The-Pineal-Gland, dmt
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THE PINEAL GLAND
The function
of this
small organ near the center of the
mammalian
brain
has long been
a mystery. Recent studies
indicate that it is
a "biological
clock" that regulates the activity
of
the
sex glands
by Richard
J.
Wurtman and
Julius Axelrod
Buried
nearly in the center of the
brain in
any mammal is a small
white structure, shaped
somewhat
like a pinecone,
called the pineal body.
In man this organ is roughly a
quarter
of an inch long and weighs about a
tenth of a gram.
The function of the
pineal body has never been clearly
understood. Now that the role of the
thymus gland in establishing
the body's
immunological
defenses has been dem-
onstrated, the pineal has become
per-
haps the last great
mystery in the
physiology of mammalian organs. This
mystery
may be nearing a solution:
studies conducted within
the past few
years indicate that the pineal is an
in-
tricate
and sensitive "biological clock,"
converting cyclic nervous
activity gen-
erated by light in the environment into
endocrine-that is,
hormonal-informa-
tion. It
is not yet certain what physio-
logical processes depend
on the pineal
clock for cues, but the evidence at hand
suggests
that the pineal participates in
some way in the regulation of the go-
nads, or sex glands.
eal in young
female rats was frequently
followed by an enlargement of the
ovaries, but the microscopic appearance
of the ovaries
did not change consistent-
ly, and replacement of the extirpated
pineal by transplantation seemed
to
have little or no physiological effect.
Most experimental animals could sur-
vive the loss of the pineal body
with no
major
change in appearance or function.
In retrospect
much of the difficulty
early workers had in exploring
and de-
fining
the glandular function of the
pineal arose from limitations
in the
traditional concept of an endocrine or-
gan.
Glands were once thought to be
entirely dependent
on substances in
the
bloodstream both for their own con-
trol and for their effects
on the rest of
the body: glands secreted hormones into
the blood
and were themselves regu-
lated by other hormones, which
were
delivered to them by the circulation.
The secretory activity of a
gland was
thought to be maintained at a fairly
con-
stant
level by homeostatic mechanisms:
as the level of a particular
hormone in
the bloodstream rose, the gland invari-
ably responded by decreasing its secre-
tion of that hormone; when the
level of
the hormone fell, the gland increased
its secretion.
In the past two decades this
concept
of how the endocrine system works has
proved inadequate to explain several
kinds of glandular response,
including
changes in hormone secretion brought
about by
changes in the external en-
vironment and also regular cyclic
changes in the secretion of certain hor-
mones (for example,
the hormones re-
sponsible for the menstrual cycle
and
the steroid hormones
that are produced
on a daily cycle by the adrenal gland).
Out of the realization that
these and
other endocrine responses must depend
in some way on interactions between the
glands
and the nervous system the new
discipline
of neuroendocrinology
has
developed.
In
recent years much attention has
centered on the problem
of locating the
nervous structures that participate in
the control
of glandular function. It
has been known for some time that spe-
cial types
of organs would be needed to
"transduce" neural information into
en-
docrine information. Nervous tissue is
specialized
to receive and transmit in-
formation directly from
cell to cell; ac-
cording to the traditional view, glands
are
controlled by substances in the
bloodstream and
dispatch their mes-
sages to target organs by the secretion
of hormones into the bloodstream.
In
order to transmit information from the
nervous
system to an endocrine organ
a hypothetical
"neuroendocrine trans-
ducer" would require some of the spe-
cial characteristics of both neural
and
endocrine tissue. It should respond to
substances (called neurohumors) re-
leased
locally from nerve endings, and
it should contain the biochemical ma-
chinery necessary for synthesizing a
hormone and releasing it into the blood-
stream. Three such neurosecretory
sys-
tems have so far been identified. They
are (1) the hypothalamus-posterior-
pituitary system, which secretes the
antidiuretic hormone and oxytocin, a
hormone that causes the uterus to con-
tract during labor; (2) the pituitary-
releasing-factor
system, also located in
the hypothalamus, which secretes
poly-
peptides that control the function of
the pituitary gland, and (3) the adrenal
medulla, whose cells respond to a ner-
vous input by
releasing adrenaline into
the bloodstream.
The advent
of neuroendocrinology
has provided a conceptual framework
A Fourth Neuroendocrine Transducer
Until quite recently most
investi-
gators thought that the mammalian pin-
eal was simply
a vestige of a primitive
light-sensing organ: the "third eye"
found in certain cold-blooded
verte-
brates such as the frog. Other workers,
noting the precocious sexual develop-
ment of some
young boys with pineal
tumors, had proposed that in mammals
the pineal was a gland. When
the stan-
dard endocrine tests were applied to
determine
the possible glandular func-
tion of the pineal, however, the results
varied so much
from experiment to ex-
periment that few positive
conclusions
seemed justified. Removal of the pin-
50
PINEAL BODY
CORPUS CALLOSUM
CEREBELLUM
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PINEAL BODY
CEREBELLUM
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CALLOSUM
TWO
VIEWS of the human
brain reveal the central
position of the
pineal body. Section
at top is cut in the
median sagittal plane
and
is viewed from
the side. Section
at bottom is cut
in a horizontal
plane
and is viewed
from above; an additional
excision has
been
made
in this view to reveal
the region immediately
surrounding
the pineal. In mammals
the pineal
is the only unpaired
midline
organ
in the brain. The name
"pineal" comes
from the organ's
re-
semblance to a pinecone,
the Latin equivalent
of which
is
pinea.
51
out of its "storage bin" in the lateral
ventricles of the brain. In the 17th
century Ren6
Descartes embellished this
notion; he believed that the pineal
housed the seat of the rational soul. In
his formulation the eyes perceived the
events of the real world and
transmitted
what they saw to the pineal by way of
"strings" in the brain
[see illustration
below].
The pineal responded by allow-
ing humors to pass down hollow tubes
to the muscles, where they produced
the appropriate responses. With the
hindsight of 300 years
of scientific de-
velopment, we can admire this prophet-
ic formulation of the pineal as a neuro-
endocrine transducer!
In the late 19th and early 20th cen-
turies the pineal fell from its exalted
metaphysical state. In 1898 Otto Heub-
ner, a German physician, published a
case report of a young boy who had
shown precocious puberty and was also
found to have a pineal tumor. In the
that has been most helpful in charac-
terizing the role of the pineal gland. On
the basis of recent studies conducted by
the authors and their colleagues at the
National Institute of Mental Health, as
well as by investigators at other institu-
tions, it now appears that the pineal is
not a gland in the traditional sense but
is a fourth neuroendocrine transducer;
it is a gland
that converts a nervous in-
put into a hormonal output.
course of the next 50 years many other
children with pineal tumors and pre-
cocious sexual development
were de-
scribed, as well
as a smaller number of
patients whose pineal tumors were as-
sociated with delayed sexual develop-
ment. Inexplicably almost all the cases
of precocious puberty were observed in
boys.
In a review of the literature on pin-
eal tumors published in 1954 Julian I.
Kitay, then a fellow in endocrinology at
the Harvard Medical School,
found that
most of the tumors associated with pre-
cocious
puberty were not really pineal
in origin but either were tumors of sup-
porting tissues or were teratomas (prim-
itive tumors containing many types of
cells). The tumors associated with de-
layed puberty, however, were in most
cases true pineal tumors. He concluded
that the cases of precocious puberty
resulted from reduced pineal function
due to disease of the surrounding tis-
sue, whereas delayed sexual develop-
ment
in children with true pineal tumors
was a consequence of increased pineal
activity.
The association of pineal tumors and
sexual malfunction gave rise to hun-
dreds of research projects designed to
test the hypothesis
that the pineal was
a gland whose
function was to inhibit
the gonads. Little appears to have re-
sulted from these early efforts. Later
in 1954 Kitay and Mark D. Altschule,
director
of internal medicine at McLean
Hospital
in Waverly, Mass., reviewed
the entire world literature on the pin-
eal: some 1,800 references, about half
of which dealt with the pineal-gonad
question. They concluded that of all
the studies published only
two or three
had used enough experimental animals
and adequate controls for their data to
be analyzed statistically.
These few
papers suggested a relation between the
pineal
and the gonads but did little to
characterize it. After puberty the human
pineal is hardened by calcification; this
change in the appearance of the pineal
led many investigators to assume that
the organ xwas without
function and
further served to discourage research in
the field. (Actually calcification appears
to be unrelated to the pineal functions
we have measured.)
As long ago as 1918 Nils Holmgren,
a Swedish anatomist, had examined the
pineal region of the frog and the dogfish
with a
light microscope. He was sur-
prised to find that the pineal contained
distinct sensory cells; they bore a
marked resemblance to the cone cells of
the retina and were in contact with
nerve
cells. On the basis of these obser-
A Prophetic Formulation
The existence of the pineal body has
been known
for at least 2,000 years.
Galen, writing in the second century
A.D.,
quoted studies of earlier Greek
anatomists who were impressed with the
fact that the pineal was perched atop
the aqueduct of the cerebrum and was
a single structure rather than
a paired
one; he concluded that it served as a
valve to regulate the flow of thought
SEAT OF THE RATIONAL SOUL was the function assigned to the human pineal
(H)
by
Ren6 Descartes in his mechanistic theory of perception. According to Descartes, the
eyes
perceived the events of the real world and transmitted what they saw
to the pineal by way
of "strings" in the brain. The pineal responded
by allowing animal humors to pass down
hollow tubes to the muscles, where they produced the appropriate responses. The size of
the pineal
has been exaggerated in this wood engraving, which first appeared in 1677.
52
vations he suggested that the pineal
might function as a photoreceptor, or
"third eye," in cold-blooded vertebrates.
In the past five years this hypothesis has
finally been confirmed by electrophysi-
ological studies: Eberhardt Dodt and
his colleagues in Germany have shotwn
that the frog pineal is a wavelength dis-
criminator: it converts light energy of
certain wavelengths into nervous im-
pulses. In 1927 Carey P. McCord and
Floyd P. Allen, working at Johns Hop-
kins University, observed that if they
made extracts of cattle pineals and add-
ed them to the media in which tadpoles
were
swimming,
the
tadpoles'
skin
blanched,
that is, became
lighter in
color.
Such was the state of knowledge
about the pineal as late as five or six
years ago. It appeared to be a photo-
receptor in the frog, had something to
do with sexual function in rats
and in
humans (at least those with pineal tu-
mors) and contained a factor (at least
in cattle) that blanched pigment cells in
tadpoles.
INNERVATION
OF RAT PINEAL
was the subject of
a
meticulous study
by the Dutch
neuroanatomist Johannes Arians Kappers in 1961. He demonstrated that the pineal of the
adult rat is extensively innervated by nerves from the sympathetic nervous system. The
sympathetic nerves to the pineal originate in the neck in the superior cervical ganglion,
enter the skull along the blood vessels and eventually penetrate the pineal at its blunt end
(top
).
Aberrant neurons from the central nervous system sometimes run up the pineal stalk
from its base, but these generally turn and run back down the stalk again without synaps-
ing. The pineal is surrounded by a network of great veins, into which its secretions proba.
bly pass. According to AriEns Kappers, the innervation of the human pineal is quite similar.
The Discovery of AMelatonin
Then in 1958 Aaron B. Lemer and
his co-workers at the Yale University
School of Medicine identified a unique
compound, melatonin, in the pineal
gland of cattle [see "Hormones and Skin
Color," by Aaron B. Lerner; SCIENTIFIC
ANIERICAN, July, 1961]. During the next
four years at least half a dozen other
major discoveries were made about the
pineal by investigators representing
many different disciplines and institu-
tions. Lerner, a dermatologist and bio-
chemist, was interested in identifying
the substance in cattle pineal extracts
that blanched frog skin. He and his col-
leagues prepared and purified extracts
from more than 200,000 cattle pineals
and tested the ability of the extracts to
alter the reflectivity of light by pieces
of excised frog skin. After four years of
effort they succeeded in isolating and
identifying the blanching agent and
found that it was a new kind of biologi-
cal compound: a methoxylated indole,
whose biological activity requires a
methyl group (CH,) attached to *an
oxygen atom
[see illustration on next
two pages].
Metloxylation had been noted pre-
viously in mammalian tissue, but the
products of this reaction had always ap-
peared to lose their biological activity as
a result. The new compound, named
melatonin for its effect on cells contain-
ing the pigment melanin, appeared to
lighten the amphibian skin by causing
SYMPATHETIC NERVE terminates directly on a pineal cell, instead of on a blood
vessel or smooth muscle cell, in this electron micrograph of a portion of a rat pineal made
by David
Wolfe of the Harvard Medical School. The nerve ending is characterized by dark
vesicles, or sacs, that contain neurohumors. Magnification
is about 12,500 diameters.
53
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C-C-C-C-NH
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SEROTONIN
5-HYDROXYTRYPTOPHAN
hydroxytryptophan by the enzyme 5-hydroxytryptophan decarbox-
ylase.
Serotonin,
the product
of this reaction, is
then enzymatically
SYNTHESIS OF MELATONIN in the rat pineal begins with the
removal of a carboxyl
(COOH)
group from the amino acid
5-
sequently they found that all mamma-
lian pineals shared this biochemical prop-
erty but that no tissue other than pineal
could make melatonin. Extensive studies
of a variety of mammalian species have
confirmed this original observation that
only the pineal appears to have the
ability to synthesize melatonin. (In am-
phibians and some birds small amounts
of melatonin are also manufactured by
the brain and the eye.) Other investiga-
tors have found that the pineal contains
all the biochemical machinery needed
to make melatonin from an amino acid
precursor, 5-hydroxytryptophan, which
it obtains from the bloodstream. It was
also found that circulating melatonin is
rapidly metabolized in the liver to form
6-hydroxymelatonin.
the aggregation of melanin granules
within the cells. It was effective in a
concentration of only a trillionth of a
gram per cubic centimeter of medium.
No influence of melatonin could be
demonstrated on mammalian pigmenta-
tion, nor could the substance
actually be
identified in amphibians, in which it
exerted such a striking effect. It re-
mained a biological enigma that the
mammalian pineal should produce a
substance that appeared to have no bi-
ological activity in mammals but was a
potent skin-lightening agent in amphib-
ians, which were unable to produce it!
Both aspects of the foregoing enigma
have now been resolved. Subsequent
research has shown that melatonin does
in fact have a biological effect in mam-
mals and can be produced by amphib-
ians. Spurred by Lerner's discovery of
this new indole in the cattle pineal,
Nicholas J. Giarman, a pharmacologist at
the Yale School of Medicine, analyzed
pineal extracts for their content of other
biologically active compounds. He found
that both cattle and human pineals con-
tained comparatively high levels of sero-
tonin, an amine whose molecular struc-
ture is similar to melatonin and whose
function in nervous tissue is largely un-
known. Studies by other investigators
subsequently showed that the rat pineal
contains the highest concentration of
serotonin yet recorded in any tissue of
any species.
A
year before the discovery of mela-
tonin one of the authors (Axelrod) and
his co-workers had identified a meth-
oxylating enzyme (catechol-O-methyl
transferase) in a number of tissues. This
enzyme acted on a variety of catechols
(compounds with two adjacent hydroxyl,
or OH, groups on a benzene ring) but
showed essentially no activity with
respect to single-hydroxyl compounds
such as serotonin, the most likely pre-
cursor of melatonin. In 1959 Axelrod
and Herbert Weissbach studied cattle
pineal tissue to see if it might have the
special enzymatic capacity to methox-
ylate hydroxyindoles. They incubated N-
acetylserotonin (melatonin without the
methoxyl group) with pineal tissue and
a suitable methyl donor and observed
that melatonin was indeed formed. Sub-
Anatomy of the Pineal
While these investigations of the bi-
ochemical properties of the pineal were
in progress, important advances were
being made in the anatomy of the pin-
eal by the Dutch neuroanatomist Jo-
hannes Ariens Kappers and by several
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DAYS AFTER OPERATION
AGE OF RATS (WEEKS)
DARK
LIGHT
PLACEBO
-
MELATONIN
-
EFFECTS OF LIGHTING
on the estrus cycles of three groups of
female rats are shown in the graphs on
these two
pages. The
groups,
each
consisting of about
20
rats, were subjected
respectively to
a
sham operation
(left),
removal of their superior cervical ganglion
(middle)
and removal of their eyes
(right).
Each group was then
further subdivided, with about half being placed in
constant light
EFFECT OF MELATONIN
on the estrus cycles of female rats is
de-
picted
here. Rats
that had
been given daily injections of melatonin
starting in
their fourth
week of life developed a longer estrus
cycle
than
rats that
had been similarly treated
with a placebo. When
the
melatonin-treated
animals were
10
weeks old, a placebo was substi-
tuted
for the melatonin and the estrus cycle returned to
normal.
54
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