Tryptophan availability, 5ht synthesis and 5HT function

Pmg.

Neuro-Psychopharmacol.

8 Biol. Psychiat. reserved

Printed inGreat Britain. All rights

TRYPTOPHAN

1989,

Vol. 13, pp.373-379

027tb5646/69

$0.00 + 50

Copyright0 1989 Pergamon Press plc

AVAILABILITY, 5HT SYNTHESIS AND 5HT FUNCTION

SIMON N. YOUNG AND KAREN L. TEFF Department of Psychiatry and Department of Medicine, Division of Experimental Medicine, Montreal, Quebec, Canada.

(Final form,July 1988)

Abstract 1. Introduction 2. Factors affecting firing of 3. Effect of tryptophan on CSF 4. Tryptophan availability and 5. Tryptophan availability and 6. Tryptophan and pain 7. Conclusions Acknowledgements References

5HT neurons 5HT aggression mood

373 374 374 375 375 376 377 377 378 378

Abstract

Young, Simon N. and Karen L. Teff: Tryptophan availability, 5HT synthesis and 5HT function. Prog. Neuro-Psychopharmacol.& Biol. Psychiat.1989, g:373-379 1. Tryptophan increases 5HT synthesis, but the extent to which it increases 5HT release and therefore 5HT function is unclear. 2. The possibility that increased 5HT levels will lead to increased 5HT release is enhanced when 5HT neurons are firing at a higher rate. The rate of firing of 5HT neurons is increased as the level of behavioral arousal increases. Thus, altered tryptophan levels will be more likely to influence brain function at higher levels of arousal. 3. In the rat, tryptophan administration increased CSF 5HT appreciably when the animals were aroused by being put in the dark, but not when they were left in a lighted room. 4. In monkeys, the level of behavioral arousal does seem to influence the effect of altered tryptophan levels on aggression. This is consistent with the fact that altered tryptophan levels had no effect on aggression in normal subjects, but that tryptophan had a therapeuticeffect in pathologically aggressive patients. 5. The confusing literature on the antidepressanteffect of tryptophan can, to some extent, be explained by considering the circumstances in which tryptophan administrationwill lead to increases in 5HT release as well as increases in 5HT synthesis. 6. Although in some circumstances tryptophan can decrease pain perception by activation of spinal 5HT pathways, when it was given to postoperative patients it attenuated morphine analgesia by activation of a 5HT pathway in the brain.

373

K.L.Teff

S. N.Young and

7. The effect of altered which it is given. Keywords: Aggression, pain, tryptophan,

tryptophan

levels

cerebrospinal

antidepressant,

Abbreviations: cerebrospinal inhibitor (MAOI).

fluid

depend critically

on the circumstances

fluid,

5_hydroxytryptamine,

(CSF), 5-hydroxytryptamine

in

mood,

(5HT), monoamine

oxidase

1. Introduction

In humans, as in experimental saturated giving

with its substrate

tryptophan

on the effect

can increase

of tryptophan

The assumption 5HT synthesis

animals,

in clinical

necessarily

conditions

in 5HT function.

we argue that in some circumstances while

We feel

in 5HT function.

aggression

are the end result

in 5HT release will large enough possibility behavior

to overcome

will

Complex

increase

aspects

tryptophan

of factors that influence

apparent

discrepancies

in the studies

2.

When rats are given rate of 5HT neurons 5HT within obviously

5HT release.

scope for altered levels

of arousal

various

aspects

5HT levels tryptophan

systems.

help

levels

to explain

decrease

is mediated

some of the They also

1976).

increase

in the firing

by a local

and the level

increase

in

This effect will

in 5HT levels

apart from 5HT, many other neuronal

to alter

Thus, the

effects of tryptophan.

and Aghajanian,

from systems will

In the cat there is a of behavioral

the rate of 5HT release.

is more likely

Alterations

change in 5HT release.

when 5HT neurons are firing slowly,

of brain function.

systems.

use of tryptophan.

the firing rate of raphe neurons.

At low arousal,

In

firing of 5HT neurons

the tryptophan-mediated However,

justified.

not increase 5HT

when tryptophan

there is a dose-dependent

between raphe unit activity

1979).

the clinical

(Gallager

in

and thus

alter an aspect of mood or

5HT release

and Jacobs, 1976), which

the raphe perikarya

to regulate

correlation Jacobs,

tryptophan

will

on the clinical

Factors affecting

(Trulson

tend to prevent

potentiating interact

concerning

will

of many neuronal

can be modulated

Consideration

hypotheses

is not always

effect of other neuronal

change.

lead to testable

from neurons,

tryptophan

where there is a larger

how 5HT release

5HT (Young, 1986).

is that an increase

only if the changes in 5HT function are

availability

in circumstances

In this review we discuss

trials

of brain function such as mood and

these behaviors

the homeostatic

that

tryptophan may lead to significant

of the interactions

influence

that altering

that this assumption

in other situations

elevations

unstated,

giving

only half

This means

and has led to numerous

lead to an increase in 5HT release

this review

appreciably,

is normally

1981).

which may involve

which is usually

an increase

release

hydroxylase

(Young and Gauthier,

the rate of 5HT synthesis,

behind these trials, will

tryptophan

tryptophan

arousal

(Trulson and

there will

However,

be little

at higher

to enhance 5HT release and thus alter

375

Tryptophan availability, 5HT synthesis and 5HT function

Effect

3.

One possible the

way of

CSF presumably

is

5HT release

derived

from

extracellular

fluid

effect

various

that

the

rat

drugs

(Anderson

amitriptyline,

et

do not

other

hand three

behavioral

cause

carbidopa,

all

that

plus

In preliminary rat

CSF 5HT.

was a trend signif

towards

icant.

were

data).

will

increase

experiment

the

Because

of

a large

normal (T-)

human males

amino acid

proportion

of

supplemented

rat

subjects

(Smith

mixture, tryptophan

brain

were

for

based

inadequate

to detect

of

the

were not other

be tested

by giving

Three

changes

systems subjects

the

various

that

on

home cage

there

statistically day,

but

increase

the animals CSF 5HT, there

and Young,

elevated

levels

of

5HT has an inhibitory levels

received

protein,

Five its

and pencil

to

provocation

have

that

occurred

been

aggression.

amino acid

mixtures

in

plasma

by a T- diet

after in

in the

receiving

the

tests

the

T-group,

the

and also

a

from a “partner”.

either

or because

to any appreciable

the

or a tryptophan

hours

paper

containing

depletion

caused

lowest

in

a tryptophan-free

mixture

casein,

depletion

effect

on aggression

either

a marked acute

could

influence

of

to

(B) amino acid

1974).

response

overcome, which

groups

was at

We used

in hostility to

that

caused

al,

This

was not

same time

tryptophan

tryptophan

subjects’

was found.

the

and aggression

in a normal

et

with

administration

in their

in CSF 5HT (Teff

indicating

tryptophan

aggression.

sufficient

neuronal

(Biggio

and 5-

inhibitor

on 5HT release.

balanced

of plasma

tryptophan

the idea

altering

1986).

occurs

on the

in aggression

of

The T- mixture

level

difference

release

that

when plasma

tested

test

al,

5HT by half

mixtures,

behavioral

et

the

availability

data

but

the serotonin

was consistent

administration

with

tryptophan

animal

of

increase

a nutritionally

A similar

lowered

of

our data

in

On the

pargyline,

decarboxylase

the daytime

at

the

acutely,

3-fold.

and cause

plus

in CSF 5HT that

consistent

at the effect

(T+) mixture.

tryptophan.

amino acid

of

in

from

at

5HT.

effect

rats

tryptophan

Tryptophan

body

we looked

to

significant

4.

on aggression

at the

was performed

are

effect

Thus, active

(10-15X)

room after

These data

enhance

looked

greatly

amino acid

ZO-fold.

was given

5HT function

tryptophan

aromatic

and passed

inhibitor

CSF 5HT about

5HT function

5HT in

on CSF 5HT levels

uptake

potentiate

CSF.

we looked

5HT function

fenfluramine,

functionally

we have

from neurons

and the

to

in the

hypothesis

increased

increase of

of

and statistically

unpublished

thought

effects,

CSF 5HT 16 to

in a darkened

was a larger

arousal

dose

a small

When the

placed

are

5HT levels

this

The MAOI pargyline

which

When tryptophan

at

was released

influence

an index

studies

look

are known to

the peripheral

increased

to

To test

which

a high

CSF 5HT is

5HT that

behavioral

treatments

syndrome,

is

on CSF 5HT

to the CSF.

1987).

gross

hydroxytryptophan

idea

al,

two compounds

which

tryptophan

studying

the brain of

of

because the

extent,

changes

the

The second and then

the

No tests

homeostatic

possibility subjecting

were

in 5HT effect could them to

S.N. Young and K.L.Teff

376

arousing stimuli which would enhance the effect of altered tryptophan levels on SHT release,

Because of doubts about the practicality of giving human subjects a treatment (the Tmixture) that might increase aggression, and then increasing their levels of arousal, we performed this experiment on monkeys (Chamberlain et al, 1987). The design was similar to the human experiment, with animals receiving T-, B or T+ amino acid mixtures. Testing was started five hours later. After a period of observation of the spontaneous acts of aggression in a social group of the animals, they were fed. Because food had been withdrawn the previous evening the animals were hungry and became highly aroused even at the sight of the food. This increased acts of aggression, but more importantly it increased the effects of the amino acid mixtures on aggression. Thus, this study provided some support for our hypothesis that elevated

levels

of

arowa

1 would increase

the functional outcome of altered tryptophan levels.

If elevated levels of arousal do enhance response to tryptophan,then tryptophan should have a therapeuticeffect in impulsive aggressive patients, even if it does not influence measures of aggression in normal subjects. We have obtained preliminary evidence that this may be so. In a double-blind placebo-controlled study of 12 pathologically aggressive schizophrenicpatients, there were significantly fewer incidents on the ward when the patients were on tryptophan than when they were on placebo (Morand et al, 1983).

5.

Tryptophan availability and mood

The literature on tryptophanand mood is confusing and full of apparently contradictory results. We feel that there is a direct association between SHT and mood, because administrationof T- mixtures to normal subjects induces an acute lowering of mood (Young et al, 1985: Smith et al, 1987). However, studies on the antidepressant action of tryptophan have produced mixed results. In a recent review on this topic (Young, 19861, we have suggested that the data are explained by the conclusions that (i) tryptophan potentiates the antidepressantaction of MAOIs (ii) tryptophan is not an antidepressant,by itself, in severely depressed patients (iii) tryptophan is an effective antidepressant in mildly depressed patients.

When tryptophan is given with MAOfs the concomitant increase in 5HT synthesis and decrease in its breakdown results in "spill-over" of 5HT into the synaptic cleft (Grahame-Smith,1971). The "spill-over" is not dependent on neuronal firing and there is a large increase in functionally active 5HT. We demonstrated this in our experiments on rat CSF 5HT (Anderson et al, lY87). Presumably this accounts for the ability of tryptophan to potentiate the action of MAOIs. When tryptophan is given to severely depressed patients the lack of antidepressantaction presumably reflects the fact that

377

Tryptophan availability, 5HT synthesis and 5HT function

there

is

insufficient

exhibit of

effect

of

(Thomson degree

augmentation

psychomotor

al,

1982)

5HT neurons

retardation

may be firing of

the

seen

In some circumstances Thus,

humans.

of

in all

attenuate Young,

this

morphine

this

fact

Tryptophan

in

looked

morphine

but

that

the

the many factors

better

that

tryptophan. effect

is

in depressed

a suitable

that

pain

produced

an ascending

abdominal

for

infusion

the

treatment

1982;

of

surgery. requirements spinal

Abbott

(Abbott

and

or results

et

5HT function

brain

can

tryptophan

Preliminary

morphine

can activate

in

5HT system

and Melzack,

can activate it

spinal

perception

some encouraging

that

(Abbott

the

pain

be useful

after

increases

al, to

5HT pathways

to

Conclusions

it

is

data

exercise

of is

than retarded better

that

response available,

agitated

depressed

level

that

of

(de Coverley

program

should

depressed

potentiate

to

that

should

1987;

of

only

impulsive

enhance

Szabadi,

the antidepressant

to

should

patients. their

is

one

is

be considered

leads

patients

may have

critically

arousal

tryptophan

it

Similarly

by itself,

Veale,

is

depend

level

patients

aggressive

patients

levels

that

but can still

patients.

exercise,

patients

of

as a hypothesis

than overcontrolled

the arousal interesting

it

tryptophan

The hypothesis

the

the clinical

these

of altered

given.

may influence

of

respond

increase It

their

sufficient

by 5HT in

will

intravenous

circumstances

One advanrage

to tryptophan

factors

have

of

tryptophan

how the effects

The first

should

the

Thus,

provide

to decrease

suggest

injury effect

tryptophan

in which

some of

hypothesis.

patients

exhibit

requirements.

illustrates

predictions.

ability

tryptophan

requirements

in different

circumstances

with

its

studies

7.

consistent

do not

can be modulated

for

tissue

at

suggest

working

lack

outpatients

inpatients. to

the

and pain

afferents

Animal

in some circumstances

increase

of

for

often

for

depressed

patients

tryptophan

not mean that

study

review

such

patients

may account

in mildly

rate

by Young (1986),

does

Thus, pain,

This

depressed

arousal

depressed

reviewed

and morphine

decrease

on the

that

tested

analgesia

We have

on pain

1986).

of

in severely

has been

circumstances.

1988).

placebo of

studies,

However,

pain

level

tryptophan

at a sufficient

nociceptive

tryptophan

These

results.

low

5HT release.

6.

cord.

Severely

5HT release.

of

may be due to

psychomotor

augmentation

of

and their

The efficacy

tryptophan.

et

of

retardation

a

testable respond aggressive

Also,

external

response

to

some antidepressant 1988). effect

We predict of

that

tryptophan.

S. N. Young and K. L. Teff

378

Acknowledgements

Some of the work described

here was supported

by grants

Counci 1 and the Nationa 1 Health Research and Development

from the Medical

Research

Program of Canada to S.N.

Young.

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THOMSON, RANKIN, H., ASHCROFT, G.W., YATES, C.M., MCQUEEN, J.K. and CUMMINGS, S.W. (1982) The treatment of depression in general practice: A comparison of L-tryptophan, amitriptyline, and a combination of L-tryptophan and amitriptyline with placebo. Psychol. Med. -12: 741-751.

Tryptophan availability, 5HT synthesis and 5HT function

379

TRULSON, M.E. and JACOBS, B.L. (1976) Dose-response relationships between systematically administeredL-tryptophan or L-5-hydroxytryptophanand raphe unit activity in the rat. Neuropharmacology,-15: 339-344. TRULSON, M.E. and JACOBS, B.L. (1979) Raphe unit activity in freely moving cats: Correlationswith level of behavioral arousal. Brain Res., -169: 135-150. YOUNG, S.N. and GAIJTHIER,S. (1981) Effect of tryptophan administrationon tryptophan, 5-hydroxyindoleaceticacid and indoleacetic acid in human lumbar and cisternal cerebrospinalfluid. J. Neurol. Neurosurg. Psychiatry,-44: 323-328. YOUNG, S.N.,SMITH, S.E.,PIHL, R.O.and ERVIN F.R.(1985) Tryptophan depletion causes a rapid lowering of mood in normal males. Psychopharmacology-87: 173-177. YOUNG, S.N. (1986) The clinical psychopharmacologyof tryptophan. In: Nutrition and the Brain, R.J. Wurtman and J.J. Wurtman (Eds.), pp 49-88. Raven Press, New York.

Inquiries and reprint requests should be addressed to: Dr. S.N. Young Department of Psychiatry McGill University 1033 Pine Avenue West Montreal, Que. H3A 1Al Canada