlations in all of the 9 analyses of which were on a significant level (p
MAO three

3

Product-moment correlations between concentrations of 5-HT and MAO activities in various parts of the human brain. Figures within brackets indicate number of brains investigated ** ** of the brain Caudatus Putamen *** Caudatug,, 0.24 (19) 0.14 (20) 0.24 (19) Putamen *** 0.09 (20) 0.35 (19)* Thalamus 0.40 (20)* * pco.05 ** MAO activities correlated to 5-HT concentrations *** 5-HT concentrations correlated to MAO activities Part

Thalamus 0.21 0.34 0.28

**

(20) (20)* (20)

Levels of 5-HIAA and MAO activities were estimated in five parts of the Mesencephalon and Medulla oblongata. brains; N. Caudatus, Putamen, Thalamus, In 16 of the 25 possible correlation analyses the correlation coefficients were positive and in three of these on a significant level (Table 4).

228

R. Adolfsson

Table Product-moment correlations and MAO activities in Part

of the brain

Caudatus**** Putamen**** Thalamus**** Mesencephalon**** Medulla oblongata****

et al.

4

between concentrations various parts of the

Caudatus***

Putam$**

Thalamus***

(n=19)

(n=20)

(n=20)

0.04 0.33* 0.30 0.29 0.28

-0.30 -0.12 0.01 0.12 0.01

-0.06 0.12 0.22 0.43* 0.45**

human

of S-HIAA brain

Mesencephalon*** (n=20) 0.07 0.25 0.12 -0.01 -0.10

Medulla oblongata (=20)

***

-0.08 -0.02 -0.01 0.10 -0.02

* **

pco.05 pco.01 ET:* Concentrations MAO activities

of 5-HIAA correlated to MAO activities correlated to 5-HIAA concentrations Discussion

The present data demonstrate a positive correlation between concentrations of !!I-HT and 5-HIAA in the brain regions investigated (Table 1). Thus a relatively low rate of biotransformation of 5-HT is found in the same individuals who also have a low rate of synthesis of 5-HT. This observation may be interpreted to imply that the number of serotoninergic neurons is of major importance for the turnover of 5-HT. Data in Tables 3 and 4 shows that there is a weak positive correlation between MAO activity and 5-HT and/or 5-HII\A levels in the different parts Whether such a correlation exists also with of the brain investigated. other monoamine transmitter agents than serotonin, for MAO activities assessed with substrates other than tryptamine (Tipton et al., 1973) and for brain tissue from patients with psychiatric or neurological diseases, needs to be investigated. Robinson et al. (1972) found a significant positive correlation between level of S-HIAA and MAO activity in human hindbrain. The correlation, however, only prevailed in patients above 65 years of age and was explained by the fact that above this age there is an increase both in the level of 5HIAA and in the MAO activity. We found no correlation between age and concentrations of 5-HIAA or 5-HT, which would be expected as in our material (n=20) only two patients were older than 65 years. Since the concentrations of 5-HT and 5-HIAA varied independently with age in our material, the significant positive correlations obtained between MAO-activity and levels of 5-HIAA and 5-HT, respectively, cannot be explained by influence of age. A positive correlation between MAO activity and serotoninergic activity could be explained by a mechanism similar to that which causes induction of other enzyme systems e.g. the microsomal drug hydroxylating system in the liver. A positive relation between MAO and monoaminergic activities in rat brain has experimentally been demonstrated both after electroconvulsive shocks (Pryor et al., 1972) and after chronic administration of 1-dopa (Wiberg et al., 1975). However, considering the rather small changes in the MAO-activities obtained by those authors in spite of drastic, long-term treatments and the small differences in the concentrations of 5-HT and 5HIAA observed in brain tissue from human controls (Beskow et al., 19761, such a mechanism seems less likely. Another both the

possibility serotoninergic

would be that a common constitutional turnover and the MAO activity in

the

factor brain.

regulates Such an

229

MAOand 5-HT in human brain explanation is well compatible both with the finding that each individual has a MAO activity that is highly intercorrelated between the different parts of the brain (Table 2) as well as the findings that levels of mouse brain MAO activity is dependent on the genotype of the mouse (Macpike and Meier, 1976).

In brain, only a small part, less than 10 per cent, of the MAO is located within the nerve cells. A correlation between serotoninergic activity and MAO activity thus presupposes either that the small neuronal ~00.1 of MAO varies greatly enough to be discovered in spite of a large pool of unchanged extraneuronal MAO, or, that the extraneuronal MAO is also correlated to the serotoninergic activity. In favour of the last hypothesis are the findings that levels of MAO in thrombocytes seem to be related to monoaminergic activity in the brain. It has been found that patients with suicidal behaviour, besides having low 5-HIAA levels in the CSF (Asberg et al., 1976b) and low MAO activities in the brain (Gottfries et al.. 1975). also have low thrombocyte MAO activities (Buchsbaum et al., 1976)..Low;MAb activities also seem to be present in alcoholics, probability indicating low serotoninergic activity in the CNS of those patients as well (Wiberg et al., 1977). Acknowledgements This research was supported by grants from The Swedish L.O. (No 41451, B-E.R. (No 165-14) and by Lions Council, tion, University of Umea, C-G.G. and B.W. (No 35/1973).

Medical Research Research Founda-

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