J Neurosurg 63:321-341, 1985

Review Article

The pineal gland: anatomy, physiology, and clinical

significance

STEPHANIE S. ERLICH, M.D., AND MICHAEL L. J. APUZZO, M . D .

Department of Neurological Surgery, University of Southern California School of Medicine, Los
Angeles, California

Since the discovery of melatonin approximately 25 years ago, there has been intense study regarding the
details of the structure and function of the pineal gland. This work is reviewed, with particular emphasis on
those aspects of importance to human physiology and disease.

KEY WORDS pineal gland

" 9 melatonin - arginine vasotocin 9
suprachiasmatic nuclei ~ circadian rhythm

T
HE existence of the pineal gland has been recog-
nized since ancient times. Kappers, v9 in his sur-
vey of the advances in pineal research, divided
its history into three major periods. The first began
circa 300 B.C. when the human pineal gland was dis-
covered by Herophilus. Galen introduced the term
"konareion" (conarium in Latin) for the pineal gland
because in man the structure is shaped like the cone of
a pine tree. The word survives in the designation "nervi
conarii," the pineal nerves. "Pineal" is derived from the
Latin pinealis, pinea meaning pine cone. It has also
been referred to as the epiphysis, or "what is grown on
something." Vesalius (1514-1564) elaborately de-
scribed the topography and consistency of the pineal
gland. Descartes (1596-1650) believed that it was the
seat of the soul. For over two miIlenia, multiple organs
and regions of the brain were at one time or another
considered to be the seat of the soul. These included
the heart (Aristotle), cerebral ventricles (Herophilus),
cerebral parenchyma (Galen), pia mater, septum pel-
lucidum, corpus striatum, corpus callosum, medulla,
centrum semiovale, and even the stomach. 28 In essence,
This contribution is the 18th in a series of review articles
selected jointly by the Committee on Graduate Education of
the American Association of Neurological Surgeons and the
Congress of Neurological Surgeons, and the Journal of Neu-
rosurgery. - - Editor.
no substantive knowledge regarding pineal anatomy or
function was realized during these first 23 centuries.
The second period lasted from about the middle o f
the 19th century to the middle o f the present century.
It was characterized by interest in pineal comparative
anatomy, histology, and embryology, owing to the de-
velopment o f m o r e refined sectioning and staining
methods. In 1850, Kolliker observed the presence o f
nerve fibers in the m a m m a l i a n pineal gland, and, in
1904, Cajal found m a n y branching nerve fibers in the
mouse pineal gland and suggested that they were o f
sympathetic origin. Physiologists became interested in
the pineal gland because o f the discovery of the endo-
crine glands and, by the end o f the 19th century, some
thought that the m a m m a l i a n pineal gland might play
an endocrinological role. This concept appeared to be
supported by a c a s e r e p o r t 73 describing a boy with
precocious puberty who suffered from a pineal tumor.
It was subsequently theorized ~3 that the h u m a n pineal
gland is an endocrine organ which inhibits the function
o f the hypothalamus, and therefore the development o f
the reproductive system. However, most clinicians still
believed that the pineal gland was o f no functional
significance.
The third period encompasses approximately the past
30 years to the present and has been marked by the
rapid development o f pineal biochemistry, pharmacol-
ogy, and endocrinology. Near the beginning of this
period, Kitay and Altschule 83 wrote their landmark

J. Neurosurg. / Volume 63/September, 1985 321


Definitions of Abbreviations
ACTH = adrenocorticotrophichormone
ALS = amyotrophic lateral sclerosis
AVT = arginine vasotocin
CAT = choline acetyltransferase
cAMP = cyclicadenosine 3%5'-monophosphate
cGMP = cyclicguanosine 3',5'-monophosphate
CRF = corticotropin-releasingfactor
DST = dexamethasonesuppression test
EEG = electroencephalograph
GCMS = gas chromatography-massspectrometry
GFAP = glial fibrillaryacidic protein
HIOMT = hydroxyindole-O-methyltransferase
HRP = horseradish peroxidase
MSH = melanocyte-stimulatinghormone
NAT = N-acetyltransferase
REM = rapid eye movement
RHT = retinohypothalamictract
RIA = radioimmunoassay
SCG = superior cervicalganglia
SCN = suprachiasmatic nuclei
book summarizing the world's literature on the pineal
gland. A major breakthrough in pineal studies occurred
in 1958, when Lerner, et al., 98 isolated and character-
ized a potential pineal hormone, the same compound
that had been present in the pineal extracts which, when
fed to amphibians, had caused their skin to lighten. 116
Lerner named it "melatonin," from the Greek words
m e & s , meaning black, and tosos, meaning labor. In
1959, Lerner and Case 9s found that melatonin lightens
frog skin by contracting melanophores. Shortly there-
after, the importance o f light and dark in controlling
pineal function 53 and the dramatic effects o f the pin-
eal gland on m a m m a l i a n reproduction were demon-
strated. 22z These findings, with the definition of legiti-
mate functions, laid the foundation for thousands of
investigations over the past two decades.
Current Experimental Techniques
The development o f m o d e r n research tools, such as
electron microscopy and radioimmunoassay (RIA)
techniques to measure melatonin, 9 has led to rapid
progress in this field. The central neural pathway by
which lighting information reaches the pineal gland by
way o f the hypothalamus, spinal cord, and superior
cervical ganglia (SCG) has been elucidated. The com-
pounds and enzymes involved in the melatonin biosyn-
thetic and metabolic pathways have been discovered,
and much work has been d o n e to determine the factors
responsible for their circadian rhythmicity. Besides reg-
ulating reproductive function, the mammalian pineal
gland has also been shown to influence other endocrine
organs, such as the thyroid and adrenal glands, and
nonendocrine functions such as growth, body temper-
ature, blood pressure, m o t o r activity, and sleep. 175
The laboratory rat and hamster have been the mare-
322
S. S. E r l i c h a n d M . L. J. A p u z z o
mals most thoroughly studied, but the mouse, guinea
pig, rabbit, and monkey have also been used. Tissue
culture studies have involved the use of organ explants
such as pineal gland, SCG, pituitary, testis, and hypo-
thalamus; J22 continuous cell lines such as neuroblas-
toma, melanoma, and Chinese hamster ovary cells; and
primary cell cultures such as astrocytes. 2~
The morphological techniques presently used include
transmission and scanning electron microscopy and
immunohistochemistry, particularly to localize mela-
tonin and serotonin. Studies using horseradish peroxi-
dase (HRP) and autoradiography are few, but should
become more c o m m o n in the future in order to further
elucidate the anatomical connections of the pineal
gland and the localization of melatonin. In the past,
biochemical studies used bioassay 223'224 and later RIA
methods to measure melatonin, but the more specific
and accurate methods of high-performance liquid chro-
matography (HPLC) and gas chromatography-mass
spectrometry (GCMS) are now coming into more wide-
spread use. 174 Receptor methods have been used exten-
sively to measure neurotransmitter, hormone, and mel-
atonin receptors both in the pineal gland and in the
areas affected by melatonin. Behavioral studies have
used electronic monitoring of locomotor activity and
electroencephalographic recordings (EEG's).
Multiple manipulations employing surgery, exoge-
nous chemicals, and physical agents have been per-
formed to assess function. Surgical manipulations have
usually involved ablation o f key regions, such as pine-
alectomy, superior cervical ganglionectomy, 122 gona-
dectomy, and blinding, and isolation by deafferentation
or destruction of strategic sites, such as the suprachias-
matic nuclei (SCN) of the hypothalamus. Pineal tissue
has even been transplanted to other anatomic locations.
Numerous hormones have been administered, includ-
ing melatonin and testosterone, using various injection
methods and, more recently, via implants and orally.
Various radionuclides, neurotransmitters, and drugs 227
have been used, particularly those affecting norepineph-
fine, serotonin, and dopamine pathways. The most
extensively studied physical agent has been light, partic-
ularly the effects of photoperiod length (that is, the
length of the light phase) and the time of administration
of compounds within the photoperiod. More recently,
the effects of temperature, the intensity and wavelength
of light, 26 and electric 2~7and magnetic ~82fields are being
studied.
A natural consequence o f all the animal data which
have been obtained is that the human pineal gland and
its hormones, particularly melatonin, are now being
actively investigated and have been shown to be of
clinical importance. Melatonin is being studied as a
marker of human pineal function and as a possible
therapeutic drug.
The first section of the present review is intended to
serve as an introduction to some of the basic aspects of
pineal structure and function in mammals. The second
section will highlight a n u m b e r of clinically related areas
J. Neurosurg. / Volume 63/September, 1985
The pineal gland
that are currently under active investigation in both
animals and man.
Pineal Structure and Function
Anatomy
The anatomical relationships of the human pin-
eal gland are similar to those of the lower mam-
mals. 78'124'144"t61"196The pineal gland is in contact with
two recesses o f the third ventricle: the pineal recess
proper and the dorsal suprapineal recess, which con-
tains choroid plexus. The pineal gland is attached to
the posterior roof of the third ventricle, between the
posterior commissure and the more dorsal habenular
commissure. The posterior choroidal arteries provide
the arterial supply, and the venous drainage is via the
internal cerebral veins, which course dorsal to the pineal
gland.
Photosensory information reaches the mammalian
pineal gland via a complex polyneuronal pathway
which begins at the retina 6~ (Fig. 1). The first part of
this anatomical route, from the retina to the SCN, has
received a great deal o f attention in recent years. Retinal
photoreceptors convert environmental light into elec-
trical impulses which are conveyed to the SCN via the
retinohypothalamic tract (RHT).120 This monosynaptic
retinal pathway has been demonstrated in all major
orders of mammals. 12I The R H T mediates light-dark
entrainment of the SCN, which interprets day length
(that is, the photoperiod). The R H T is the most impor-
tant pathway by which visual information reaches the
SCN, but some information also reaches the SCN from
the primary optic tract via the lateral geniculate bodies.
Various wavelengths of light differ in their ability to
entrain the circadian system via the SCN; yellow-green
is most effective.223"224In adult mammals there are no
known photoreceptors outside the retina, but extra-
retinal photoreceptors may exist in very young animals.
In blinded newborn rats, environmental lighting persists
in influencing the pineal rhythm of serotonin content
for almost 1 month. The R H T consists of small fibers
that project exclusively to the SCN. The SCN are paired
clusters of small neurons located in the medial anterior
ventral hypothalamus. They are situated on either side
of the optic recess o f the third ventricle, immediately
dorsal to the optic chiasm. Each SCN receives a bilateral
retinal projection with predominantly contralateral in-
nervation, with most of the fibers crossing over at the
optic chiasm. However, species differences are present,
the great apes having a predominantly ipsilateral pro-
jection. The ventral and lateral parts of the SCN receive
the most innervation.
The second, multisynaptic part of this route is cir-
cuitous? 24 From the SCN, synaptic connections are
made in the lateral hypothalamus. Within the brain
stem, the pathway from the lateral hypothalamus to the
spinal cord is not well established, but probably involves
the medial forebrain bundle. Descending projections
then pass through the intermediolateral column of the
J. Neurosurg. / Volume 63/September, 1985
RHT
(Optic Chiasm)
Lateral Hypotbalamus ]
MFB
I Nervi Conarii
(Brain Stem) (Tentorium Cerebelli)
1
lntermediolateralcolumn I
Preganglionic L
Fibers
FIG. 1. Neural innervation of the mammalian pineal
gland. RHT = retinohypothalamic tract; SCN = suprachias-
matic nuclei; MFB = medial forebrain bundle; SCG = supe-
rior cervical ganglia.
cord, from which preganglionic fibers reach the S C G . 37
Horseradish peroxidase studies have shown that neu-
rons of the cord projecting to the rat SCG are restricted
to spinal segments C8-T5, and that 75% of these neu-
rons are found in the intermediolateral nucleus.159 Post-
ganglionic noradrenergic fibers from the SCG reach the
pineal gland via the nervi conarii, which pass through
the tentorium cerebelli.
The techniques used to determine the above input
route have mostly involved degeneration following the
destruction of specific regions and the incorporation o f
tritiated amino acids. In some mammals, a parasym-
pathetic acetylcholinergic pineal innervation has been
demonstrated. ~24The preganglionic fibers course in the
superficial petrosal nerves and reach the pineal gland
via the nervi conarii. They synapse with intramural
parasympathetic neurons, whose axons terminate freely
in the parenchyma or in pericapillary spaces. More
recent H R P studies have shown that there may be direct
connections between the habenular nucleus and the
pineal gland. This third type o f pineal innervation
consists of aberrant fibers o f the habenular and posterior
commissures, which may be present in the pineal stalk
or (in species that possess one) in the deep pineal gland.
As opposed to the great detail in which the neural
input to the mammalian pineal gland has been estab-
lished, the neural connections o f the h u m a n pineal
gland are less precisely defined, due to the limitations
o f studying h u m a n subjects. O f major importance has
been the identification of a region o f the h u m a n hypo-
thalamus believed to be the SCN. 1~ This structure had
been overlooked for m a n y years because it is more
diffuse than other hypothalamic nuclei, and extends
only about 0.33 m m in the anteroposterior dimen-
sion. ~2~ A recent investigation comparing postmortem
323

tissue from patients with optic nerve damage to control
tissue ~79 has provided evidence for the existence of a
retino-suprachiasmatic pathway in man. That study
employed a recently developed method that uses para-
phenylenediamine to stain for degenerating axons and
axon preterminals.
As in other mammals, the h u m a n pineal gland might
also receive sympathetic innervation. A study o f mela-
tonin rhythms in quadriplegic patients 88 suggests that
the h u m a n pineal gland is regulated by sympathetic
nervous connections. In these patients, the normal day-
night variation in urinary melatonin excretion (see
below) was not detected. No differences were found
between day and night levels. Larger amounts o f mel-
atonin were excreted in each 24 hours than in control
subjects, with most o f this increase occurring during
the daytime when melatonin levels should have been
low. These subjects also had abnormal sexual function,
slight testicular atrophy, and sympathetic dysfunction.
It was suggested that these abnormalities might be due
to "decentralization" of the pineal due to their trau-
matic cervical spinal cord lesions interrupting descend-
ing sympathetic fibers. These patients also had dimin-
ished periods o f total sleep and reduced percentages of
Stage 3 and 4 and rapid eye movement (REM) sleep,
suggesting a possible relationship between pineal func-
tion and sleep (see below). Treatment with the adrener-
gic beta-blocker propranolol leads to decreased mela-
tonin levels, providing further support that melatonin
production in man might be under noradrenergic con-
trol. 213
Nervi conarii are also thought to be present in the
h u m a n pineal region, coursing from the tip of the gland
to the tentorium cerebelli. 16~ Thick bundles of unmye-
linated nerves enter the septae and follow the course of
the capillaries. Nerve bundles also enter the pineal gland
from the habenular and posterior commissures. Fibers
from both these sources send numerous branches into
the parenchyma.
Histological a n d Ultrastructural Findings
A distinct pineal gland is present in virtually all
vertebrate species. However, this structure is very oc-
casionally lacking, as in the alligator 176 and arma-
dillo. 67"~57Certain species, such as the golden hamster 72
and white-footed mouse, ~8~ possess both a superficial
and a deep pineal gland. 69 In some species, the cellular
pattern of the pineal gland is not homogeneous, but
instead, a cortex and a medulla can be discerned. 68
The cell types within the adult mammalian pineal
gland are generally divided into parenchymal and in-
terstitial cells (Table 1 and Fig. 2). The parenchymal
cell is the pinealocyte (also referred to as "pineocyte"),
which shows characteristics of both a paraneuron 2~ and
of a cell belonging to the amine precursor uptake and
decarboxylation (APUD) series. 142.157Pinealocytes stain
positively for neuron-specific enolase, an immunohis-
tochemical marker for neurons and central neuroen-
324
S. S. E r l i c h a n d M . L. J. A p u z z o
TABLE l
Pineal cells and their main neurotransmitters and
immunohistochemical markers
Cell Type Transmitter Marker
pinealocyte serotonin neuron-specific enolase
interstitial cell serotonin glial fibrillaryacidic protein
S-100 protein
vimentin
Cl antigen
sympathetic norepinephrine,
nerve serotonin
terminals
FIG. 2. Photomicrograph of pineal gland from an adult
C57BL/SJ mouse. Note the uniformity of the main pineal
parenchymal cells, the pinealocytes. Semi-thin section. Tol-
uidine blue, x 110.
docrine cells.ml2 Two or more types of pinealocytes have
rarely been reportedfl 9 The classification of the intersti-
tial cells (also called "supportive cells") is uncertain, but
many may be o f glial origin. They have been shown to
stain positively for vimentin, C l antigen, glial fibrillary
acidic protein (GFAP), 72 and S-100 protein. 7~Serotonin
has been identified histochemically in the pinealocytes,
interstitial cells, and sympathetic nerve endings of the
mouse pineal gland. In certain species, such as the rabbit
and squirrel, intrinsic neurons are believed to be pres-
ent. Endothelial and connective tissue cells are invari-
ably present. Skeletal muscle fibers and lymphocytes
have also been described, and the lymphocytes may
even form nodular or dispersed lymphoid infiltrates. 29
The morphology of the h u m a n pineal gland is similar
to that described in other mammals. It is surrounded
by a capsule and composed of lobules separated by
connective tissue septae. Astrocytes comprise a signifi-
cant component of the h u m a n pineal gland 132and show
pronounced differentiation at 24 weeks of gestation.
With GFAP staining, it has been established that proc-
esses form an extensive interstitial network of fibers
which surround almost every pinealocyte in the adult.
J. Neurosurg. / Volume 63/September, 1985
The pineal gland

FIG. 3. Ultrastructure of a pineal gland from an adult C57BL/6J mouse. Various organelles and inclusions
are present, including clear (small arrow) and dense-core (large arrow) vesicles, a myeloid body (arrowhead),
and lipid (L). Lead citrate and uranyl acetate, x 17,700.

Astrocytic endfeet form a barrier between perivascular
spaces and the parenchyma and a limiting lamina at
the periphery of the gland. In degenerated areas, astro-
cytes commonly degenerate and proliferate, and mi-
croglia have been noted. Cells indistinguishable from
oligodendrocytes have been seen.
Various compounds, including lipid, melanin, and
lipofuscin, are present in parenchymal cells, and recent
studies have utilized immunohistochemical techniques
to demonstrate the presence of several hormones and
proteins in the h u m a n pineal gland. Immunoreactive
arginine vasotocin (AVT), arginine vasopressin, and
oxytocin, and neurophysins I and I157 have been iden-
tified in human pineal autopsy specimens. Alpha-al-
bumin, a protein specific for glial cells and identical to
GFAP, has also been f o u n d ) ~
The mammalian pineal gland contains various types
of ultrastructural features involved in intercellular com-
munication, such as synapses, and gap junctions and
tight junctions. The boundaries o f the lobule-like com-
partments of the pineal gland seen in some species, such
as the hamster, 72 are formed by the interstitial cells with
their large flat cytoplasmic processes. These processes
have tight junctions and surround groups of pinealo-
cytes. The presynaptic terminals o f the sympathetic
postganglionic fibers from the SCG generally synapse
in the perivascular regions. At most, these terminals
come in close contact with pinealocytes, but do not
form true synapses with them. The junctions between
pineal parenchymal cells vary between species. No gap
junctions and gap/tight junction combinations are
found in the hamster, 72 but they are present in the rat.
The types o f junctions between pineal cells may be
important in determining the degree of access of these
cells to the neurotransmitters released in the perivas-
cular spaces.
The cytoplasmic organelles o f pinealocytes are nu-
merous and varied. In addition to having organelles
c o m m o n to many other cell types, pinealocytes show
features indicative of an active secretory process, in-
cluding dense-core, clear, granular, and agranular
vesicles 181 (Fig. 3). Certain characteristics of these cells

J. Neurosurg. / Volume 63/September, 1985 325


make them distinctive. 146 These include synaptic rib-
bons (also referred to as "vesicle-crowned rodlets"),
synaptic ribbon fields, "unusual membranous organ-
elles," anulate lamellae, and myeloid bodies.~8~ Myeloid
bodies have been described in the retinal pigment epi-
thelium of most lower vertebrates, and are thought to
be somehow involved in either photopigment metabo-
lism, photoreception, or photoneuroendocrine activity.
Biochemical Results
The direct input to and output from the pinealocyte
has changed substantially throughout its phylog-
eny.~27'~s7 Pinealocytes are photoreceptors in fish and
amphibians, directly converting light into an electrical
signal. The pineal gland of birds is considered a pho-
toendocrine transducer, converting light into a hor-
monal signal. In mammals, the pineal gland has been
termed a "neuroendocrine transducer," converting an
electrical signal into a hormonal signal) 2
Melatonin is the major secretory product of the pin-
eal gland, and it fits the definition of a hormone.
Melatonin, or N-acetyl-5-methoxytryptamine, is an in-
doleamine with a 232 molecular weight. 96 Melatonin
synthesis depends on environmental lighting condi-
tions, m4'~54 It is stimulated by the beta-adrenergic post-
ganglionic sympathetic fibers from the SCG, which are
stimulated by darkness. Light is inhibitory. Both nor-
epinephrine and serotonin can be released from the
sympathetic terminals. The initial precursor for mela-
tonin is the indole amino acid, tryptophan, which is
taken up from the plasma by the pineal gland (Fig. 4).
Most of the tryptophan is used in the indole pathway,
but a small a m o u n t is used in protein synthesis. Tryp-
Tryptophan Hydroxylase
Pinealocyte
1
5-H~ droxylryplophan
I
Aromatic-l..-Amino Acid
Decarboxylase
Beta-Adrenergie
1
I s~roto,i,,
- "~Adenyl Cyclase
I constant darkness). 6~ Because NAT is the key enzyme
Receptor
I N-Acelyllransfcrase
I
I
1
[
1
N-Acetylserotonin
i nists and antagonists mimic the effect of light and dark
I
Norepinephrine 1 I
Hydrox~,indole-O-
( Postganglionic Fibers) Met hyltransferase
l
I Mcl~to,~, ]
FIG. 4. Stages of melatonin synthesis. ATP = adenosine tri-
phosphate; cAMP = cyclic adenosine 3',5'-rnonophosphate.
396
S. S. Erlich and M. L. J. Apuzzo
tophan is hydroxylated in the pinealocyte to 5-hydroxy-
tryptophan by tryptophan hydroxylase. 5-Hydroxytryp-
tophan is decarboxylated by aromatic-L-amino acid
decarboxylase to become 5-hydroxytryptamine (sero-
tonin). In some mammalian pineal glands, serotonin
levels and turnover are higher than in any other part of
the brain. Within the pineal gland, serotonin is pro-
duced only in pinealocytes, and some of it is taken up
into adjoining nerve terminals. N-acetyltransferase
(NAT), the rate-limiting enzyme, converts serotonin
into N-acetylserotonin, which becomes melatonin via
the action of hydroxyindole-O-methyltransferase
(HIOMT).
Norepinephrine acts on pinealocytes via cyclic
adenosine 3',5'-monophosphate (cAMP) and beta-
adrenergic receptors in the membrane of these cells) 2
Stimulation of the beta-adrenergic receptors on the
pinealocyte by the postganglionic fibers causes an acti-
vation of adenylcyclase, leading to increased cAMP.
This in turn increases N A T levels, causing a rise in
melatonin synthesis. Besides beta-adrenergic receptors,
bovine and rat pineal glands also contain alpha recep-
tors. 56 Several functions have been attributed to an
alpha-adrenoceptor-cyclic guanosine 3',5'-monophos-
phate (cGMP) mechanism in the pineal gland, includ-
ing beta-receptor desensitization s6 (see below).
Melatonin rapidly disappears from the blood follow-
ing intravenous injection, *9and rapidly disappears from
the brain following intracisternal administration. 33 The
half-life is short during the initial few minutes, followed
by a second longer phase. 59 Most melatonin is conju-
gated in the liver to 6-hydroxymelatonin and is then
excreted into the urine, s9 Melatonin in the rat can also
be metabolized to N-acetylserotonin. 93 The metabolic
pathway in the brain is different from that at the
periphery, s5 Plasma melatonin levels also fall quickly
(Blood) after melatonin administration to humans.
Chronobiological Studies
[
Light is the main Zeitgeber (entraining agent or
synchronizer) regulating the duration and phase of mel-
atonin production. The SCN serve as the "master
clock," a circadian pacemaker having an endogenous,
self-sustained oscillation, through which lighting infor-
I
mation reaches the pineal gland. 2~ Circadian rhythms
in NAT are present in free-running conditions (that is,
in melatonin synthesis and shows an endogenous cir-
[
cadian rhythmicity, it has been extensively investi-
gated. 2~176 Dibutyryl cAMP and beta-adrenergic ago-
on NAT. There is a rapid decline in cAMP and NAT
following exposure to light or treatment with propran-
olol. Toward the end of the scotophase (dark phase),
NAT levels decline prior to the initiation of the photo-
phase, possibly because of a compound that may serve
as an NAT inactivator.
Several studies have been performed to examine the
effects of light on melatonin production. 99 The human
J. Neurosurg. / Volume 63/September, 1985
The pineal gland
response to light is qualitatively similar to that of other
species) ~ Bright artificial light suppresses nocturnal
melatonin secretion in normal humans, but room light
of less intensity fails to do so. Different types of mela-
tonin circadian secretory rhythms are present in blind
subjects.I~ Some appear to have a free-running rhythm,
while others secrete during the day. ,88
Melatonin in the pineal gland, blood, cerebrospinal
fluid (CSF), and extrapineal sites, and melatonin recep-
tors all show diurnal cycles. Melatonin levels in the
pineal gland and serum show a rise during the scoto-
phase of the diurnal cycle in all vertebrates, whether
the animal is nocturnal or diurnal. The variation in
melatonin receptor levels2~ has led to a theory of recep-
tor down-regulation '62 to account for the opposing re-
productive effects of melatonin administration, depend-
ing on the time point within the photoperiod in which
it is given (see below). Pineal beta-adrenergic receptors
exhibit a circadian rhythm in their sensitivity, and
pineal super- or subsensitivity may depend on the de-
gree and duration of prior stimulation. 56
Melatonin has been measured in a number of human
body fluids and tissues, 2~3"2z5 including blood, CSF,
urine, saliva, lymph, amniotic fluid, pineal gland, ret-
ina, and sciatic nerve. In blood, melatonin has been
measured in plasma and serum by bioassay, RIA, or
G C M S . 100'223'224 Most studies show a clear circadian
rhythm with peak values during the dark phase in both
men and women. 9''89 Whether or not melatonin is
additionally secreted episodically throughout the 24-
hour period is controversial. Secretory episodes have
been reported during the waking day in the presence of
bright light. 2~176176 The nocturnal melatonin secretion
pattern also exhibits secretory episodes. 23 Spontaneous
waking episodes are associated with melatonin peaks,
and periods of REM sleep with melatonin nadirs, sug-
gesting that melatonin secreted in connection with
arousals during the night might in turn act to restore
sleep. However, other studies have shown no correlation
between the stages of sleep and melatonin concentra-
tions. As in blood, circadian rhythms of melatonin are
present in the h u m a n pineal gland 64 and in urine, with
high nighttime values and low daytime levels.Ill
Numerous compounds, including melatonin precur-
sors, enzymes, neurotransmitters, hormones, peptides,
and receptors, are present in the pineal gland, '87 and
many also show diurnal variation. Tryptophan levels
rise during the photophase and serotonin concentra-
tions decrease during the scotophase. 223'224Pineal sero-
tonin in man decreases well before the NAT activity
increases, as distinct from other mammalsJ 89 The
mechanism for this is unknown. The activity of NAT
and H I O M T in postmortem pineal specimens is directly
related to the time o f death o f the subject, resulting
in a nyctohemeral (pertaining to both night and day)
rhythm similar to that o f serum melatonin. Therefore,
any clinical interpretation o f pineal dysfunction in
disease states should take this normal rhythm into
consideration. Is9 Other compounds found in the hu-
J. Neurosurg. / Volume 63/September, 1985
man pineal gland include histamine, inositol, taurine,
pteridines, iodinated compounds, angiotensin I, and
a possible pro-opiocortinJ 66 Three other methoxyin-
doles are present in postmortem pineal glands: 5-meth-
oxytryptamine, 5-methoxytryptophol, and 5-methoxy-
indole-3-acetic acid.~8
The pineal gland and melatonin also show ultradian
(rhythms shorter than 24 hours), 17~ infradian (rhythms
longer than 24 hours), estrous cycle, and circannual
(seasonal) rhythms. '62 Changes in melatonin patterns
enable animals to "anticipate" the future, resulting in
the proper timing o f seasonal hibernation, temperature
changes, and reproduction. 1s7 Melatonin m a y be in-
volved in regulation of the h u m a n menstrual cycle,
since elevated serum levels have been found at the time
o f the menses, with a nadir at the time o f ovulation? '6
Seasonal variation in plasma melatonin has been dem-
onstrated in men and women, and in young and elderly
adults, '~176176
but is different in young and elderly sub-
jects, zoo The variable factor o f race has also been ex-
amined in studies o f melatonin rhythms. African chil-
dren show higher daytime melatonin levels than do
comparable Caucasian children, but, in both groups,
the circadian rhythms are comparable. 65
Melatonin Localization and Secretion
It had long been believed that melatonin was pro-
duced only by the pineal gland; however, evidence has
accumulated recently for extrapineal sources o f mela-
tonin. 158 Some, but not all, 1~ studies show that pineal
ablation does not eliminate all circulating melatonin.
Circulating melatonin is present in alligators 176 and
armadillos, 67 although these animals lack a pineal gland.
It has been measured by RIA in the hypothalamus and
brain stem o f several species, including man, indicating
either local uptake or synthesis. 9~176176 It has been
demonstrated by bioassay in peripheral nerves o f cows,
monkeys, and man. 14.96.97Melatonin has been identified
immunohistochemically in the SCN, Harderian gland,
retina, and intestine, and the enzymes necessary for the
synthesis o f melatonin (NAT and H I O M T ) have been
found in these areas. 2' Substantial a m o u n t s o f melato-
nin are present in the h u m a n retina; ~28in fact, in certain
mammals the retina may produce the majority o f mel-
atonin.t58
Melatonin is probably not stored in the pineal gland,
but is secreted immediately and by simple diffusion;
however, it is unclear whether it is initially secreted into
the blood or CSF. In several mammals, the CSF con-
centration is less than that in the plasma, 17~and in the
rat, at least, melatonin is probably secreted into the
blood. Circulating melatonin is taken up by all organs,
and an effective blood-brain barrier to melatonin is
absent. 223'224 The pineal gland lacks a blood-brain bar-
tier. '24 Approximately 70% o f circulating melatonin is
albumin-bound, 34 but both free and albumin-bound
melatonin rapidly crosses from the blood into the
CSFJ 33 Melatonin accumulates in the choroid plexus,
which pumps it from CSF into the blood.'9~
327

In humans, melatonin levels are higher in serum than
in lumbar or ventricular C S F , 9'195 supporting the view
that melatonin is primarily secreted into the blood-
stream. Also, oral administration of melatonin to hu-
mans results in markedly increased plasma and CSF
melatonin concentrationsf126 However, plasma to CSF
melatonin ratios are similar in patients who receive and
in those who do not receive melatonin, and no gradient
in melatonin concentration between the basal cisterns
and lumbar CSF is found; these findings again support
the idea that melatonin is released from the pineal gland
into the blood and reaches the CSF via the blood. 226
There is placental transfer of melatonin from the
mother to the fetus, 168 and transfer to the newborn via
the milk. 169Therefore, the melatonin-generating system
may be established in utero prior to the development
of the necessary anatomic pathways, 87 and prior to the
differentiation of pineal cell types. 3~
Physiological and Behavioral Effects o f Melatonin
Since the pineal gland transduces photoperiodic in-
formation, it plays an integral role in the temporal
organization of numerous metabolic, physiological, and
behavioral processes. T M Its effects can be generally clas-
sified as endocrinological or non-endocrinological. En-
docrine function of the pineal gland consists of its
reproductive effects and its effects on nongonadal en-
docrine organs, such as the thyroid and adrenal glands.
The reproductive effects have been extensively investi-
gated and summarized. 30.78.151.161-164It was long believed
that the reproductive effects of melatonin were solely
antigonadotrophic, in both maturing and adult mam-
mals. Some of the effects of chronic administration to
maturing animals include retardation of the normal
increase in ovarian weight, delay of normal vaginal
opening time, and decrease in incidence ofestrus, z21 In
adult male rats, melatonin injections lead to a decrease
in size of the seminal vesicles. Darkness, produced
either by blinding, prolongation of the daily scotophase,
or retention in constant environmental darkness, causes
atrophy of the sex organs by stimulation of the pineal
gland. Pinealectomy can accelerate maturation of go-
nadal function and induces a high incidence o f estrus,
which can be blocked by melatonin administration.
It has since been found that melatonin does not
consistently produce antigonadotrophic effects. 162 Ex-
ogenous administration may lead to paradoxical
(counter-antigonadotrophic or progonadotrophic) re-
productive effects, or even to functional pinealectomy.
These effects are dependent on the time point within
the photoperiodic cycle in which it is administered (that
is, they show diurnal sensitivity), the length of the
photoperiod, the dose of melatonin given, and the
species.
Numerous studies have been performed to determine
the role of the pineal gland in the secretion of the
anterior pituitary hormones prolactin, luteinizing hor-
mone, and follicle-stimulating hormone. 124,225The ma-
jority of these reports suggest that melatonin acts at the
328
S. S. E r l i c h a n d M . L. J. A p u z z o
level of the hypothalamus, affecting the production of
the releasing factors for these hormones. However, a
number of studies suggest that melatonin might act on
the pituitary gland directly. 162
The endocrine effects of melatonin are also exerted
in areas not involved in reproductive function, such as
the adrenal and thyroid glands. 124"151'163'2~ Melatonin
can have either concurrent antigonadal and antithy-
roid actions, or concurrent counter-antigonadal and
counter-antithyroid effects, depending on its route and
time of administration. This suggests that melatonin
might act at a single site to influence pituitary secretion
of hormones involved in gonadal and thyroid func-
tion. 2~ Exogenous melatonin and pinealectomy have
been shown to alter adrenal gland weight and glucocor-
ticoid and mineralocorticoid secretion, but the reports
so far have been very contradictory. 163
The non-endocrinological effects of the pineal gland
have not been as systematically investigated as its en-
docrine role. Numerous behavioral and physiological
studies have been performed to study the effects of
exogenous melatonin administration and/or pinealec-
tomy in animals. 166 The influences of melatonin on
locomotor activity are controversial, 16~ but most
studies show that the pineal gland acts to reduce this
activity. It also appears to influence aggression (possibly
via an interaction with melanocyte-stimulating hor-
mone (MSH)), TM passive avoidance (having an effect
opposite to that of MSH), 44 ethanol preference, and salt
preference. Social isolation and stress can affect pineal
morphology and biochemistry. 166 The pineal gland is
involved in hibernation and thermoregulation. 81'166Al-
tered temperatures can produce pineal changes, and the
pineal gland can influence the level and rhythmicity of
core body temperature and daily torpor; it may also
influence the porphyrin content of the Harderian
gland, TM glucose and energy metabolism, food intake,
the gastrointestinal tract, kidney and liver function,
nerve growth factor, and hair color. 166
Melatonin Sites o f Action
Many studies have been conducted to determine the
site of action o f melatonin (Table 2). Many regions,
both within and outside the nervous system, may be
sites of action. These include the hypothalamus, mid-
brain, pituitary gland, pineal gland, peripheral nerves,
and gonads. The spinal cord has been almost completely
ignored in these studies, except for recent work in our
laboratory.47 Both in vivo and in vitro studies have been
undertaken to determine if the effects are directly on
certain cells. Direct cellular effects have been demon-
strated in the hypothalamus, pituitary gland, gonads,
and pineal gland in vitro. 24
Within the central nervous system (CNS), the hypo-
thalamus is considered by most to be the main target
of melatonin. Hypothalamic melatonin implants, SCN
lesions, and surgical deafferentation studies support this
concept. 162,164 The cellular effects of melatonin are
prominent in areas that are concerned with reproduc-
J. Neurosurg. / Volume 63/September, 1985
The pineal gland
TABLE 2
Some of the potential sites and physiological actions of
melatonin
Site Function Altered by Melatonin*
nervous system
hypothalamus microtubule protein content, ultrastruc-
ture, protein synthesis, serotonin &
GABA content, neurotransmitter levels,
cAMP & cGMP accumulation
midbrain serotonin concentration, electrical activity
cerebral cortex protein synthesis
peripheral nerve microtubule numbers, microtubule assem-
bly, axonal transport
superior cervical choline acetyltransferaseactivity
ganglia
endocrine system
pineal gland microtubule protein content, microtubule
numbers, ultrastructure, neurotransmit-
ter uptake & release, melatonin synthe-
sis, NAT & HIOMT activity
pituitary gland gonadotropin secretion, MSH release
thyroid gland thyroid hormone levels, guanylate cyclase
adrenal glands glucocorticoid & mineralocorticoidsecre-
tion, weight, & size
gonads & accessory seminiferous tubule contractility, guanylate
organs cyclase, estrus incidence, weight, & size
other systems
eyes pigment aggregation
skin melanosome aggregation, melanin produc-
tion
Harderian glands porphyrin content
* GABA = gamma-aminobutyric acid; cAMP = cyclic adenosine
3',5'-monophosphate; cGMP = cyclic guanosine 3',5'-monophos-
phate; NAT = N-acetyltransferase;HIOMT = hydroxyindole-O-meth-
yltransferase; MSH = melanocyte-stimulatinghormone.
tive function and contain steroid receptors, or show a
high uptake of steroids, including the hypothalamus,
testis, and pineal gland. Steroid receptors, including
those for estradiol, progesterone, prolactin, testosterone,
and 5-alpha-dihydrotestosterone, are present in the pin-
eal gland. Melatonin possibly alters the number or
sensitivity of hypothalamic steroid receptors, or the
intracellular processing of steroid-receptor complexes. 24
The cellular (and probably neuronal) effects of mel-
atonin have been studied most thoroughly in the hy-
pothalamus. 3~ Several hypothalamic metabolic func-
tions change after melatonin treatment. These include
protein synthesis, neurotransmitter levels and uptake,
serotonin and g a m m a - a m i n o b u t y r i c acid content, and
n e u r o h o r m o n e release. Some of the hypothalamic ac-
tions of melatonin probably involve effects on cyclic
nucleotide levels. Melatonin decreases cAMP accumu-
lation in rat medial basal hypothalamus in vitro, and
pinealectomy increases this accumulation. 122Melatonin
applied onto neurons in the preoptic area of the hypo-
thalamus in rats and hamsters alters their excitatory
responses.
There is evidence that melatonin might affect non-
hypothalamic neurons and even astrocytes. Melatonin
injected intravenously inhibits spontaneous neuronal
activity of the rat mesencephalic reticular formation.14'
J. Neurosurg. / Volume 63/September, 1985
Melatonin affects protein synthesis in rat cerebral cor-
tex. 35 Pineal cells enhance choline acetyltransferase
(CAT) activity in sympathetic neurons in vitro, a n d
conditioned media from pineal cultures inhibit C A T
activity in S C G cultures. 177 Incubation o f astrocyte
cultures with melatonin causes an i m p a i r e d beta-adre-
noceptor-mediated increase of c A M P levels. 2~
Sites o f action m a y also be suspected if m e l a t o n i n is
found n o r m a l l y in certain regions, if m e l a t o n i n is pref-
erentially t a k e n up in certain regions, or if receptors for
melatonin are present. Melatonin has been d e m o n -
strated by bioassay in peripheral nerves o f cows, m o n -
keys, a n d m a n . 14'96'97 T h e only study examining the
spinal c o r d showed by bioassay that bovine spinal cord
had no significant melatonin activity. 14 M o r e specific
RIA and G C M S analyses have shown an uneven distri-
bution o f brain melatonin in several species, with higher
levels reported in the pineal gland, h y p o t h a l a m u s , mid-
brain, p o n s - m e d u l l a region, and cerebellum.13~176 Intra-
venously administered tritiated m e l a t o n i n is selectively
taken up by the hypothalamus, midbrain, and periph-
eral nerves. 33"222 The strongest evidence for sites o f
action c o m e s f r o m the demonstration o f cytoso139 and
m e m b r a n e 36"2~ melatonin receptors in the hypothala-
mus, midbrain, and pineal gland. Since the pineal gland
contains m e l a t o n i n receptors, these m a y serve an au-
toregulatory role in melatonin production. Melatonin
has been detected by RIA in the h u m a n brain in several
areas, including the hypothalamus, habenula, substan-
tia nigra, a n d area postrema. 9~
M e c h a n i s m o f Action b y M e l a t o n i n
Melatonin m a y act via the serotonergic pathway, 186
particularly on neurons utilizing serotonin as a neuro-
transmitter. 6 It has been hypothesized that m e l a t o n i n
exerts its anti- a n d progonadotrophic effects by primar-
ily acting on the parvocellular h y p o t h a l a m i c nuclei,
probably b y m e a n s of an intrinsic neural serotonergic
hypothalamic system, j86 Intraperitoneal injections o f
melatonin increase the concentration o f serotonin in
h y p o t h a l a m u s a n d midbrain, 5'6 and there is extensive
biochemical, anatomical, and morphological evidence
for h y p o t h a l a m i c innervation by serotonergic raphe
neurons. Serotonergic midbrain neurons have axons
projecting to the h y p o t h a l a m u s and limbic system via
the medial forebrain bundle. The fact that serotonin
inhibits g o n a d o t r o p i n release 24 is consistent with the
hypothesis that m e l a t o n i n inhibits g o n a d o t r o p i n output
via stimulation o f serotonergic mechanisms. This inhi-
bition might be responsible in certain species for alter-
ations in the circadian r h y t h m s in h y p o t h a l a m i c sero-
tonin. However, melatonin is not a c o m p e t i t o r for
serotonin binding to serotonin receptors, a n d serotonin
is only a very weak competitor for m e l a t o n i n binding
on m e m b r a n e receptor sites. 36 The effects o f m e l a t o n i n
administration to h u m a n s on serotonin m e t a b o l i s m are
controversialf126
It has been hypothesized that the m e c h a n i s m o f
action o f m e l a t o n i n is via microtubules, 21s although the
329

evidence is controversial. 31'149 Microtubules are intra-
cytoplasmic organelles which n u m e r o u s studies suggest
are involved in m a n y forms o f movement, including
cellular division, growth and motility, and axonal trans-
port. 27 Ultrastructural and axonal transport studies sup-
port this concept. Melatonin causes an ultrastructural
decrease in microtubules in toad sciatic nerve, and has
a colchicine-like effect in preventing microtubular reas-
sembly during temperature recovery? 48 Melatonin
treatment in vivo decreases rat hypothalamic microtu-
bule protein content and causes tubular and "crystal-
loid" formations in axons of the median eminence. 32
The ultrastructural changes produced by melatonin
have been compared to those produced by drugs which
cause intracellular microtubule aggregation, and to
those produced by nerve transection. There are several
reports of the effects of melatonin o n pineal morphol-
ogy, interpreted as pineal "activation" or "hyperfunc-
tionality," including increased microtubules. 55 Melato-
nin impairs axonal transport in sciatic nerve ~52 and in
the visual pathway. 32
It has been postulated that "certain melatonin-sensi-
tive tissues contain microtubule proteins with high spe-
cific affinity for melatonin. ''218 Melatonin might bind
to tubulin at the colchicine-binding site and thereby
prevent the assembly o f the 6S tubulin dimer into
microtubules. Through this mechanism it is thought
that melatonin may influence hypothalamic gonadotro-
pin release by affecting axonal transport of neurosecre-
tory products. 32 The effects o f melatonin on mitosis
might also be due to a colchicine-like effect on micro-
tubules. 54
Since melanocytes are neural crest derivatives, the
effects o f melatonin on skin m a y be important in
understanding how melatonin affects neurons. ~3 Mela-
tonin exerts its skin-lightening effects in amphibians by
aggregating melanosomes in melanocytes. 58,94,157Since
this action might also involve microtubules, it is possi-
ble that the mechanism of action o f melatonin in mel-
anocytes and neurons is similar. Melatonin receptors
have been reported in skin, 39 and a c o m m o n receptor
may mediate melatonin's effects on amphibian skin
and brain. Melatonin inhibits skin darkening in re-
sponse to MSH both directly and also by inhibiting
M S H production by the pituitary.
Melatonin regulates not only skin pigmentation, but
also eye pigmentation. Melatonin administration to
guinea pigs causes aggregation o f pigments in cells of
the retina and choroid, resulting in a lightening effect.131
Whether ocular a n d / o r extraocular melatonin are in-
volved with retinal pigment remains to be deter-
mined. 157
T h e mechanism of action o f melatonin might also
involve c G M P 226 and prostaglandins. 3~ Several
studies suggest that c G M P m a y be a mediator of mel-
atonin's CNS actions, and a general effect of melatonin
m a y be an increase in c G M P in target tissues. Injection
o f melatonin into the cisterna magna of rabbits in-
creases the concentration o f c G M P in the CSF, and oral
330
S. S. E r l i c h a n d M . L. J. A p u z z o
melatonin administration increases cGMP in the CSF
of humans. 226 Cyclic GMP-mediated mechanisms may
be involved in the effects of melatonin on testes, semi-
niferous tubule contractility, the inhibition of melanin
production in melanocytes, 2~ and beta-adrenergic re-
ceptor sensitivity. 86 Prostaglandins and norepinephrine
influence each other's release in the pineal gland.
Clinical Significance of the Pineal Gland
Ontogeny
Although changes in serum melatonin concentra-
tions are associated with normal puberty, 184.2o8the phys-
iological role of the pineal gland in human puberty is
still obscure. 6s'225 In both sexes, nocturnal levels are
highest in children aged 1 to 5 years, and decrease
steadily until the end of puberty. 2~ By the end of
puberty, peak melatonin levels have decreased 75%
from early childhood values. Melatonin levels in the
daytime are uniformly low and bear no relationship to
the age of the child.
Proof that melatonin controls puberty is still lack-
ing. 84 Many other physiological parameters also change
during puberty. It has been found that the 24-hour
profiles of plasma melatonin are similar in prepubertal,
pubertal, and adult males to those in patients with
isosexual precocity, 45 thus not supporting a role for
melatonin in the initiation of normal or precocious
puberty in man. There is no correlation between the
daily excretion rate in the urine of 6-hydroxymelatonin
(the conjugated major metabolite of melatonin) and
age in children, and the excretion rates are similar to
those in adults. 199 Children of all ages have normal
circadian excretion patterns. However, a significant in-
crease in 6-hydroxymelatonin excretion is observed at
the time of the onset of breast development in girls.
Melatonin excretion increases when the initial signs of
puberty are present, a finding inconsistent with an
inhibitory influence of melatonin on pubertal develop-
ment. 143
Further documentation indicating that plasma mel-
atonin may not play a role in the onset o f puberty
comes from a study of children with Prader-Willi syn-
drome, who have a delayed onset of puberty. 193 These
children showed similar melatonin profiles to those of
exogenously obese children. In the latter children, levels
were low during the day and high at night, and the
profile did not vary as a function of weight or pubertal
status. However, children with idiopathic precocious
puberty have day-night increments in serum melatonin
lower than in an age-matched control group, whereas
children with constitutionally delayed puberty show
normal increments.l
Pineal neoplasms can produce precocious puberty,
delayed puberty, or no gonadal s i g n s , 83'124 but the etiol-
ogy of these changes still remains obscure. Proposed
mechanisms have included hormones secreted by the
tumor itself, disturbances in hormone production by
the adjacent normal pineal parenchyma, or interfer-
J. Neurosurg. / Volume 63/September, 1985
The pineal gland
ence, possibly by compression, of the hypothalamic-
pituitary axis.
The pineal gland may be active throughout the entire
life span of man. The weight of the pineal gland in an
adult is maintained into old age, and enzyme studies of
pineal glands in patients aged from 3 to 70 years have
shown that they retain the capacity to synthesize mel-
atonin. 22~ The circadian rhythms of plasma melatonin
in humans are not modified in old age or in senile
dementia. 2~176
The nyctohemeral acrophases are remark-
ably stable whatever the season, age, or sex; however,
24-hour mean levels of plasma melatonin in the elderly
are half those in the young, but are not influenced by
sex or mental condition. Melatonin activity in the CSF
is also reported to decrease with increasing age. 226 The
decline of melatonin levels might be related to changes
in the release of the hormone, an increase in its metab-
olism or excretion, an increased sensitivity to light in
the aged, or decreased or nonresponsive pineal beta-
adrenergic receptors. 2~176
Effect of Melatonin on Movement
Investigations in both animals and humans suggest
that the pineal gland may play a role in several neuro-
logical diseases, such as movement, sleep, and seizure
disorders. Administered in high doses (400 mg/kg) to
mice and rats, melatonin can produce toxic effects,
including ataxia, motor incoordination, lack of motor
activity, muscle relaxation, ptosis, piloerection, and
vasodilatation o f the extremities) 9~ At higher doses of
melatonin, flexor reflexes are impaired, body tempera-
ture is reduced, and slow, labored respiration precedes
death. Melatonin is most potent 15 to 30 minutes after
administration. 19
Melatonin may be relevant to Parkinson's disease.
Melatonin blocks the adventitious movements induced
by L-dopa in intact mice, 4~ and L-dopa administration
increases rat pineal melatonin content) 1~ Melatonin
has been detected by RIA in the human substantia
nigra, 9~ and chronic oral administration of melatonin
ameliorated the tremor and rigidity of Parkinson's
disease. 7
It is conceivable that melatonin may be involved in
the motor neuron disease, amyotrophic lateral sclerosis
( A L S ) . 47 Melatonin affects axonal transport and micro-
tubules in sciatic nerve, the motor component of which
is derived from anterior horn cells, which are known to
degenerate in ALS. Also, melatonin may act via the
serotonergic system, and anterior horn cells may be part
of this system. Since the cellular effects of melatonin
are prominent in areas containing steroid receptors,
and anterior horn cells also have steroid receptors, it is
possible that the anterior horn cell may also be a site of
action. 47 It has been hypothesized that androgen recep-
tor loss may play a role in the etiology of ALS. 21~ If
melatonin interacts directly or indirectly with the an-
drogen receptor, or acts selectively on motor neurons
bearing these receptors, it may be involved in the path-
ogenesis of ALS as well.
J. Neurosurg. / Volume 63/September, 1985
Electroencephalographic A ctivity
The pineal gland and melatonin have a significant
role in regulating and modulating brain electrical activ-
ity, ~9~ and have been shown to be involved in seizure
mechanisms, sleep, and sleep disorders. Exogenous mel-
atonin administration is beneficial in several animal
models o f epilepsy, and pinealectomy and antimela-
tonin antibodies can result in seizures. These effects are
species-dependent. It is effective in two models o f epi-
lepsy in rodents: pentylenetetrazol-produced or electri-
cally-kindled seizures. In the mouse, high doses (greater
than 200 mg/kg) were necessary to produce an increase
in the seizure threshold following pentylenetetrazole
administration. 191 In the baboon with photosensitive
epilepsy, melatonin causes a slight decrease o f light
sensitivity.175 Antimelatonin:antibody demonstrates an
epileptogenic action when injected intraventricularly in
rats. 48 Melatonin is effective against seizures induced
by pinealectomy in Mongolian gerbils. 147 In a study
testing the effects o f 12 different anticonvulsant drugs
on N A T and H I O M T activity o f the pineal gland, it
was found that sulthiame inhibited N A T in the n o r m a l
therapeutic range of the drug.~23
The pineal gland is involved in sleep and activity
rhythms in several species. Melatonin was first shown
to induce sleep, lasting about 2 hours, when adminis-
tered directly into the hypothalamus o f unrestrained
cats) TM Intraperitoneal melatonin prolongs sleep time
induced by hexobarbitone, pentobarbitone, and barbi-
tone in the m o u s e and r a t . 13'191 The inhibition o f m o t o r
activity is dose-dependent. Mice became inactive soon
after injection; they appeared to be sleeping, and were
readily arousable.l 91
The pineal gland may be important in regulating the
circadian rhythmicity o f paradoxical (REM) sleep. Pin-
ealectomy in the rat causes no changes in the total
amount o f R E M and slow-wave sleep in a 24-hour
period, or in the diurnal variations of slow-wave sleep,
but almost abolishes the circadian periodicity o f para-
doxical sleep. 125 Melatonin given to rats in the morning
decreases n o n - R E M sleep, but when given at night has
no effect on sleep stages) ~7 An analysis o f plasma
melatonin levels in 19 epileptic men and six normal
men during sleep showed no significant difference be-
tween the two groups; ~85 however, it was f o u n d in both
groups that melatonin levels preceded by R E M sleep
were higher than those preceded by n o n - R E M sleep.
Since REM sleep is associated with increased auto-
nomic activity, the higher melatonin levels might be
due to increased pineal norepinephrine release with
resulting increased synthesis o f melatonin.
Relatively few studies have been conducted to deter-
mine the effects o f exogenously administered melatonin
on EEG activity and sleep in normal humans. More
than 20 years ago, it was observed that intravenous
melatonin could produce sedation in an adult man. 94
Most of the subsequent investigations have shown that
melatonin administration to h u m a n s does m o d i f y the
EEG and r h y t h m s o f sleep and m o t o r activity) 24'225
331

Fifteen to 20 minutes following intravenous adminis-
tration of melatonin, subjects fell asleep, and the period
of REM sleep increased. 7 After the subjects were awak-
ened, there was an increase of EEG alpha activity and
a feeling of well-being and elation. Chronic oral mela-
tonin administration led to enhancement of sleep Stages
3 and 4, and increased periods of REM sleep, Melato-
nin decreased paroxysmal EEG activity in epileptic
patients, and acute administration was followed by sleep
both in normal subjects and in epileptic patients. Sleep
changes were minimal and not related to clinical im-
provement in patients with Parkinson's disease (see
above). Intranasal administration caused sleep within
30 minutes in some subjects, z~
The mechanism by which melatonin produces its
sedative and anticonvulsant effects is not known. The
two main hypotheses are an interaction with seroton-
ergic neurons or with brain benzodiazepine receptors.19'
The inhibitory effect of melatonin on the spontaneous
neuronal activity of the mesencephalic reticular for-
mation may contribute to changes in the sleep-wake
cycle and to anticonvulsant activity, 41 However, doses
that had a clear sedative/hypnotic effect (20 mg/kg) in
rodents failed to alter whole-brain serotonin concentra-
tions. '9' Benzodiazepine receptors are present in the
bovine ~~ and rat 1,5 pineal gland. Benzodiazepines can
prolong and increase the norepinephrine stimulation of
NAT activity and, at higher doses, diazepam can stim-
ulate NAT in the absence of norepinephrine. Since
NAT is the major enzyme regulating melatonin pro-
duction, it is possible that human melatonin levels may
be increased by benzodiazepine therapy. '~5 However,
intravenous administration of melatonin to rats pro-
duced a rise in seizure threshold and totally abolished
exploratory activity, but these effects were not demon-
strated to be produced by binding to the benzodiazepine
receptor. 63
The above studies suggest that melatonin administra-
tion may be useful as a treatment for insomnia. 191Low
doses have a specific sleep-promoting action in animals,
and even large doses (up to 6 gm) can be safely given
to humans without any apparent adverse effects.
Narcolepsy may represent an impairment of the mel-
atonin-AVT control (see below) in the induction and
circadian organization of REM sleep associated with an
immaturity of REM-triggering centers. 138Arginine vas-
otocin administered intranasally and melatonin admin-
istered intravenously to narcoleptic patients dramati-
cally increased the amount of REM sleep and decreased
REM sleep latency. In a comparison of narcoleptic to
symptomatic hypersomniac patients, no significant dif-
ference could be detected in REM induction and in-
crease of REM sleep caused by AVTJ 5~The symptoms
of narcolepsy might be related to a "hypermelatonin-
emia, ''zz since serum melatonin levels are much higher
in narcoleptic patients than in control subjects, both
during the day and night, and show no circadian
changes.
332
S. S. Erlich and M. L. J. Apuzzo
Psychiatric Disorders
Melatonin and the pineal gland may be important
in stress and in certain psychiatric diseases, such as
depression and schizophrenia. 2'4,225 Several investiga-
tions have been undertaken in animals to analyze the
interactions of the pineal gland and melatonin with
psychiatric drugs, such as antidepressant56 and antipsy-
chotic agents. 4' Antidepressant drugs can cause changes
in the densities and circadian rhythms of pineal beta-
adrenergic receptors, thereby altering pineal enzyme
and melatonin levels, 6 The acute administration of
various antidepressant agents, such as imipramine, des-
methylimipramine, clomipramine, pargyline, and L-5-
hydroxytryptophan, increases pineal and plasma mela-
tonin levels, probably as a result of a beta-adrenergic
agonist action of these drugs. However, chronic treat-
ment with imipramine or clomipramine reduces these
elevations, and repeated administration of the anti-
depressant drugs desmethylimipramine or nialamide
reduces the elevation in melatonin concentrations in
the pineal gland produced by either darkness or the
beta-adrenergic agonist, isoproterenol. This diminished
hormonal responsiveness is believed to be related to
the development of beta-adrenergic subsensitivity with
prolonged drug usage. Chronic lithium treatment in
the rat sometimes, but not in all studies, suppresses
pineal melatonin, also causing a shift in the peak night-
time concentrationJ 6 The antipsychotic drugs chlorpro-
mazine and haloperidol inhibit the activity of HIOMT
(the final enzyme in the melatonin synthetic pathway).4'
There may be a close relationship between melatonin
and adrenocorticotropic hormone (ACTH)-cortisol in
man. 2~5 It has been hypothesized that patients with
major depressive illness who show no cortisol response
to dexamethasone may have an enhanced corticotro-
pin-releasing factor (CRF) production secondary to a
subfunction of a proposed pineal factor inhibiting
CRF. 2'5 Subgroups of patients with Cushing's disease
or major depressive disorders have low levels of noctur-
nal serum melatonin. Depressed patients with an ab-
normal dexamethasone suppression test (DST) have
lower melatonin levels than patients with a normal
DST. Low melatonin levels may be a genetic trait
marker for vulnerability to depression; however, high
melatonin values were reported in manic-depressive
patients who were also supersensitive to light. ,05
Results of studies of schizophrenia have been contro-
versial. Reduced melatonin levels have been reported
in chronically schizophrenic patients, although an effect
of body weight might have partly accounted for the
difference from a control group. 49 These authors cau-
tioned that body weight must be controlled in studies
of patients with psychiatric disease. No significant dif-
ference in HIOMT activity was revealed between the
postmortem pineal specimens of schizophrenics and
those of control subjects, and no significant effect of
age, sex, or neuroleptic treatment on HIOMT activity
was found. ,29 Also, no significant differences in morn-
J. Neurosurg. / Volume 63/September, 1985
The pineal gland
ing CSF melatonin levels were identified between
healthy control subjects and paranoid schizophrenic
patients, with or without neuroleptic agents.Z9However,
it is still unknown whether diurnal melatonin rhythms
in schizophrenic patients are disturbed.
Analgesia and Stress
The pineal gland may be involved in opioid analgesia.
Several animal studies suggest a role of endogenous
opioids in the regulation of pineal function, ~~ and
melatonin has been found to have analgesic properties
in mammals? 2 It has been suggested that at least one
opioid synapse may be involved in the modulation of
the nocturnal rise of pineal melatonin, 1~ since nalox-
one-treated rats show a smaller pineal melatonin peak
as well as a slower decrease from peak values. Strain
differences in sensitivity to the analgesic effects of mel-
atonin might account for the contradictory results ob-
tained following naloxone treatment. 82"191 The pineal
gland and melatonin are also involved in modulating
the diurnal rhythms of analgesia and in influencing the
age-related changes in opioid responses in mice. 82 An-
algesia induced by morphine lasts longer during the
scotophase, but this diurnal variation is absent in pi-
nealectomized mice. Des-tyrosine-gamma-endorphin
injected subcutaneously increased melatonin levels in
the rat pineal gland, and a dose-dependent induction of
pineal melatonin synthesis was seen in rats injected
with several endorphin derivatives.
A relationship exists between the pineal gland, visual
input, and ketamine-induced catatonia in the chick,
cat, and rat. 219 Catatonia induced by ketamine is aug-
mented during the scotophase, but this augmentation
is abolished by pinealectomy. Similarly, the duration of
ketamine-induced catatonia during the photophase is
prolonged by adrenergic agonists, melatonin precursors,
and melatonin. Pineal involvement in morphine-in-
duced analgesia and ketamine-induced catatonia might
be via similar mechanisms.219 Melatonin might act by
releasing endogenous peptides which perform at opioid
receptors that induce either analgesia or catatonia.
The pineal gland may play a role in stress. Hypertro-
phy and hyperplasia of pinealocytes in auditory stress,
and numerous glial plates, cavities, and acervuli in the
pineal glands of patients with ulcer disease have been
reported. It9 It is possible, if melatonin is truly episodi-
cally secreted during the diurnal waking period, that
these episodes may be related to stress. 5~Vigorous phys-
ical activity elicits transient increases in plasma mela-
tonin in both sedentary and physically trained women? 8
"Jet lag" is associated with decreases in mean plasma
melatonin levels, shifts in the acrophase (peak), or even
total desynchronization of the rhythm. 52 Under the
particular conditions of that study,52 it took many days
for the melatonin circadian periodicity to adapt. The
study also suggested that daylight might influence the
amplitude of the melatonin rhythm, and it was also
noted that, in the unperturbed basal state, episodic
J, Neurosurg. / Volume 63/September, 1985
fluctuations occurred throughout the entire 24-hour
period. In a study in which subjects were kept under
constant conditions of no sleep, isolation from time
cues, and controlled activity for 64 hours, it was found
that urinary melatonin levels varied directly with fatigue
and sleepiness. 3
Nontumor Pathology and Tumor-Related
Conditions
Little is known about the non-neoplastic pathology
of the pineal gland in animals75 or in man. Necrosis,
calcification, cystic degeneration, hyaline degeneration,
hemosiderin deposits, hyperemia, and petechiae have
been reported in the pineal gland of the horse. A circling
syndrome in a mule was believed to be caused by pineal
hyperplasia.
In man, reports usually describe common degenera-
tive changes such as glial cysts, scars, and calcifica-
tion 83"t24A65,I72,j96 (Fig. 5). The pineal glands of females
below the age of 60 years are heavier than those of
males, possibly in part because of their higher calcium
content. Fibrosis increases progressively throughout life
in females, but is much more variable in males. Pineal
gliosis is much greater in men than in women aged 30
to 60 years. Calcification (also called "pineal acervuli,"
"pineal sand," "calcospherites," or "corpora arenacea")
has been seen histologically in pineal glands of children
who died in the first decade of life, and the amount
remains fairly constant beyond the age of 30 years. The
degree of calcification may actually be a reflection of
past secretory activity rather than an indicator of degen-
eration.196 The calcification consists of carbonate-con-
taining hydroxyapatite, and magnesium, strontium,
and calcium sulfate have also been detected.
Other lesions include pineal atrophy, hypertrophy,
hemorrhages, and cysts) 24 One report concerns two
FIG. 5. Photomicrograph of the adult human pineal gland.
The suprapineal recess contains choroid plexus (arrow) and
the parenchyma shows a faintly lobular pattern and a large
glial cyst. H & E, • 16.
333

sisters and a brother who developed a syndrome of
pineal hypertrophy, sexual precocity, hyperplasia o f the
adrenal cortex, and diabetes mellitusJ s6 Acute devel-
o p m e n t of a pineal region syndrome secondary to hem-
orrhage into a pineal cyst in a patient undergoing
anticoagulant therapy has been observed. 8 A develop-
mental malformation in the pineal region has been
described, consisting of a small neuroepithelial cyst
containing papillary infoldings and choroid plexus; 183
however, it is possible that the description was o f the
normal suprapineal recess.
Several types o f pineal t u m o r s have been reported in
animals. These can be induced, or, rarely, they arise
spontaneously. 4"75 Experimental pineocytomas can be
induced in hamsters by the h u m a n JC papovavirus, m
Dysgerminomas have been reported in the silver fox,
horse, and rat, 75 and a pineoblastoma has been seen
recently in a horse, vj The influence o f melatonin on
non-pineal t u m o r growth has been reported in animals.
Patients with malignant neoplasms may show morpho-
logical abnormalities of the pineal gland, as well as
changes in melatonin levels and rhythmicity. The sub-
ject of human pineal tumors is extensive and will not
be covered in the present review, except for its relevance
to the use of melatonin as a t u m o r marker.
Pineal morphology has been studied in animals and
h u m a n s with cancer. 198 In benzanthracene-induced fi-
brosarcoma in rats, the pinealocytes and their nuclei
are larger and contain more lipid than in control ratsJ 98
In a gross and microscopic study of the pineal gland of
275 patients with cancer, 66 31 glands were enlarged and
showed degenerative changes not previously described
in cancer patients. The findings were considered similar
to those accompanying old age, except that the patients
were less than 30 years old.
Many investigators have examined the effects in
animals of pinealectomy or exogenous melatonin ad-
ministration on t u m o r growth, such as melanoma,
m a m m a r y carcinoma, Walker 256 carcinosarcoma,
leukemia, Yoshida sarcoma, and Lewis lung carci-
noma. 92"124'166'197 Most studies have suggested an inhib-
itory role of the pineal gland on t u m o r growth, possibly
via effects on mitotic activity, immunocompetence, or
growth hormone, somatomedin, adrenocortical, or cat-
echolamine secretion.155'197 Pinealectomy increases the
growth of transplanted m e l a n o m a in hamsters, and
melatonin given to pinealectomized animals abolishes
this effect. 46 The incidence o f benzanthracene-induced
m a m m a r y carcinoma increased in pinealectomized
rats. 91 The effect of melatonin on t u m o r growth is
dependent on the photoperiod and the time o f day it
was administered. ~7
Melatonin levels and rhythmicity have also been
examined in t u m o r patients. In breast cancer patients,
24-hour urinary melatonin levels are lower than in
control subjects, and the rhythmicity is abnormalJ 6 In
a study o f patients with benign and malignant tumors
of the prostate gland, it was found that young men and
elderly men with benign prostate tumors had similar
334
S. S. E r l i c h a n d M . L. J. A p u z z o
serum melatonin rhythms, although in elderly men the
amplitudes were less pronounced. 15In elderly men with
malignant tumors, rhythms were absent.
Levels of plasma melatonin may be useful as tumor
markers. Low nocturnal levels may indicate the pres-
ence of estrogen receptor-positive breast cancer, since
there is a decreased nocturnal peak in patients with this
diseaseJ 94 Women with the lowest peak concentration
had tumors with the highest concentrations of estrogen
receptors. Complete disappearance of plasma melato-
nin has been reported after removal of a tumorous
pineal glandJ 26 Besides providing evidence that the
pineal gland is the sole source o f plasma melatonin in
humans, this also may be a reliable means of assessing
the completeness of pinealectomy. H u m a n chorionic
gonadotropin and alpha-fetoprotein levels have been
used as markers for h u m a n pineal tumors. 2
Other Clinical Manifestations
Numerous reports suggest that the pineal gland may
play a role in a variety of animal conditions which
might be relevant to human diseases, such as hyperten-
sion, disorders of myelin, and eye disease. 166The pineal
gland might be involved in blood pressure regulation.
Several studies have shown that pinealectomy in rats
induces hypertension, which can be blocked by mela-
tonin administration. It has been hypothesized that the
hypertension may be secondary to overactivity of the
renin-angiotensin-aldosterone system, or that melato-
nin might act as an antihypertensive agent via stimu-
lation of central inhibitory adrenergic pathways. Pin-
ealectomy also causes increased vascular reactivity to
various vasoconstrictor agents. 42 Although pineal epi-
nephrine is high in both spontaneously hypertensive
and neurogenically hypertensive rats, it is unknown
whether changes in pineal catecholamines are in any
way causally related to experimental hypertension) TM
However, in doses o f 10 mg/kg, melatonin failed to
change the blood pressure in cats or to alter the con-
tractile force or electrocardiogram of the dog.13
Pinealectomy leads to myelin alterations. Neonatal
pinealectomy in the rat causes a delay in brain matu-
ration, first decreasing brain lipid levels, and then de-
creasing the amount of myelin itself. 167 Subsequent
work 77 showed that neonatal pinealectomy altered the
levels of long-chain fatty acids in myelin. These findings
may prove to be significant in human myelin diseases,
or in diseases resulting in demyelination, since, for
example, ultrastructural abnormalities of the pineal
gland have been reported in Tay-Sachs disease.1
There are many other reports of the role of the pineal
gland in various human diseases, such as glaucoma, z~2
porphyria, 2~3 hemochromatosis, and endocrine disor-
ders. TM In some cases of idiopathic hemochromatosis,
a disease in which many endocrine disorders occur,
especially hypogonadism, the circadian melatonin
rhythmicity is disturbed 51 and can even be absent. In
congenital adrenal hyperplasia, the nocturnal peak in
melatonin is lower than in normal children, and occurs
J. Neurosurg. / Volume 63/September, 1985
The pineal gland
earlier in the night. 6~ In patients with Turner's syn-
drome, the average night melatonin value is similar to
the value recorded at the onset of darkness. Children
with growth hormone deficiency, hypogonadism, and
Turner's syndrome have abnormally high daytime mel-
atonin levels, but children with seizures have low values.
Other Potential Pineal Hormones
It was long believed that melatonin was the only
pineal hormone, but other pineal factors have since
been shown to have hormonal activityfl5'223'224 These
compounds comprise two groups: peptides (such as
AVT) and other methoxyindoles. In the early 1960's, it
was suspected that pineal polypeptides would be im-
portant antigonadotrophic compounds. A polypeptide
was isolated from bovine pineal glands which, in addi-
tion to showing pressor and oxytocic activities, also had
an antigonadotrophic effect in prepubertal mice,~8 and
this compound was believed to be AVT. It is believed
that some of the metabolites ofmelatonin may be active
and may also be hormones, such as 5-methoxytrypto-
phol and 5-methoxytryptamine. 3~
The nonapeptide hormone, AVT, is normally found
in the pituitary gland of lower animals. In the mam-
malian brain, it is synthesized by specialized cells of the
pineal recess and subcommissural organ, and is stored
in undefined cells of the pineal gland, m It differs from
arglnine vasopressin by one amino acid, having isoleu-
cine instead of 3-phenylalanine, and from oxytocin by
having arginine instead of 8-1eucine. Its effects are very
similar to those of melatonin, although it is far more
potent. It has been hypothesized that melatonin may
be the releasing factor for A V T , 137 causing its release
into CSF. Cultured cells from human fetal pineal glands
release a peptide, presumably identical to AVT, into
the culture medium.
Like melatonin, AVT may be of clinical significance.
It has been most studied in relation to its effects on
sleep and brain maturation. Also like melatonin, AVT
has sleep-inducing and anticonvulsant effects. The ef-
fects of AVT on sleep in adult mammals are controver-
sial, but in newborns they are more consistent. Ex-
tremely small amounts of AVT injected into the third
ventricle induce slow-wave sleep in the cat, and com-
pletely suppress paradoxical sleep. ~36'~4~The release of
AVT into human CSF may be REM sleep-dependent? 39
The CSF of normal men contains AVT when it is
withdrawn after the subject awakens from REM sleep,
but AVT is not detectable after they awaken from
non-REM sleep. Subcutaneously administered AVT an-
tagonizes pentylenetetrazol-induced convulsions in
the rat. s~
Daily administration of AVT to newborn kittens
induced an increase of total sleep and of active sleep,
the ontogenetic precursor of adult REM sleep, 62 as well
as increasing the number of REM's during an active
sleep episode, and decreasing locomotor and investiga-
tive activities. The mechanism by which AVT exerts its
sleep-inducing effects is unknown, but it may be via the
J. Neurosurg. / Volume 63/September, 1985
serotonergic pathway. 136It has been suggested that AVT
may interfere with serotonin release at postsynaptic
receptor sites. ~36 It has also been theorized that AVT
exerts its hypnogenic effects by activating a descend-
ing gamma-aminobutyrate-containing habenulo-raphe
pathway.6j Arginine vasotocin delays brain maturation.
Daily administration decreased total lipid levels, and
delayed eye opening in the kitten, 62 but did not change
the normal daily increase in body weight and brain
weight. However, in the rat, pinealectomy impaired
brain myelination, t67
Summary
A wealth of knowledge is currently available regard-
ing the structure and function of the mammalian pineal
gland and its hormones. The pineal gland is essential
for transmitting information as to day length, and is a
key organ in the regulation of mammalian reproduction
and of many circadian rhythms. Many animal studies
have indicated that pineal compounds, particularly
melatonin and AVT, exert pronounced cellular effects.
These studies, along with behavioral investigations
demonstrating effects of these compounds on motor
activity, sleep, and seizures, indicate that melatonin and
AVT might directly affect certain neurons within the
CNS. However, it still remains unclear as to what the
sites of action of melatonin are and how melatonin
works. Future research into these areas will almost
certainly help explain the cellular and behavioral effects
of the pineal gland. Other subjects requiring further
investigation include the nonsympathetic innervation
of the pineal gland and the role of other pineal hor-
mones.
It has been reported that factors such as inactivity
and position may modify melatonin rhythms in hu-
mans. Urinary melatonin rhythms were abolished in
three young patients kept supine in bed with healing
leg fractures. TM The weightless state encountered by
astronauts subjected to zero gravity has been considered
to possibly be analogous to the quadriplegic situation,
in which proprioceptive input is reduced or eliminated,
and in which abnormalities of the melatonin rhythm
have been described. 88 Studies of the circadian time-
keeping mechanism during space flight have just been
initiated, 192and an examination of melatonin rhythms
in astronauts would probably prove to be quite inter-
esting, s8
The circadian rhythm of melatonin is disturbed in
several human diseases; therefore, melatonin levels
might be useful as a diagnostic marker. Exogenous
melatonin administration generally exerts a sedative
effect, 175so melatonin administration may be useful as
a therapeutic tool. An extensive amount of literature is
accumulating indicating that the human pineal gland
might play a role in the pathophysiology of puberty,
sleep, seizure, and psychiatric disorders. A detailed un-
derstanding of the interactions of the human pineal
gland, light, and circadian rhythms has only just begun
to lead to strategies for treating endogenous chrono-
335

b i o l o g i c d i s o r d e r s 1~ a n d e x o g e n o u s l y p r o d u c e d disturb-
ances, such as "jet lag. ''43 F o r these reasons, future
r e s e a r c h will p r o v e to be very r e w a r d i n g in u n d e r s t a n d -
ing b o t h the b a s i c f u n c t i o n s o f t h e p i n e a l g l a n d a n d its
role in h u m a n disease.
Acknowledgments
The authors wish to acknowledge Michael H. Erlich, M.D.,
for his helpful critique of the manuscript, and Ms. Anne Marie
Hire for photographic assistance.
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Manuscript received December 19, 1984.
Dr. Erlich is a recipient of Teacher-Investigator Develop-
ment Award 5K07 NS00789 from the National Institute of
Neurological and Communicative Disorders and Stroke, and
a grant from the Keck Foundation.
Address reprint requests to: Stephanie S. Erlich, M.D.,
Department of Neurological Surgery, University of Southern
California School of Medicine, Los Angeles, California 90033.
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