Are There Differences between the Brains of Males

and Females?
Renato M.E. Sabbatini, PhD

That men and women are different, everyone knows that.

But, aside from external anatomical and primary and secondary sexual differences, scientists
know also that there are many other subtle differences in the way the brains from men and
women process language, information, emotion, cognition, etc.

One of the most interesting differences appear in the way men and women estimate time, judge
speed of things, carry out mental mathematical calculations, orient in space and visualize
objects in three dimensions, etc. In all these tasks, women and men are strikingly different, as
they are too in the way their brains process language. This may account, scientists say, for the
fact that there are many more male mathematicians, airplane pilots, bush guides, mechanical
engineers, architects and race car drivers than female ones.

On the other hand, women are better than men in human relations, recognizing emotional
overtones in others and in language, emotional and artistic expressiveness, esthetic
appreciation, verbal language and carrying out detailed and pre-planned tasks. For example,
women generally can recall lists of words or paragraphs of text better than men (13).

The "father" of sociobiology, Edward O. Wilson, of Harvard University (10), said that human
females tend to be higher than males in empathy, verbal skills, social skills and security-
seeking, among other things, while men tend to be higher in independence, dominance, spatial
and mathematical skills, rank-related aggression, and other characteristics.

When all these investigations began, scientists were skeptical about the role of genes and of
biological differences, because cultural learning is very powerful and influential among
humans. Are girls more prone to play with dolls and cooperate among themselves than boys,
because they are taught to be so by parents, teachers and social peers, or is it the reverse
order?

However, gender differences are already apparent from just a few months after birth, when
social influence is still small. For example, Anne Moir and David Jessel, in their remarkable and
controversial book "Brain Sex" (11), offer explanations for these very early differences in
children:

"These discernible, measurable differences in behaviour have been imprinted long before
external influences have had a chance to get to work. They reflect a basic difference in the
newborn brain which we already know about -- the superior male efficiency in spatial ability,
the greater female skill in speech."

But now, after many careful controlled studies where environment and social learning were
ruled out, scientists learned that there may exist a great deal of neurophysiological and
anatomical differences between the brains of males and females.

Studying Differences in the Brain

There are now a number of sophisticated neuroscientific methods which allow scientists to
probe minute differences between any two groups of brains. There are several approaches,
brought forth by advancements in computerized image processing, such as tomography
(detailed imaging of the brain using "slices"):

1. volumetric measurements of brain parts: a region is defined, and the computer,

working with a pile of slices, calculates the areas of the brain region, and then
integrates numerically several areas in order to calculate its approximate volume.
Statistical analysis of samples containing several brains are able to discover (or not)
any differences in volume, thickness, etc.
2. functional imaging: using advanced devices, such as PET (Positron Emission
Tomography), fMRI (functional Magnetic Resonance Imaging) or Brain Topographic
Electroencephalography, researchers are able to visualize in two and three dimensions
what parts of brain are functionally activated when a given task is performed by the
subjects.
3. post-mortem examinations. The brains of deceased individuals are excised and sliced.
Modern image analysis techniques are used to detect quantitative differences, such as
the number and form of neurons and other brain cells, the area, thickness and volumes
of brain regions, etc.

Scientists working at Johns Hopkins University, recently reporting in the "Cerebral Cortex"
scholarly journal (1), have discovered that there is a brain region in the cortex, called inferior-
parietal lobule (IPL) which is significantly larger in men than in women. This area is bilateral
and is located just above the level of the ears (parietal cortex).

Furthermore, the left side IPL is larger in men than the right side. In women, this asymmetry is
reversed, although the difference between left and right sides is not so large as in men, noted
the JHU researchers. This is the same area which was shown to be larger in the brain of Albert
Einstein, as well as in other physicists and mathematicians. So, it seems that IPL's size
correlates highly with mental mathematical abilities. Morphological brain differences in
intellectual skills were suspected to exist by neurologists since the times of phrenology
(although this was proved to be a wrong approach), in the 19th century. The end of the 20th
century has witnessed the first scientific proofs for that.

The study, led by Dr. Godfrey Pearlson, was performed by analyzing the MRI scans of 15 men
and women. Volumes were calculated by a software package developed by Dr. Patrick Barta, a
JHU psychiatrist. After allowing for the natural differences in overall brain volume which exist
between the brains of men and women, there was still a difference of 5% between the IPL
volumes (human male brains are, on average, approximately 10 % larger than female, but this
is because of men's larger body size: more muscle cells imply more neurons to control them).

In general, the IPL allows the brain to process information from senses and help in selective
attention and perception (for example, women are more able to focus on specific stimuli, such
as a baby crying in the night). Studies have linked the right IPL with the memory involved in
understanding and manipulating spatial relationships and the ability to sense relationships
between body parts. It is also related to the perception of our own affects or feelings. The left
IPL is involved with perception of time and speed, and the ability of mentally rotate 3-D figures
(as in the well-known Tetris game).

Another previous study by the same group led by Dr. Godfrey Pearlson (9) has shown that two
areas in the frontal and temporal lobes related to language (the areas of Broca and Wernicke,
named after their discoverers) were significantly larger in women, thus providing a biological
reason for women's notorious superiority in language-associated thoughts. Using magnetic
resonance imaging, the scientists measured gray matter volumes in several cortical regions in
17 women and 43 men. Women had 23% (in Broca's area, in the dorsolateral prefrontal cortex)
and 13% (in Wernicke's area, in the superior temporal cortex) more volume than men.
These results were later corroborated by another research group from the School of
Communication Disorders, University of Sydney, Australia, which was able to prove these
anatomical differences in the areas of Wernicke and of Broca (3). The volume of the Wernicke's
area was 18% larger in females compared with males, and the cortical volume the Broca's area
in females was 20% larger than in males.

On the other hand, additional evidence comes from research showing that the corpus
callosum, a large tract of neural fibers which connect both brain hemispheres, is enlarged in
women, compared to men (5), although this discovery has been challenged recently.

In another research, a group from the University of Cincinnati, USA, Canada, presented
morphological evidence that while men have more neurons in the cerebral cortex, women have
a more developed neuropil, or the space between cell bodies, which contains synapses,
dendrites and axons, and allows for communication among neurons (8). According to Dr.
Gabrielle de Courten-Myers, this research may explain why women are more prone to dementia
(such as Alzheimer's disease) than men, because although both may lose the same number of
neurons due to the disease, "in males, the functional reserve may be greater as a larger
number of nerve cells are present, which could prevent some of the functional losses."

The researchers made measurements on slices of brains of 17 deceased persons (10 males
and seven females), such as the cortex thickness and number of neurons in several places of
the cortex.

Other researchers, led by Dr. Bennett A. Shaywitz, a professor of Pediatrics at the Yale
University School of Medicine, discovered that the brain of women processes verbal language
simultaneously in the two sides (hemispheres) of the frontal brain, while men tend to process it
in the left side only. They performed a functional planar magnetic resonance tomographic
imaging of the brains of 38 right-handed subjects (19 males and 19 females). The difference
was demonstrated in a test that asked subjects to read a list of nonsense words and determine
if they rhyme (7). Curiously, oriental people which use pictographic (or ideographic) written
languages tend also to use both sides of the brain, regardless of gender.

Although most of the anatomical and functional studies done so far have focused on the
cerebral cortex, which is responsible for the higher intellectual and cognitive functions of the
brain, other researchers, such as Dr. Simon LeVay, have shown that there are gender
differences in more primitive parts of the brain, such as the hypothalamus, where most of the
basic functions of life are controlled, including hormonal control via the pituitary gland. LeVay
discovered that the volume of a specific nucleus in the hypothalamus (third cell group of the
interstitial nuclei of the anterior hypothalamus) is twice as large in heterosexual men than in
women and homosexual men, thus prompting a heated debate whether there is a biological
basis for homosexuality (6). Dr. LeVay wrote an interesting book about the sex differences in
the brain, titled "The Sexual Brain" (6).

Evolution versus Environment

What is the reason for these gender differences in structure and function?

According to the Society for Neuroscience, the largest professional organization in this area,
evolution is what gives sense to it. "In ancient times, each sex had a very defined role that
helped ensure the survival of the species. Cave men hunted. Cave women gathered food near
the home and cared for the children. Brain areas may have been sharpened to enable each sex
to carry out their jobs". Prof. David Geary, at the University of Missouri, USA, a researcher in
the area of gender differences, thinks that "in evolutionary terms, developing superior
navigation skills may have enabled men to become better suited to the role of hunter, while the
development by females of a preference for landmarks may have enabled them to fulfill the
task of gathering food closer to home." (2) The advantage of women regarding verbal skills
also make evolutionary sense. While men have the bodily strength to compete with other men,
women use language to gain social advantage, such as by argumentation and persuasion,
says Geary.

Author Deborah Blum, who wrote "Sex on the Brain: The Biological Differences Between Men
and Women" (12), has reported the current trend towards assigning evolutionary reasons for
many of our behaviors. She says: "Morning sickness, for example, which steers some women
away from strong tastes and smells, may once have protected babes in utero from toxic items.
Infidelity is a way for men to ensure genetic immortality. Interestingly, when we deliberately
change sex-role behavior -- say, men become more nurturing or women more aggressive --
our hormones and even our brains respond by changing, too."

During the development of the embryo in the womb, circulating hormones have a very
important role in the sexual differentiation of the brain. The presence of androgens in early life
produces a "male" brain. In contrast, the female brain is thought to develop via a hormonal
default mechanism, in the absence of androgen. However, recent findings have shows that
ovarian hormones also play a significant role in sexual differentiation.

One of the most convincing evidences for the role of hormones, has been shown by studying
girls who were exposed to high levels of testosterone because their pregnant mothers had
congenital adrenal hyperplasia (4). These girls seem to have better spatial awareness than
other girls and are more likely to show turbulent and aggressive behaviour as kids, very similar
to boys'.

Fact and Prejudice

But do these differences mean a superiority/inferiority relationship between men and women?

"No", says Dr. Pearlson. "To say this means that men are automatically better at some things
than women is a simplification. It's easy to find women who are fantastic at math and physics
and men who excel in language skills. Only when we look at very large populations and look
for slight but significant trends do we see the generalizations. There are plenty of exceptions,
but there's also a grain of truth, revealed through the brain structure, that we think underlies
some of the ways people characterize the sexes."

Dr. Courten-Myers concurs: "The recognition of gender-specific ways of thinking and feeling --
rendered more credible given these established differences -- could prove beneficial in
enhancing interpersonal relationships. However, the interpretation of the data also has the
potential for abuse and harm if either gender would seek to construct evidence for superiority
of the male or female brain from these findings."

The conclusion is that neuroscience has made great strides in the 90s, regarding the discovery
of concrete, scientifically proved anatomical and functional differences between the brains of
males and females. While this knowledge could in theory be used to justify misogyny and
prejudice against women, fortunately this has not happened. In fact, this new knowledge may
help physicians and scientists to discover new ways to explore the brain differences in the
benefit of the treatment of diseases, the personalized action of drugs, different procedures in
surgeries, etc. After all, males and females differ only by one Y chromosome, but this makes a
real impact upon the way we react to so many things, including pain, hormones, etc.

To Know More
Sabbatini, R.M.E.: The PET Scan: A New Window Into the Brain
Gattass, R.: Thoughts: Image Mapping by Functional Nuclear Magnetic Resonance
Cardoso, S.H.: Why Einstein Was a Genius?
Sabbatini, R.M.E.: Paul Broca: Brief Biography
Sabbatini, R.M.E.: Mapping the Brain
 References

1. Frederikse, M.E., Lu, A., Aylward, E., Barta, P., Pearlson, G. Sex differences
in the inferior parietal lobule. Cerebral Cortex vol 9 (8) p896 - 901, 1999
[MEDLINE].
2. Geary, D.C. Chapter 8: Sex differences in brain and cognition. In "Male,
Female: the Evolution of Human Sex Differences". American Psychological Association
Books. ISBN: 1-55798-527-8 [AMAZON].
3. Harasty J., Double K.L., Halliday, G.M., Kril, J.J., and McRitchie, D.A. Language-
associated cortical regions are proportionally larger in the female brain. Archives in
Neurology vol 54 (2) 171-6, 1997 [MEDLINE].
4. Collaer, M.L. and Hines, M. Human behavioural sex differences: a role for gonadal
hormones during early development? Psychological Bulletin vol 118 (1): 55-77, 1995
[MEDLINE].
5. Bishop K.M. and Wahlsten, D. Sex differences in the human corpus callosum: myth or
reality? Neuroscience and Biobehavioural Reviews vol 21 (5) 581 - 601, 1997.
6. LeVay S. A difference in hypothalamic structure between heterosexual and homosexual
men Science. 253(5023):1034-7, 1991 [MEDLINE].
See also: LeVay, S.: "The Sexual Brain". MIT Press, 1994 [AMAZON]
7. Shaywitz, B.A., et al. Sex differences in the functional organisation of the brain for
language. Nature vol 373 (6515) 607 - 9, 1995 [MEDLINE].
8. Rabinowicz T., Dean D.E., Petetot J.M., de Courten-Myers G.M. Gender differences in
the human cerebral cortex: more neurons in males; more processes in females. J Child
Neurol. 1999 Feb;14(2):98-107. [MEDLINE]
9. Schlaepfer T.E., Harris G.J., Tien A.Y., Peng L., Lee S., Pearlson G.D. Structural
differences in the cerebral cortex of healthy female and male subjects: a magnetic
resonance imaging study. Psychiatry Res. 1995 Sep 29;61(3):129-35 [MEDLINE].
10. Wilson, E.O. - "Sociobiology". Harvard University Press, 1992 [AMAZON].
11. Moir A. and Jessel D. - "Brain Sex". 1993 [AMAZON] See also: Excerpts from the book
12. Blum, D. - "Sex on the Brain: The Biological Differences Between Men and Women".
Penguin, 1998 [AMAZON]
13. Kimura, D. - "Sex and Cognition". MIT Press, 1999 [AMAZON]

The Author

Renato M.E. Sabbatini holds a doctorate in neurophysiology by the Faculty of Medicine of the
University of São Paulo at Ribeirão Preto, Brazil, and was a guest scientist and post-doctoral fellow at
the Max Planck Institute for Neurobiology in Munich, Germany. He is currently chairman of medical
informatics and adjunct professor at the Faculty of Medical Sciences of the State University of
Campinas, in Campinas, Brazil; associate editor and chairman of the editorial board of "Brain & Mind"
Magazine.
Email: sabbatini@nib.unicamp.br
Differences between males and females in rates of
serotonin synthesis in human brain
S. Nishizawa,†‡ C. Benkelfat,§ S. N. Young,§ M. Leyton,§ S. Mzengeza,†‡ C. PubMed
de Montigny,§ P. Blier,§ and M. Diksic†¶ articles
† § ‡
Departments of Neurology and Neurosurgery, and Psychiatry, and Montreal Neurological Institute,
McGill University, Montreal, Quebec, H3A 2B4 Canada
¶
To whom reprint requests should be sent at: Montreal Neurological Institute, McGill University,
by
3801 University Street, Montreal, Quebec H3A 2B4, Canada. e-mail: Mirko@pet.mni.mcgill.ca
Alfred P. Wolf, Brookhaven National Laboratory, Upton, NY
. these
Received April 3, 1996; Accepted January 13, 1997.
This article has been cited by other articles in PMC.
authors
ABSTRACT
Rates of serotonin synthesis were measured in the human brain using • Nishizawa,
S.
positron emission tomography. The sensitivity of the method is indicated by • Benkelfat,
the fact that measurements are possible even after a substantial lowering of C.
• Young, S.
synthesis induced by acute tryptophan depletion. Unlike serotonin levels in • Diksic, M.
human brain, which vary greatly in different brain areas, rates of synthesis
of the indolamine are rather uniform throughout the brain. The mean rate of
PubMed
synthesis in normal males was found to be 52% higher than in normal
related
females; this marked difference may be a factor relevant to the lower
articles
incidence of major unipolar depression in males. • ReviewPet
Keywords: tryptophan depletion, major depression/α-methyl-L-tryptophan/positron studies of
serotonin
emission tomography imaging synthesis
in the
• Other Sections▼ human
o ABSTRACT brain.
o METHODS
o RESULTS [Adv Exp Med
o DISCUSSION Biol. 1999]
o REFERENCES
• Human
brain
Low brain serotonin (5-HT) levels or function have been implicated in serotonin
synthesis
various types of psychopathology, including depression, suicide, capacity
aggression, anxiety, and bulimia (for reviews see refs. 1–3). Until recently, measured
in vivo
the principal methods for studying serotonin metabolism in human brain with alpha-
were determination of the metabolite of serotonin 5-hydroxyindole-3-acetic [C-
11]methyl-
acid (5-HIAA) in cerebrospinal fluid (CSF) and postmortem measurements L-
of brain serotonin and 5-HIAA. Both methods have limitations. In tryptophan
.
particular, neither provides a direct measure of serotonin synthesis in the
living brain. Recently, a method for measuring serotonin synthesis in the [Synapse. 1998]
brain of living mammals has been developed (4–5) and tested successfully
• Serotonin
in dogs (6). The method uses positron emission tomography (PET) and α-
synthesis
[11C]methyl-L-tryptophan as a tracer. The tracer is converted in part to α- rate
measured
[11C]methylserotonin, which accumulates in serotonin neurons, because it is
in living
not a substrate for monoamine oxidase and does not cross the blood–brain dog brain
by positron
barrier.
emission
We report here in vivo measurements of serotonin synthesis in the brain of tomograph
y.
healthy volunteers. Both male and female subjects were studied because
CSF studies suggest that the rate of brain serotonin metabolism is higher in [J Neurochem.
1991]
females than in males (7–8), and because the incidence of major unipolar
depression is higher in women (9). We measured rates of serotonin • Cortical
trapping of
synthesis under two conditions: at baseline and after acute tryptophan
alpha-
depletion (ATD). For ATD, subjects ingest a tryptophan-free mixture of all [(11)C]met
hyl-l-
the essential amino acids. This induces protein synthesis, which
tryptophan
incorporates body stores of free tryptophan into protein, thus reducing the , an index
of
level of this amino acid in tissues, including brain (10). Because tryptophan
serotonin
is the precursor of serotonin, its reduction is thought to lower the rate of synthesis,
is lower in
serotonin synthesis in brain (11–12). ATD was used in the present study for
females
several reasons. First, low serotonin levels have been proposed to relate to than males.
various types of psychopathology (for reviews see refs. 1–3), so any useful
[Neuroimage.
method of in vivo measurements of the serotonin synthesis rate must have a 2006]
demonstrated capability for measuring low rates of serotonin synthesis.
• ReviewAlp
Second, ATD induces a transient reappearance of depressive symptoms in ha[C-
patients under treatment with antidepressants (13). Moreover, ATD also 11]methyl-
L-
produces a mild lowering of mood in normal subjects with a family history tryptophan
of depression (14). It is therefore of interest to determine the degree of PET maps
brain
reduction in serotonin synthesis associated with changes in mood. Data serotonin
obtained in rats suggest that lowering brain tryptophan causes a synthesis
and
compensatory increase in tryptophan hydroxylase (15), which might offset kynurenine
the extent to which ATD lowers serotonin synthesis. pathway
metabolis
m.
• Other Sections▼
o ABSTRACT [J Cereb Blood
o METHODS Flow Metab.
o RESULTS
 o DISCUSSION
o REFERENCES 2000]

METHODS • » See
Selection of Subjects. reviews... |
» See all...
Eight male and seven female subjects, aged from 18 to 35 years old, were
recruited through newspaper advertisements. Inclusion criteria for all
subjects included willingness to participate, good physical and mental
health, and a knowledge of the psychiatric health of their first-degree
Recent
relatives. Exclusion criteria included evidence of a past or present axis-I or
Activity
axis-II DSM-III-R (Diagnostic Statistical Manual) diagnosis in the subject Clear Turn Off Turn
On
or first-degree relatives, and any significant medical illness. Psychiatric
• Differences
evaluations were conducted using the Structured Clinical Interview for between males
and females in
DSM-III-R, nonpatient version (16). All subjects who participated in the rates of serotonin
synthesis in
study gave written informed consent. The study was approved by the human
brainDifferences
Research and Ethics Committee of the Montreal Neurological Institute and between males
and females in
Hospital and the Ethics Committee of McGill University. rates of serotonin
synthesis in
Overview. human brain
On the test day, the subject arrived at 7 a.m. for a MRI of the head, after
Your browsing
which mood was rated (see below), a venous blood sample taken, and a activity is empty.

PET scan performed. The subjects then ingested a tryptophan-deficient Activity recording
amino acid mixture (see below). Five hours later, mood was reevaluated, is turned off.

and a second PET scan performed. Turn recording

back on
ATD.
ATD was performed as described previously (14). The day before the test
day, subjects ingested a low-protein diet. Prepacked, precooked meals, Links
delivered to the subject’s home, contained 160 mg/24 h of tryptophan, 22.6
• Compound
g/24 h protein, and 2,212 kcal/24 h. Subjects were instructed to eat at • PubMed
regular hours and were allowed ad libitum water and up to 3 cups of coffee
• Substance
or tea per day. On the test day the subject arrived, having fasted since the
previous evening. After the first PET scan, the subject ingested a
tryptophan-free amino acid mixture, containing 100 g of amino acids,
consisting of 15 amino acids in 200 ml, as used by Young et al. (17). The
amino acids mixture consisted of L-alanine 5.5 g, L-arginine 4.9 g, L-cysteine
2.7 g, glycine 3.2 g, L-histidine 3.2 g, L-isoleucine 8 g, L-leucine 13.5 g, L-
lysine monohydrochloride 11 g, L-methionine 3 g, L-phenylalanine 5.7 g, L-
proline 12.2 g, L-serine 6.9 g, L-threonine 6.9 g, L-tyrosine, 6.9 g, and L-
valine 8.9 g. This is approximately the amount of amino acids in a 500-g
steak. Because of the unpleasant taste of methionine, cysteine, and arginine,
these amino acids were put into capsules and administered separately. The
rest of the amino acids were mixed with 150 ml of water, 40–50 ml of
chocolate syrup, and 0.5 g of sodium cyclamate. Subjects were asked to
swallow the suspension in as short time as possible because of its somewhat
unpalatable taste. For the next 5 hr, subjects stayed in a single room and
were entertained by being shown one or two of three movies (the same
video movies for all subjects) and allowed to read magazines. The movies
and reading material were chosen to be relatively affectively neutral. Five
hours after the ingestion of amino acids, rating scales were again
administered, and a second blood sample drawn. At the completion of the
session, each subject was given a high-protein snack and was administered
a 1-g L-tryptophan tablet to restore their tryptophan levels. The tryptophan
preparation used is available on prescription in Canada and has not been
associated with any cases of eosinophilia myalgia syndrome (18).
Possible mood changes were evaluated with objective and subjective rating
scales: the Hamilton Depression Rating Scale (19), the Bipolar Profile of
Mood States (POMS) (20, 21), and the Visual Analogue Mood Scale
(VAMS) (22). The bipolar form of the POMS, the principal measure of
mood used in these studies, is composed of six bipolar scales: agreeable–
hostile, composed–anxious, elated–depressed, confident–unsure, energetic–
tired, and clearheaded–confused, and is highly sensitive to nonclinical
changes in mood states. The VAMS consists of 16 100-mm horizontal lines,
each representing a bipolar dimension of a mood state, on which the subject
is instructed to place a perpendicular mark that best describes his mood
state.
PET Scanning.
The radiopharmaceutical, α-[11C]methyl-L-tryptophan, was prepared by the
method reported by Mzengeza et al. (23). The authenticity and
stereochemical configuration of the final compound was confirmed by its
coelution with a known sample of α-methyl-L-tryptophan. After injection of
about 20 mCi of tracer over 2 min, venous blood samples (13 samples) were
drawn at progressively longer time intervals to obtain the plasma input
function. The main reason for using venous blood was ethical, because
otherwise it would have been necessary to keep an arterial catheter in for
about 8 hr, or two catheters would have had to be inserted in the same day.
In another group of subjects scanned with 6-[18F]fluorodopa, the
concentrations of amino acids as well as that of plasma-free tryptophan
were found to be similar in arterial and venous plasma (M.D. et al.,
unpublished work). In an attempt to correct for a possible bias in using the
venous input function in the calculation of K*(ml/g per min), we have
evaluated influence of the venous plasma curve on the calculation of K*, in
a separate group of subjects, in which we sampled venous and arterial blood
simultaneously to determined both input functions. These two input
functions were different during the first 15–20 min, but after 20 min the
values of both curves coincided. From this experiment, we were able to
calculate a correction factor that was used to normalize venous input
function (actual data not given). In this correction, the venous input function
is normalized to the exposure time (θ; min) at 20 min [θ(20) = 33.5 min;
unpublished data]. After venous curves were corrected, the calculated
values of K* agreed within a few percent (the average difference was less
than one) of those calculated by using the arterial input function. This
correction factor also was applied to the data analysis of subjects reported
here. These experiments also showed that the venous input function in the
first 20 min could be corrected by the sagittal sinus curve from individual
subjects (unpublished data). Therefore, on the basis of the above-mentioned
data and consideration of the well-being of the subjects, it was decided that
it was valid to use the venous blood for the input function. The plasma free
tryptophan was measured in the ultrafiltrate of plasma (10,000 molecular
weight cut-off; centrifuged for 5 min at 8,000 × g at 4°C).
PET and MRI images were coregistered and superimposed to help in the
delineation of the brain structures on PET images (24). The anatomical
regions were identified in the MRI, from which outlines were transformed
onto PET images. The MRI and PET images were coregistered using a
program developed at the McConnel Brain Imaging Center, Montreal
Neurological Institute (24). The PET images were acquired by the
Scanditronix PC-2048 15B scanner with 6.5-mm intervals between slices.
The T1-weighted MRI images of 2-mm thickness were used for the detailed
anatomical identification and the coregistration of the PET images. For the
coregistration from each dynamic study, two sets of cumulative images
were generated. The first set represented a sum of images acquired between
3 and 8 min after tracer injection, and the second set by summing images
acquired between 20 and 60 min after tracer injection. The coregistration of
the MRI and PET images was carried out by selecting between 15 and 20
anatomical landmarks. Some of the points used for the alignment of images
were: the sinus confluence, the junction of the transverse and sigmoid sinus,
a center of the cavernous sinus, anterior tip of the straight sinus (early
images), the center of the orbit, the petrous pyramid and frontal sinus,
frontal and occipital poles of the brain, the genu of the corpus callosum, the
midline of the thalamus, and the base of the frontal and temporal lobes. The
tracer concentrations read from these regions were used for further
calculations.
The measurements of serotonin synthesis rates are based on the
unidirectional trapping of α-methyltryptophan in the brain (4, 6). The
method is similar to the deoxyglucose method of Sokoloff et al. (25). We
wish to emphasize that it has been shown before that this tracer is not
incorporated into proteins (4), is not a substrate for tyrosine hydroxylase
(26), and there is no appreciable amount of a metabolite present in the
plasma, so that the plasma level of radioactivity (M.D. et al., unpublished
data), at all times, relates directly to the amount of tracer present. The PET
approach used here is based on the serotonin synthesis measurements in the
dog brain (6). In short, the tissue unidirectional uptake of tracer (K*; ml g−1
min−1) or the slope of the linear portion (4, 6) of the tracer distribution
volume (DV; ml/g) as a function of the exposure time [θ = ∫0T Cp*(t)
dt/Cp*(T); note that θ was normalized as described above] was calculated by
the least-squares method. The slopes (K*) were individually calculated for
10 brain structures in each subject, using the tissue uptake curve between 20
and 60 min (exposure time θ being between approximately 35 and 100
min). The calculation was done on the tissue time–activity curves before
(baseline) and after ATD. From the slope K*, the plasma free tryptophan
(Cp; pmol g−1 min−1), and the in vivo measured lumped constant (LC = 0.42)
(5), regional serotonin synthesis rates (R; pmol g−1 min−1) were calculated as
R = Cp K*/LC (6). The LC is defined in one formulation as the ratio of the
ratios of the Michaelis–Menten constants and the tissue volume of
distribution for tracer and tracee. It can also be defined as the ratio of the
tissue uptake of tracer and tracee (5). The regional LC was measured in vivo
by a direct comparison of the unidirectional tissue uptake of tryptophan and
α-methyltryptophan in the rat brain (5). There is no evidence that the LC in
human and rat brain are the same. However, the LC consists of the ratio of
constants for α-methyltryptophan and tryptophan. Thus, it is likely that the
ratio does not vary much between different species, nor between different
brain regions (5, 25). For example the LC for 2-deoxy-D-glucose in human
brain is similar to the one in rat (27). It is not known whether the LC is the
same in the subject’s brain before and after ATD. However, rat protein
synthesis in the brain does not change when an amino acid is increased, in
contrast to some other organs (e.g., liver; refs. 28, 29). At any rate, if there
were a change in the LC, it would probably be the same in males and
females rendering sex comparison valid.
The reduction in serotonin synthesis (ratio of values before and after ATD)
in the individual subjects was calculated as an antilogarithm of the
differences of the log-transformed synthesis rates. Because in the log-
transformed data the ratios represent differences between the logarithms,
calculation of the SD of the ratio was simplified. The SD of the mean was
calculated as the square root of the sum of squares of the relative errors of
the individual serotonin synthesis rates. The log transformation of the data
yielded normal distribution of data meeting the requirements for the
statistical analysis of the ratios. Statistical analysis of all data was done
using BMDP statistical programs (BMDP, Los Angeles, 1993).

• Other Sections▼
o ABSTRACT
o METHODS
o RESULTS
o DISCUSSION
 o REFERENCES

RESULTS
Examples of the plots of the tissue distribution volume (DV; ml/g) as a
function of the exposure time (θ; min) exemplifying the shape of the curve,
and the existence of a linear portion suggesting that the biological system
achieved an apparent steady state, are shown in Fig. Fig.11 for male (Fig.
(Fig.11A) and female (Fig. (Fig.11B) subjects. In Fig. Fig.1,1, the curves
obtained at baseline (upper curves) and after tryptophan depletion (lower
curves) are shown. The analysis of these curves was also carried out by
fitting them to the full operation equation (4) in an attempt to compare
values of K* obtained using a sinus corrected venous curve as input
function. There was an excellent agreement between values of K*
calculated from the linear portion of the graph and those obtained from the
fit to the full-operation equation, indicating further that the biological
system came to or close to an apparent steady-state. The latter are
requirements for the validity of the use of the approach described by Patlak
et al. (30).
Figure 1
A set of representative plots exemplifying the tissue distribution
volume (ml/g) in the frontal cortex of a male (A) and female (B)
subjects as a function of the exposure time θ [θ = ∫0T Cp*(t)
dt/Cp*(T); (more ...)

Figure 1
A set of representative plots exemplifying the tissue distribution volume (ml/g) in the
frontal cortex of a male (A) and female (B) subjects as a function of the exposure time
θ [θ = ∫0T Cp*(t) dt/Cp*(T); min]. The upper curves in A and B were obtained at baseline,
and the lower curves were obtained after tryptophan depletion.
Examples of PET images obtained in a male and a female subject are
provided in Fig. Fig.2.2. Regional serotonin synthesis rates are color coded
(vertical bar). Serotonin synthesis rates used to construct these pictorial
presentations were calculated from the brain radioactivity distribution with
certain approximations, because serotonin synthesis rates are related to the
slope of the curves, which cannot be visualized in a static image. The
images collected between 30 and 60 min after tracer injection were summed
to obtain a better visual representation for regional serotonin synthesis rates.
Briefly, the brain radioactivity (nCi/g) was converted into DV(T) (ml/g) by
dividing it with the plasma tracer concentration [Cp*(T); nCi/ml]. From
these plots, the K* (ml g−1 min−1), and the apparent volume of the precursor
(Vapp; ml/g) were calculated for each brain structure as described for the dog
brain before (6). The average value of Vapp (ml/g) was calculated from the
values for the individual brain structures in a particular subject, and this
average value of Vapp was subtracted from the DV images on pixel by pixel
bases. DV images were then converted into serotonin synthesis rate images
by multiplying them by Cp (plasma free tryptophan; pmol/ml) and dividing
them by LC. This conversion is also supported by our recently reported
experiments in rat brain (31), where we showed that the Vapp is almost
uniform through the rat brain.
Figure 2
Representative PET images obtained from a male and a female
subject are shown. The serotonin synthesis rates for this
representation were calculated as described (see text). Images are
shown before (A and B) and after (C and D) depletion of the
plasma (more ...)

Figure 2
Representative PET images obtained from a male and a female subject are shown. The
serotonin synthesis rates for this representation were calculated as described (see text).
Images are shown before (A and B) and after (C and D) depletion of the plasma
tryptophan. A and B were obtained from a male and a female subject before tryptophan
depletion, respectively. The color bar on the right in the same row gives an indication
of synthesis. C and D were obtained from a male and female subject after tryptophan
depletion, respectively. The color bar on the right in the same row cross-references
colors in the images and the synthesis rates. E shows MRI images obtained at the same
level as the PET images. Images in male and female subjects are at the same level.
The average rates of serotonin synthesis obtained in male (n = 7) and female
(n = 7) subjects before and after ATD are given in Table 1. These rates at
baseline were about 75 and 50 pmol g−1 min−1 in males and females,
respectively (Table 1). After the ATD the rates of synthesis were about 9.5
and 1.5 pmol g−1 min−1 in males and females, respectively. The rate of
serotonin synthesis was reduced by ATD by a factor of about 9.5 in males
and of about 40 in females. One male was excluded from these calculations
on the basis of the χ2 statistic, (P < 0.001), indicating that he was an outlier.
The rates in this subject were rather high and although they would not affect
the mean of the male subjects significantly, they would substantially
increase the SDs. However, the inclusion of this subject’s values did not
change the main effects observed.
Table 1
Serotonin synthesis rates in male and female subjects before and
after tryptophan depletion

The rates of serotonin synthesis (Table 1) were rather uniform throughout

the terminal fields of serotonergic neurons of the human brain, as is the case
in the rat brain (5). The resolution of our scanner did not permit
determination of serotonin synthesis rates in the serotonergic cell body
areas of the brain stem.
Male subjects had higher levels of plasma free tryptophan than female
subjects (Table 2), but there was no significant correlation between plasma
free or total tryptophan levels and rates of serotonin synthesis in either
group of subjects (Tables 1 and 2). There was no significant difference in
total plasma tryptophan in male and female subjects either at baseline or
after ATD (Table 2). The use of the ratios of free or total plasma tryptophan
to the plasma levels of other large neutral amino acids as covariate in the
ANOVA analysis did not affect the degree of significance of differences
between serotonin synthesis rates in male and female subjects. ATD
induced a significant reduction (P < 0.05 for the sex–time interaction; two-
way repeated measures ANOVA on the log transformed data) of serotonin
synthesis, as indicated by the ratios of synthesis rates before and after ATD.
ATD did not have a statistically significant (P > 0.05; two-tailed paired t
test) effect on mood ratings overall, though one of seven female subjects
(but none of the male subjects) showed signs of distress, low mood, and a
crying spell by the end of the second scan.
Table 2
Plasma total and free tryptophan in male and female subjects
before and after depletion

• Other Sections▼
o ABSTRACT
o METHODS
o RESULTS
o DISCUSSION
o REFERENCES

DISCUSSION
Until recently, the principal method for estimating the rate of serotonin
metabolism in the human central nervous system has been the measurement
of 5-HIAA in CSF. However, such measurements in lumbar CSF may
reflect, in part, spinal cord metabolism of serotonin, and also can be
influenced by factors such as the transport of 5-HIAA into and out of the
CSF, mixing of CSF, as well as the rate of serotonin catabolism (32). Thus,
CSF 5-HIAA level is a poor index of dynamic changes in serotonin
synthesis in brain tissue. The advantages of the PET method are substantial:
(i) it measures serotonin synthesis directly in various brain regions; (ii) it
can be repeated after a short time interval; (iii) it is less invasive than a
lumbar puncture; and (iv) the results are not influenced by a wide variety of
factors unrelated to the rate of serotonin synthesis that can alter CSF values.
Our method, like other PET methods, involves certain assumptions, as
detailed in previous papers (4, 6). The main disadvantages of our method
are cost and availability.
The mean rates of serotonin synthesis determined in the present study range
from 66 to 85 pmol g−1 min−1 for different brain areas in male subjects and
47 to 55 pmol g−1 min−1 in female subjects. A surprising uniformity in the
different areas studied, contrasting with the variable serotonin levels
measured in different areas of postmortem brains. For instance, the ratio of
serotonin levels in a region with high content, such as caudate, to an area
with a low content, such as frontal cortex, is of about 15 (33, 34). In the
present study, the ratio for the rate of synthesis in these two areas was 0.9
for male and 1.0 for female subjects. The density of serotonergic
innervation of different areas can be estimated by measuring the number of
serotonin uptake sites. In postmortem studies on the density of re-uptake
sites measured by the binding 3H-labeled imipramine, cyanoimipramine, or
paroxetine in human brain, ratios of the number of binding sites in the
caudate to that in the frontal cortex were in the range between 1.2 and 3.3
(35–38). This suggests that the serotonergic innervation of the frontal cortex
is less dense than that of the caudate. However, this difference is
substantially less than that of serotonin levels. The uniformity observed in
the present study in different brain areas suggests that the rate of serotonin
synthesis depends on factors other than the density of innervation. Using the
postmortem concentrations of serotonin reported by Young et al. (34) for
the putamen (466 ng/g) and temporal cortex (11 ng/g), and the present data
for the rates of serotonin synthesis, the time required to synthesize an
amount of serotonin equal to the tissue content is 31 and 48 min for the
putamen of males and females, respectively, and 0.8 and 1.3 min,
respectively for the temporal cortex. Thus, for yet unidentified reasons, the
storage of serotonin is very much less, in relation to its rate of synthesis, in
cortex than in basal ganglia. One could speculate that this seemingly
redundant capacity to synthesize serotonin in cortical areas could be related
to the ability of the serotonergic system to provide rapidly enough of its
neurotransmitter in situations where increased availability is required.
The marked difference in the rates of serotonin synthesis between male and
female subjects is, to our knowledge, a new finding. In the few postmortem
studies where male-female differences in the brain serotonin levels were
examined, no significant differences were found (38, 39). Moreover, no
differences have been found between the number of serotonin re-uptake
sites in the brains of male and female subjects (35, 39). However, two CSF
studies have suggested a higher rate of serotonin synthesis in female than
male subjects (7, 8), opposite to the results of the present study. One
possible explanation for this apparent discrepancy could be that the system
transporting 5-HIAA out of CSF is less active in female than male subjects.
The rate of serotonin synthesis will depend on numerous factors including
the free plasma tryptophan levels, the plasma levels of tryptophan relative
to the other large neutral amino acids, the activity of the system that
transports the large neutral amino acids into brain, the gene expression of
tryptophan hydroxylase, degradation of tryptophan hydroxylase,
compartmentalization of tryptophan and tryptophan hydroxylase in brain
cells, as well as probably numerous other factors. Any difference in the
level to which plasma CpTrp is decreased in males and females is in part
related to the metabolic differences of their bodies, and as suggested by data
presented in this manuscript, possibly could have influence, by rather
complex and not yet well understood processes, on the brain biology. If one
accepts the biological model derivation, which is based on the plasma input
function, then it must be also accepted that the rate of serotonin synthesis
must be somehow related to the plasma CpTrp, but the relationship is not
necessarily linear. Indeed, the presented data suggest that despite reduction
in the CpTrp of 10 and 3.5 times in females and males, respectively, the rate
of serotonin synthesis was reduced 40 and 10 times in females and males,
respectively. From this large difference between reduction in CpTrp and the
serotonin synthesis rate it is obvious that substantially more complex
mechanism(s) controlling brain serotinin synthesis is (are) involved here.
Averaging over the different brain areas, the rate of serotonin synthesis is
52% greater in male than in female subjects. This is one of the largest
differences between the brains of males and females that is not related to
hormone binding sites. The reason for this difference is not clear at this
time. Tryptophan is taken up into the brain by a transport system that is
common to all the large neutral amino acids. There is competition between
the large neutral amino acids for this system, and the plasma ratio of
tryptophan to the other large neutral amino acids best explains its brain
level, at least in laboratory animals (41). In the present study, using ratios of
the plasma level of free tryptophan to the levels of the other large neutral
amino acids as a covariant in the ANOVA analysis did not alter the
statistical significance of this difference. This suggests that differences in
peripheral tryptophan availability do not explain the sex difference in brain
serotonin synthesis, unless there is a large component for the entry of
tryptophan into human brain that is not affected by the other large neutral
amino acids. In rat brain under steady-state conditions, we reported a
substantial diffusion component for the blood–brain transfer of tryptophan
(42). What evidence there is from human CSF studies suggests that other
large neutral amino acids reduce, as in experimental animals, tryptophan
uptake into human brain (43–45).
The possible association between serotonin and major depression suggests
that the rate of serotonin synthesis in women may be related to the higher
incidence of major unipolar depression. Animal data indicate that female
rats adapt less readily than male rats to stress in an animal model of
depression, and that serotonin may play a role in this difference (46).
Human males and females seem to have similar stores of brain serotonin,
but, if there were increased utilization of serotonin during stressful
situations, a lower rate of synthesis in the females may not be as efficient in
maintaining adequate stores of the neurotransmitter. Thus, in such
situations, serotonin levels would decline more in female than in male
subjects, possibly increasing vulnerability to depression.
The effect of ATD in the present study (Table 1) show that (i) the PET
method is capable of measuring rates of serotonin synthesis considerably
below baseline rates (e.g. before ATD), and is therefore a suitable method
for studies of patients with low rates of serotonin synthesis, and (ii) ATD
causes a marked lowering of brain serotonin synthesis in all brain regions
examined. The magnitude of the effect in the brain was somewhat greater
than the decline in free plasma tryptophan. While the effect of ATD on
serotonin synthesis was uniform throughout the brain, the effects on
serotonin levels (as opposed to serotonin synthesis) are unlikely to be
uniform. For instance, in the cortex, where the rate of serotonin synthesis is
large compared to its level, ATD-induced decline in levels of serotonin are
likely to occur more rapidly than in other structures.
The reason for the greater biochemical effect of ATD in women than in men
is not known. We have reported that healthy women were more susceptible
than healthy men to a lowering of mood after ATD (47). The present results
suggest that this might be related to ATD causing a larger decrease in the
rate of serotonin synthesis in women.
The results of this study raise a number of questions. First, why are rates of
serotonin synthesis so similar in different brain areas, when the density of
innervation varies more, and serotonin levels vary even more? Second, what
are the causes and implications of the higher rates of serotonin synthesis in
male brains? Gender-related differences in serotonin synthesis could be
related to early serotonergic events in the brain organization and/or effects
of circulating gonadal hormones. A better understanding of the gender
differences reported here might be provided by studies of individuals with
pathologically altered levels of gonadal hormones. The possible role of
serotonin synthesis in susceptibility to depression could be investigated by
studying subjects who are at elevated risk for depression and depressed
patients presenting with a major depressive episode.
ACKNOWLEDGMENTS
We thank the staff of the Medical Cyclotron and PET Units of the
McConnell Brain Imaging Centre, Montreal Neurological Institute. This
research was supported by grants from the U.S. Public Health Service
(M.D., RO1-NS-29629) and the Medical Research Council of Canada
(S.N.Y. and C.B.). P.B. is a recipient of a Medical Research Council
Scientist Award.
ABBREVIATIONS

CSF cerebrospinal fluid

5-HIAA 5-hydroxyindole-3-acetic acid

PET positron emission tomography

ATD acute tryptophan depletion

LC lumped constant

DV distribution volume

• Other Sections▼
o ABSTRACT
o METHODS
o RESULTS
o DISCUSSION
 o REFERENCES

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FIGURES AND TABLES

Click on image to enlarge

Figure 1

Click on image to enlarge

Figure 2
Articles from Proceedings of the National Academy of Sciences of the
United States of America are provided here courtesy of
National Academy of Sciences

• A new method to measure brain serotonin synthesis in vivo. I. Theory and basic data for a biological
model.
[J Cereb Blood Flow Metab. 1990]

• Determination of the lumped constant for the alpha-methyltryptophan method of estimating the rate of
serotonin synthesis.
[J Neurochem. 1995]

• Serotonin synthesis rate measured in living dog brain by positron emission tomography.
[J Neurochem. 1991]

• Tryptophan, 5-hydroxyindoleacetic acid and indoleacetic acid in human cerebrospinal fluid:

interrelationships and the influence of age, sex, epilepsy and anticonvulsant drugs.
[J Neurol Neurosurg Psychiatry. 1980]

• Interacting neurotransmitter systems. A non-experimental approach to the 5HIAA-HVA correlation in

human CSF.
[J Psychiatr Res. 1986]

• Depression in women: implications for health care research.

[Science. 1995]

• Cycloheximide blocks the fall of plasma and tissue tryptophan levels after tryptophan-free amino acid
mixtures.
[Life Sci. 1991]

• Rapid depletion of serum tryptophan, brain tryptophan, serotonin and 5-hydroxyindoleacetic acid by a
tryptophan-free diet.
[Life Sci. 1974]
See more articles cited in this paragraph

• Mood-lowering effect of tryptophan depletion. Enhanced susceptibility in young men at genetic risk for
major affective disorders.
[Arch Gen Psychiatry. 1994]

• Tryptophan depletion causes a rapid lowering of mood in normal males.

[Psychopharmacology (Berl). 1985]

• Eosinophilia-myalgia syndrome.
[CMAJ. 1990]

• Rating depressive patients.

[J Clin Psychiatry. 1980]

• Evidence for bipolar mood states.

[J Pers Assess. 1982]

• Asymmetric radiosynthesis of alpha-[11C]methyl-L-tryptophan for PET studies.

[Nucl Med Biol. 1995]

• A new method to measure brain serotonin synthesis in vivo. I. Theory and basic data for a biological
model.
[J Cereb Blood Flow Metab. 1990]

• Serotonin synthesis rate measured in living dog brain by positron emission tomography.
[J Neurochem. 1991]

• The [14C]deoxyglucose method for the measurement of local cerebral glucose utilization: theory,
procedure, and normal values in the conscious and anesthetized albino rat.
[J Neurochem. 1977]

• Determination of the lumped constant for the alpha-methyltryptophan method of estimating the rate of
serotonin synthesis.
[J Neurochem. 1995]

• Concomitant in vivo measurement of lumped and rate constants for F-18 FDG in cat brain.
[Neurol Med Chir (Tokyo). 1988]
 See more articles cited in this paragraph

• A new method to measure brain serotonin synthesis in vivo. I. Theory and basic data for a biological
model.
[J Cereb Blood Flow Metab. 1990]

• Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data.

[J Cereb Blood Flow Metab. 1983]

• Serotonin synthesis rate measured in living dog brain by positron emission tomography.
[J Neurochem. 1991]
• ReviewAlpha-methyl-L-tryptophan as a tracer to study brain serotonergic system.
[Neurochem Res. 1995]

• Determination of the lumped constant for the alpha-methyltryptophan method of estimating the rate of
serotonin synthesis.
[J Neurochem. 1995]
• ReviewMonoamine metabolites in lumbar CSF: the question of their origin in relation to clinical studies.
[Brain Res. 1974]

• A new method to measure brain serotonin synthesis in vivo. I. Theory and basic data for a biological
model.
[J Cereb Blood Flow Metab. 1990]

• Serotonin synthesis rate measured in living dog brain by positron emission tomography.
[J Neurochem. 1991]

• Serotonin concentrations and turnover in brains of depressed suicides.

[Brain Res. 1989]

• Reduced brain 5-HT and elevated NE turnover and metabolites in bipolar affective disorder.
[Biol Psychiatry. 1994]

• Autoradiography of antidepressant binding sites in the human brain: localization using [3H]imipramine
and [3H]paroxetine.
[Neuroscience. 1988]

• [3H]paroxetine binding is altered in the hippocampus but not the frontal cortex or caudate nucleus from
subjects with schizophrenia.
[J Neurochem. 1995]

• [3H]paroxetine binding is altered in the hippocampus but not the frontal cortex or caudate nucleus from
subjects with schizophrenia.
[J Neurochem. 1995]

• Serotonergic interhemispheric asymmetry: neurochemical and pharmaco-EEG evidence.

[Prog Neuropsychopharmacol Biol Psychiatry. 1991]

• Autoradiography of antidepressant binding sites in the human brain: localization using [3H]imipramine
and [3H]paroxetine.
[Neuroscience. 1988]

• Tryptophan, 5-hydroxyindoleacetic acid and indoleacetic acid in human cerebrospinal fluid:

interrelationships and the influence of age, sex, epilepsy and anticonvulsant drugs.
[J Neurol Neurosurg Psychiatry. 1980]

• Interacting neurotransmitter systems. A non-experimental approach to the 5HIAA-HVA correlation in

human CSF.
[J Psychiatr Res. 1986]

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