Ind. J. Physiol. Pharmac., Volume 33, Number 4, 1989

REVIEW ARTICLE

THE PINEAL GLAND: ITS PHYSIOLOGICAL ANDPHARMACOLOGICAL ROLE

V. SRINIVASAN

Institute of Physiology,Madurai Medical College, Madura; - 625020

( Received on November 15, 1989)

Abstract: Our perception of pineal gland function has attained new dimenaions during the lastdecade. The gland is active throughout the life of an individual and secretes melatonin, themajor pineal hormone, and many indoles and polypeptides. The secretion of pineal gland isregulated not only by sympathetic nerve fibers but by other central pinealopetal projections also,Many neurotransmitter-receptor sites have been identified recently in the pineal gland. Thegland plays an established role in controlling reproduction and is involved in the control of sexualmaturation. It has a major influence on the circadian organization of vertebrates including humanbeings. The hormone melatonin has a potential therapeutic valve in treating disorders that areassociated with biological rhythm disturbances like sleep disorders, "jet lag" phenomena andaffective disorders. The gland is actively involved in the mechanisms controlling sleep-wakefulness cycle and human mood disorders. It actively participates in the neuroendocrinemechanism controlling stress and acts even as an oncostatic gland. The pineal gland may beconsidered an "equilibrating-tranquillizing gland" contributing to longevity.

Key wordtl : pineal glandseasonal reproductionchronobioticpsychotropic drugs

INTRODUCTION

Once considered to be an organ of littlefunctional significance, the pineal gland has nowemerged as a major "neuroendocrine transducer" (agland which converts a neural input into hormonaloutput) with specific effects on reproductive mecha-nisms, circadian organization, sleep mechanisms andcontrol of human mood. The gland acts as "ageneral synchronizing, stabilizing and moderatingorgan" for several physiological processes (I) andits hormone melatonin has been designated as"equilibrating hormone" (2).

neuroendocrine-tranducersexual maturationsleep-wakefulnessstress

pinealocytecircadian rhythmsaffective disorder

longevity

The pineal gland of vertebrates develops fromthe neural crest cells of the roof of the diencephalon.In human beings it is deeply situated in the midlineof the brain below the corpus callosum. It is"ideally placed anatomically to collect, integrateand compare information from extra cranial sourcesand intracrnial sites" (3). Calcification which occursin the human pineal gland is considered to be aphysiological process related to its past secretoryactivity rather than an indicator of present degenera-tion (4). Available evidence strongly indicates thatthe pineal gland is active throughout the life of anindividual (5).

264 Srinivasan

PINEAL GLAND STRUCTURE

The chief cellular component of the pineal glandis pinealocyte although other astrocyte lik e inter-stitial cells also have been identified recently (6).Pinealocytes are extremely modified photoreceptorcells that represent the last step in the phylogeneticevolution (7). The presence of opsin-retinalS-antigen in the pinealocytes suggests their closerelationship to retinal photo-receptor cells (8). Thecytological nature of pinealocyte stilI remainsenigmatic although it contains the usual cellularorganelles like endoplasmic reticulum, golgi complex,lipid droplets, mitochondria and different types' ofsynaptic ribbons. Neuron specific enzyme enolasealso has recently been demonstrated in thesecells (6).

BIOSYNTHESIS OF PINEAL HORMONES

The pinealocytes of all vertebrates synthesize twodifferent types of substances, namely, indoles andpolypeptides. Melatonin, or 5·methoxy Nvacetyl

Tryptophan

Ind. J. Physio!. Pharmac., Volume 33, Number 4, 1989

tryptamine, the major hormone of the pineal gland,was first isolated by Lerner in 1958 (9). Subse-quently many other hydroxy and merhoxy indoleshave been identified in the pineal gland. Thebiosynthesis of melatonin is given in Fig. I-A. Itbegins with conversion of the amino acid tryptophaninto 5-hydroxytryptophan (5-HTP) by the enzymetryptophan hydroxylase. Decarboxylation of 5HTPby 5-HTP decarboxylase gives rise to 5-hydroxy-tryptamine (5-HT) or serotonin. Serotinin isN-acetylated to form Nsacetylserotonin by theenzyme serotonin N-acetyl transferase (SNA T) whichis the rate limiting enzyme in the bio-synthesis ofmelatonin. N-acetylserotonin is methylated to formmelatonin by the enzyme hydroxyindole O-methy)transferase (HIOMT). HIOMT is almost exclusivelyfound in the pineal gland, although recent studieshave demonstrated the presence of this enzyme inretina also. The synthesis of melatonin involvesmany other cofactors like S-adenosylmethionine,S-adenosylhomocysteine, and pteridines (10). Allother 5-hydroxyindoles present in the pineal glandcan be methylated to form methoxy indoles like

II Tryptophan hydroxylaseoJ,

5-hydroxytryptophan (5-HTP)

II 5-HTP decarboxylase

t5-hydroxytryptamine (5-HT) (Serotonin)

II Sertonin N acetyl transferase (SNAT)oJ,

N-acetyIserotonin

II Hydroxy indole O-methyl transferase (HIOMT)t

Melatonin

orN-acetyl 5-methoxytryptamine

Fig. I-A : Biosynthesis of melatonin - the major pineal hormone

Ind.]. Physio!. Pharmac., Volume 33, Number 4,1989

5-methoxytryptophan, 5-methoxytryptamine,5-methoxyindole 3-acetic acid and 5-methoxy-trytophol. Figure I-B gives the bio-synthetic path-way for the formation of all these methoxy indoles.The biologically active methoxy indoles include onlymelatonin and other two methoxy indoles like5-methoxytryptophol and 5-methoxytryptamine.

Ultra structural and ultra cytochemical observa-vations have shown that pinealocytes are capable ofprotein secretion (7). With the use of bioassay,RIA (radioimmunoassay) and immunocytochemistrymany immunoreactive polypeptides have beenidentified in the pineal gland (11). Arginine vaso-tocin (AVT), a tripeptide threonine-serine-lysine,delta sleep inducing peptide (DSIP), S-antigen, andCalbindin 27 are some of the recently identifiedpolypetides in the pineal gland of vertebrates (10,12).Recently zinc-containing metallothionins also havebeen identified in the pineal gland of mammals (13).The principal route for the synthesis and secretionof proteins appears to be through endoplasmicreticulum, golgi complex and vesicular membranebound compartments (I I). The highly vascularpineal gland secretes their products directly into thecerebrospinal fluid, or into the perivascular spaces

HIOMT5-hydroxytryptophan - --+S-met hoxytryptophan

IIt

HIOMT5-hydroxytryptamine ---+5-methoxytryptamine

II mono amino oxidase (MAO)t

The Pineal Gland 265

to be transported by the blood (7) According toWurtman (14) melatonin once formed is not storedwithin the pineal gland to any appreciable extentbut is released into the circulation directly.

REGULATION OF PINEAL GLAllDSECRETION

The secretion of melatonin, the major pinealhormone is rhythmic in nature, with high levelsoccurring in the night and low levels during the day.This rhythm persists even when animals or humanbeings are housed in constant environmental condi-tions (e.g. continuous darkness) suggesting therebythat the rhythm is largely endogenous in nature (14).The suprachiasmatic nucleus, the "master circadianclock", present in the hypothalamus, is largelyresponsible for this endogenous melatonin rhythm(15). It controls the activity of the pineal glandthrough the release of norepinephrine from thesympathetic nerve fibres. (Fig. 2). Increased releaseof norepinephrine from the sympathetic nerve fibresin night time increases the rate of synthesis ofmelatonin in the pineal gland (16). Light-dark cycleentrains the melatonin rhythm generated by thesuprachiasmatic nucleus by acting through the

alcohol dehydrogenase a-acetyl transferase5-hydroxyindoles acetaldehyde-- -+5-hydroxytryptophol -+a-acetyl S-hydroxytryptophol

I I II aldehyde dehydrogenase I HIOMT I HIOMTt t t

HIOMTS-hydroxyindoleacetic acid---+5-methoxyindoleaceticacid S-methoxytryptophol a-acetyl S-methoxytryptophol

Fig. loB : Pathway showing the biosynthesis of hydroxy and methoxy indoles in the pineal gland

266 Srinivasan

retinohypothalamic tract (I7). The physiologicalsignificance of this mechanism is linked with thephotoperion con.trol of melatonin seeretion (14).

Electrophysiological and radioligand studies haveshown that light impulses reach the pineal glandalso through central pinealopetal projections (18).Many peptides like vasopressin, oxytocin, neuro-physin, vasoactive intestinal polypeptide (VIP) havebeen identified in the central pinealopetal projections(II). Neurotransmitter receptor sites like betaadrenergic, alpha adrenergic, dopaminergic, seroto-nergic, GABAergic, glutamatergic, benzodiazepi-nergic, substance P-ergic, have been identifiedrecently in the pineal glands of mammals includinghuman beings. Extensive reviews on this aspecthave been elegantly brought out by Ebadi andGovitrapong (19,20). These pineal receptor sitesare involved not only in the synthesis of melatoninand other methoxy indoles but also participate inthe "biological expression of hitherto unknownfunctions of the pineal gland (21).

PINEAL GLAND FUNCTIONS

The pineal gland exerts most of its effects onbodily systems through the secretion of its majorhormone melatonin. Biochemical and electrophy-siological techniques have revealed that this hormoneacts mainly on mid brain. hypothalamus and suprachiasmatic nucleus, although other areas likehippocampus and substantia nigra have also beenimplicated (21). Melatonin increases the concentra-tion of serotonin and catecholamines in these areasof the brain (22). Since melatonin increases theconcentration of biogenic amines, and biogenicamines themselves participate in many of the normaland disturbed functions of the central nervoussystem like mood and sleep disorders, it is likelythat melatonin exerts some of its actions on bodilysystems by influencing biogenic amine transmissionin the central nervous system (21).

Ind. J. Phy.iol. Pharmac., Volume 33, Number 4, 1989

Melatonin, when administered in physiologicaldoses, mimics the light dark cycle in the inductionof photoperiod dependent responses (23). Thehormone acts as a conveyor of photoperiodicinformation which is interpreted differently indifferent times of the year (24). Hence in recentyears studies on pineal gland function have focussedmainly in seasonal cycles rather than on dailycycles (25).

Pineal Gland and Reproduction

The physiologic effects of melatonin on repro-ductive function in animals depend on the species,but suppression of gonadal function has been welldocumented as the primary effect of melatonin andrelated compounds in most of the species that havebeen studied (26). Initial studies carried out byWurtman and his coworkers (27) showed thatmelatonin exert. a direct inhibitory action ongonads. Studies carried out on neuroendocrine-reproductive axis revealed that melatonin acts onthe hypothalamic neurons where it reduces theamplitude and/or frequency of GnRH pulses andthereby exerts an inhibitory action on gonadsthrough the inhibition of gonadotrophin secretion(28).

In certain species of animals like sheep and ewesmelatonin appears to be progonadal in nature. Thepineal gland and its hormone melatonin have beenshown to regulate the physiological status of thereproductive system on a seasonal basis. The lengthof the photoperiod determines the reproductivecompetence in these animsls (23). Gonadal activityis initiated during short days and inhibited duringlong days. The innate ability of these organisms tomeasure the passage of time has adaptive significance.It enables them to synchronize their breedingbehaviour with the most favourable environmentalconditions when the chances of survival of theiryoung ones will be great (29. 30). The fact thatmelatonin rhythm changed as a function of season

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Was first shown by Arendt (31) who clearly demons-trated that longer nights were associated with moreprolonged periods of high melatonin levels. Theinsertion of melatonin implants has been found topromote the onset of reproductive function in sheepeven when they were exposed to inhibitory photo-periods (32, 33). The reproductive responses couldreflect the presence of the "short day" produced bythe constant elevation in circulating melatonininduced by melatonin implants (34). The inductionof short photoperiod by careful administration ofmelatonin has been found to be of great commercialvalue in increasing either sheep breeding (35, 36) orgrowth of fur (37). Many studies also have pointedout that breeding in humans has two annual peaksand this has been attributed to the two distinct typesof photoperiodic responses based on geneticheterogeneity (38).

Pineal Gland and sexual maturation

The occurrence of precocious puberty in a fouryear old boy with a pineal tumour was described asearly as 1898 by O'Heubner. Studies carried out inrecent years suggest that human pineal's secretoryactivity is associated with pubescence (14). Kitayand Altschule (39) on the basis of an extensivereview of literature suggested that pineal gland hasantigonadotropic effect on human sexual maturation.

In all mammals including human beings theonset of puberty has been attributed to the pulsatilesecretion of gonadotrophin releasing hormone(GnRH) by the arcuate nucleus of the hypothalamus(40). Melatonin appears to have a direct andcontinuous regulatory action on gonadotrophinsecretory pattern from infancy to the onset ofpuberty (41). In an extensive study carried out onhuman beings belonging to different age groups(1 to 80 years) they noted a steady decline in thenocturnal plasma melatonin levels from infancy toearly adulthood and a steady maintenance of thelevels thereafter. In summarizing the evidence for

The Pineal Gland 267

the probable involvement of pineal gland in humanpuberty they have noted that melatonin deserves avery thorough examination for a possible action inthe mechanism controlling human sexual maturation(42).

Pineal gland and circadian rhythms

Every organism exhibits certain kinds ofbiological periodicity which enable it to measure thepassage of time. The most important one amongthese is the circadian rhythm which eoincides withthe 24-hour light and dark cycle. Under normalcircumstances the endogenous rhythms are synchro-nized with or entrained to external events byenvironmental cues or zeitgebers (time givers) suchas light-dark cycle (43). The daily rhythms such asrest-activity, temperature, REM sleep mechanism,electrolyte and cortisol excretion, have been wellstudied in man and other animals and are said to"free run" in the absence of any time cues whenstudied in specially constructed isolation bunkers(44, 45, 46).

Investigation on the control of these circadianrhythms has revealed the presence of an internalmaster biological clock in the supra chiasmaticnucleus (SCN) of the hypothalamus (43). Lesionsof the supra chiasmatic nucleus abolish all knowncircadian rhythms in rodents (47).

Evidence for the possible involvement of pinealgland in the synchronization of circadian rhythmshas come from the early observations of melatoninbiosynthesis which exhibits a characteristic day andnight rhythm. Melatonin is said to be one of thenaturally occurring substances that affect circadianrhythmicity (48). A functional synthronizing rolefor the pineal gland was suggested by Armstronget al (25) who administered melatonin in variousphysiological (10 microgram/kg body weight) andpharmacological doses (I rug/kg body weight) andnoted disruption of various behavioural rhythms in

268 Srinivasan

experimental animals. Tn human beings, suddenrapid transfer across several time zones duringintercontinental flights results in internal desynchro-nization, a phenomenon known as "jet lag". Short(49) first suggested that melatonin administrationafter an intercontinental flight would alleviate thejet lag phenomenon Melatonin administration hasbeen found to be really very effective in alleviatingjet lag (24, 50). In an interesting study they alsonoted that late afternoon administration of melatoninhas been shown to phase advance the fatigue-alertness rhythm (24). Melatonin is said to have adirect effect on the central rhythm generatingsystems and act as a circadian zeitgeber for darkness;hence the expression "darkness hormone". Thefunction of the mammalian pineal gland is to adjustthe phase and synchronize internal rhythms byperiodic nocturnal release of melatonin Whenadministered in pharmacological doses, melatoninacts as a powerful chronobiotic maintainingsynchronicity and preventing desynchrony withincircadian systems (5 I). It has a potential value intreating external desynchronization that may occurin some categories of people such as astronauts,submariners ond polar explorers and may be usefultherapeutically in treating such diseases associatedwith biological rhythm disturbances (I4, 24, 51).All these studies point out that pineal gland playsan important role in the physiology of circadianorganization of vertebrates, although compellingevidence for the full involvement of this gland inthe control of circadian systems is yet to be obtained.

Pineal gland and sleep mechanism

There is enough evidence to suggest that pinealgland and its hormone melatonin participate in thephysiological regulation of sleep and sleepiness (52).Intrahypothalamic administration of melatonininduced sleep in cats (53). Studies carried out inother animals also supported the sedative like effectof melatonin Following melatonin administration,sleep induction occurred in human beings also (54).

Ind. ]. Physiol. Pharmac., Volume 33, Number 4,1989

Vollroth et al (55) applied low doses of melatoninintranasally and found induction of sleep in healthyhuman volunteers. A number of other investigatorsalso have noted that melatonin acted like thehypnotic agents (52). The hormone is believed tobe released in pulses during IJght phases of humansleep and its probable physiological function is toinduce deep sleep and to prevent awakening (56).Daily late afternoon administration of melatoninhas been shown to phase advance the timing ofsleep (35). The high rate of melatonin secretionduring night hours and the induction of sleep byexogenous melatonin suggests that one of thephysiologic functions of melatonin is to do with thetiming of sleep (14). A clinical condition known asdelayed sleep phase syndrome (DSPS) due toineffective entrainment to zeitgeber (periodic events)such as light dark cycle, has been documented. Inthese patients the timing cf sleep onset is abnormal.Since melatonin seems to be the natural chronobioticit could be used effectively for correcting the sleepabnormality of these patients (51).

Melatonin and Human mood disorders

Depression, manIa or hypomania are thecommonest type of human mood disorders that aredescribed in the literature. From psychiatric pointof view depression covers a wide range of affectivestates which includes normal and abnormal moodswings. The etiology of morbid depression howeverremains unknown. Many biological theories havebeen put forward to explain the underlying causes ofdepressive illness.

Since some of these affective disorders are cyclicin nature, desynchronization of biological rhythmshas been suggested as the cause for the precipitationof manic depressive diseases (57). With the recogni-tion of pineal gland involvement in the control ofvarious bodily rhythms, much attention has beenpaid in recent years linking pineal gland withaffective disorders. Hypo-functioning of the pineal

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gland as reflected by decreased levels of melatoninin body fluids was first noted in the year 1979 byWetterberg (58). Many other investigators workingin different parts of the world have also confirmedthe presence of "low melatonin syndrome" in agroup of depressives (59). These studies revealedcertain forms of depressions could be due tobiochemical defects in the synthesis, release andactions of melatonin ((0). Supportive evidence forthe involvement of melatonin in affective disorderscame from the studies of psychoactive drug adminis-tration in experimental animals and in patients withaffective disorders, The tricyclic antidepressants(imipramine) and monoamine oxidase inhibitorantidepressants increase the pineal melatonin contentsignificantly in experimental animals (61,62,63,64).

The Pineal Gland 269

These drugs elevate the serum melatonin (6:).Urinary melatonin (59, 60 or urinary 6 hydroxy-melatonin levels (67). A schematic diagramdepicting the probable mechanism of action ofantidepressants in elevating melatonin concentrationof the pineal gland is shown in Fig. 2. Both thesedrugs ictivate the beta receptors of the pineal grandby elevating the norepinephrine concentrations atthe receptor sites. A specific disease known asseasonal affect.ve disorder (SAD) with regularlyoccurring winter depressions was first noted byRosenthal and his coworkers (68). Bright light wasfound to be very effective in treating such disordersand it seems to act by altering the profile ofmelatonin secretion in these patients (69).

PINEALO!:Y·TELIGHT

III

<!?RETINa

HYPOTHALAMIC TRACT

ASUPRACHIASM'ATIC NUCLEIOF HYPOTHALAMUS

IMEDIAL FORE BRAIN

BUNDLE

I

TRYPTOPHAN

!Try H

5 HT.P

J,CAAAD) -

SEROTONINl NATNAS+ HIOMTt

MELATONIN

BRAIN STEM RETICULARFORMATI'ONJ..

SPINAL·CORD

L

+ CL0R.t'YLINEe~)NORADRENERrC

NERVE

TERMINAL=<- SUPERIOR CE-RVICAL GANGLION

Fig. 2 : Effects of anti-depressants on pineal gland function.

270 Srinivasan

Other miscellaneous functions of the pienal gland

Recently a great number of studies have beendevoted to the study of pineal gland influences oncancer. Pineal gland extracts exert an inhibitoryeffect on tumour growth in experimental animalsand this growth inhibitory effect seems to be relatedto melatonin only and not shared by other indoles(70). Melatonin exerts an inhibitory effect onlywhere it is present in physiological concentrations(71) and the timing of melatonin administrationseems to be crucial for arresting tumour growth (72).

The pineal hormone melatonin has been foundto be antistressogenic in nature and it participatesin the overall neuroendocrine mechanism involvinghypothalamo-hypophyseal-adrenal system (3,73,74).

The gland has been suggested to play an impor-tant role in determining longevity (75). Longevityis believed to be regulated by a biological clockmechanism and pineal gland plays an important rolein synchronizing the function of this biologicalclock (76) According to Romijn (I) pineal glandis the natural tranq uiIIizing organ, the morphologicalsubstrate of the "seventh chakra", the gateway toperfect harmony and rest.

CONCLUSIONS

The pineal gland has now emerged as an organof major neuroendocrine importance. It is activethroughout life. Its secretion is regulated not only

Ind. J. Physiol. Pharmac., Volume 33, Number 4,1989

by sympathetic nerve fibers but also by centralpinealopetal projections. Many neurotransmitter-receptor sites have been identified in the pinealgland.

Melatonin, the major pineal hormone isresponsible for most of the gland's effects on bodilysystems. The pineal gland plays an established rolein controlling reproduction. Though it is mainlyantigonadotropic, it also has progonadal actions insome species of animals. In recent years there isgrowing evidence to suggest that pineal plays animportant role in the mechanism controlling sexualmaturation and puberty. Pineal hormone, mela-tonin, has a potential value in treating diseasesassociated with biological rhythm disturbances. Thegland participates in the physiological regulation ofsleep and sleepiness. Since melatonin acts as an"equilibrating hormone" it plays an important rolein controlling not only human mood disorders andstress but is also helpful in fighting against cancer.In summary, it can be said that pineal gland is agland with multiple functions, including possiblyeven tranqility and longevity.

ACKNOWLEDGEMENTS

Acknowledgements are due to Dr. (Mrs.) LalithaAnantha Subramaniam, Director of Medical Edu-cation, Government of Tamilnadu, Dr. (Mrs.) TaraNatarajan, Dean, Madurai Medical College andDr. M. Ramaraj Director, Institute of Physiologyfor their help.

REFERENCES

1. Romijn HJ. The Pineal. A Tranquillizing Organ. LifeSciences 19i8; 23 : 2257-74.

2. Trentini GP. Remarks on the third colloquium of theEPSG. EPSG N,w letter 1984; 12 : 26-29.

3. Armstrong SM, Ng KT, Coleman: GJ. Influence of"Pineal gland on brain - behaviour relationships InReiter R.J. (eds) "The Pineal gland. Vol. III ExtraReproductive effects" Boca Raton Florida eRG Press 1982;pp.81-106.

4. Tapp E. The histology and pathology of the humanpineal gland. Prog Brain RIS 1979: 52 : 481-99.

5. Young 1M, Silman RE. Pineal methoxy indoles in thehuman. In the Pineal gland Vol. III - Extra Repro-duetive effects. Ed. R. J. Reiter. GRG Press Florida 1982'189-218. '

6. Vollroth L. Neuronal properties of Mammalian Pineal-ocytes. Abstract. Proceedings of the IV Colloquium ofthe EPSG August - 31, Sept. 4 Modena Italy 1987; 4.

7. CollinJP. New data and vistas on the mechanism ofsecretion of proteins and indoles in the mammalianpinealocyte and its phylogenelic precursors, the pinealinhypothesis and preliminary comments on the membrane

Ind. J. Physiol. Pharrnac., Volume 33, Number 4, 1989

traffic. In the Pineal organ: Photobiology, Bio chrono-metry and Endocrinology Eds. A. Oksche and P. PavetElsevier/North Holland. Biomedical Press Amsterdam1981; pp. 187-220.

8. KorfHW. Photoreceptor differentiation and neuronalorganization of the pineal organ. Abstract Proceedingsof the IV Colloquium of EPSG August - 31, Sept. 4,Modena Italy 1987; p. 3.

9. Lerner AB, CaseJD, Takahashi Y, Lee TH, Mori W.Isolation of melatonin, the pineal gland factor thatlightens melanocytes] Am Chem Soe 1958; 80: 2587.

10. Ebels I, Balemans MGM. Physiological aspects ofPineal functions in mammals. Physiol Reoiaos 1986; 66:581-605.

II. Collin JP. Cellular biology of the pineal organ withspecial reference to some known and other hypotheticalmessenger substances; The CRL Concept and outlook.In The pineal gland. Current status of Pineal researchEds. B. Mess., Cs Ruzada., L. Tima and P. Pevet 1985;92-110.

12. CollinJP, Brisson P, Falcon J, Voisin P. Multiple Celltypes in the Pineal. Functional aspects. In Pineal andRetinal relationships Eds. O'Brien P.J. and Klein. D. C.Academic Press Netu York 1986; 15 32.

13. Ebadi M, Awad A, Hegazy MR. The role of Pinealmetallothionein in Nucleie acid metabolism. In ThePineal gland and Cancer Eds. D Gupta, AA, HanasioRJ Reiter. Brain Research promotion London 1~88;pp.89-106.

14. Wurtman RJ, Introduction. Melatonin in Humans. InMelatonin in Humans. Procoedngs of the first Inter-nationnal Conference on Melatonin in Hnmans. Eds.Wurtman R. J. and Waldhauser F. Vierma Austria Nov.7-9 : 1985; 1-8.

15. Klein DC, Moore RY. Pineal N. acetyl transferase andhydroxy indole 0 methyl transferase. Control by retinohypo thalamic tract and the Suprachiasmatic nucleus.Brain Res 1979; 174: 245-54.

16. Craft CM, Morgan WW,Jones DJ, Reiter RJ. Hamsterand rat pineal gland beta receptor characterization withiodocyano pin dolol and the effect of decreased Catecho-lamine synthesis on the receptor. ] Pineal Res 1985; 2:51-66.

17. Moore RY, Klein DC. Visual pathways and the Centralcontrol of a circadian rhythm in pineal serotonin Nacetyl transferase. Brain Res 1974; 71 : 17 33.

18. KorfHW, Moller M. The innervation of the mamma-lian pineal gland with special reference to CentralPinealopetal projections. Pineal Res Rev 1~-84;2 : 41-86.

19. Ebadi M, Govitrapong P. Neural Pathways and Neurotransmitters affecting melatonin synthesis ] NeuralTronsm 1986; 21 : 125-55.

20. Ebadi M, Govtirapong P. Orphan transmitters andtheir receptor sits in tbe Pineal gland. Pineal researchReviews 1986; 4 : I-54.

21. Ebadi M. Indolearninergie and peptidergic receptorsand their modulation of Pineal functions. InFundamentals and Clinics in Pineal research. Eds G. P.Trentini, C De Gaetani and P Pevet, Raven Press 1987;44: pp. 91-110.

22. Cassone VM, Manaker M.system a neuroendocrine loop.539-49.

Is the avian Circadian] Exp Zool 1984; 232:

The Pineal Gland 271

23. Kennaway DJ, Gillmore TA, Seamark RF. Effect ofmelatonin feeding on serum prolactin and gonadotrophinlevels and the onset of seasonal estrons cyclicity in sheep.Endocrinology 1982; 110: 1766-72.

24. Arendt j, Broadway J. Light and melatonin as Zeitge-bers in Man. Chrenobiolo gy Inurnationat 1987; 4 : 273-82.

25. Armstrong SM, Cassone VM, Chesworth MJ, RedmanJR, Short R V. Synchronization of mammalian circa-dian rhythms by melatonin. In Wurtman R. J. andWaldhauser.. F (eds) "Melatonin in Humans" New YorkSpringer Verlag 1986; pp 375-94.

26. Goldman BD. The Physiology of melatonin inmammals. Pineal Res Reviews 1983; I : 145-82.

27. Wurtman RJ, Axelrod ] , Chu EW. Melatonin, a pinealsubstance. Effect on the rat ovary. Science 1963; 141 :277-78.

28. Rivest RW, Lang U, Aubert ML, Sizonenko PC. Dailyadministration of melatonin delays rat vaginal openingand disrupts the first estrous cycles. Evidence that theseeffects are synchronized by the onset of light. Endosrinoi1~85; 116: 779·87.

29. Reiter RJ. SESsional aspects of Reproduction inmammals. Photoperiodic effects. In sessional effectson Reproduction, infection and Psychoses. Progress inBio.netereology 1987: 5 : 1-9.

30. Garfield E. Chronobiology: An Internal clock for allseasons. Part I. The Development of the Science ofBiological rhythms. EPSG New letter 1988; 20: 12-22.

31. ArendtJ, Wirz Justice A, Bradtke-J. Annual rhythmof serum melatonin in Man. Neurosci Leu 1977; 7:337-30.

32. Lincoln GA, Ebling FJP. Effect of constant releaseimplants as melatomn on seasonal cycles of reproduction,prolactin secretion and moulting in rams. ] Reprod Fert1985; 73 : 241·53.

33. Nowak R, Rodway RG. Effect of intravaginal inp1antsof melatonin on the onset of ovarian activity in adultand prepubertal ewes] Reprod Fert 1985; 74 : 287-93.

34. Karsch FJ. A role for melatonin as a time keepinghormone in the EWe. In melatonin in Humans Eds.R.J. Wurtman and F. Waldhauser Proceedings of thefirst International Conference on Melatonin in Humans.Vienna Austria Nov. 7-9 1985; 107 21.

35. Arendt J, Borbely AA, Franey C, Wright J. The effectof chronic small doses of melatonin given in the lateafternoon on fatigue in man : a preliminary study.Neurosci Letter 1984; 45 : 317 -21.

36. Symons AM. Arendt J, Poulton AL English J. Induc-tion of early seasonal sensitivity to melatonin in suffolk-cross ewes. Chronobiolo8)' International 1987; 4 : 219-23.

37. Allain D. Some present applications of melatonintreatment in animal production. EPSG New leiter 1986;16: 5-9.

38. Kripke DF, Mullaney DJ, GillinJC, Risch SC, JanowskyDS. Phototherapy of non-seasonal depression. InBiological psychiatry Eds Shagoss, C et al 1986: 993-95_

39. Kitay JI, Altschule MD. The Pineal gland. A Reviewof the Physiologic literature. Harvard University PressCambridge Massachusetts 1954.

4-0. Sizonenko PC, Aubert ML. Neuroendocrine changescharacteristic of sexual maturation. In: Melatonin inHumans. Proceedings of the first International Confer-ence on Metatonin in Humans. Vienna Austria Nov. 7-91985; 155-79.

272 Srinivasan

41. Waldhauser F, Steger H. Changes in melatonin Secre-tion with Age and Pubescence. In melatonin in Human s.Proceedings of the First International Conference onMelatonin in Humans. Vienna Austria Nov. 7-9 Eds.Wurtman RJ, Waldhauser F 1985; 179-91.

42. Waldhauser F, Steger H, Vorkapic P. Melatonin secre-tion in man and the influence of exogenous melatoninon some physiological and behavioural variables. InAdvances in Pineal research. Eds. Reiter RJ, FraschiniF. John Lihhty and Co., 1987; 207-21.

43. Rusak B, Zucker I. Neural regulation of circadianrhythms. Physiol Rev 1979; 59 : 449-526.

44. Arendt J. Biological rhythms. International Medicine1983; 3(2) : 6 9.

45. Aschoff J. Circadian rhythms : General features andendocrinological aspects. In Kreiger. D. T. ed.Endocrine rhythms. New York. Raven Press 1979;pp.I-48.

46. Wever RA. The circadian system of Man. SpringerVerlag No» Tork Heidelberg-Berlin 1979.

47. Takahashi ]S, Zatz M. Regulation of circadianrhythmicity. Science 1982; 217: 1104-11.

48. Undrwood H, The Pineal and circadian organizationin Fish, amphibians and Reptiles. ) n The Pineal glandVol III Extra Reproductive effective Ed RJ Reiter.CRC Press Florida 1982; 1-25.

49. Short R V. Prospects for the endocrine control ofseasonal breeding in animals. In Endocrinology,Proceedings of the Seventh Asia and Oceania Congressof Endocrinology. Amsterdam Elsevier (Ed s. ) ShizumeK, Imunra H and Shimizu N. 1982; 371-75.

50. Arendt], Aldous M, Marks V. Alleviation of "]et Lag"by melatonin: Preliminary results of a controlled doubleblind trial. Brit Medical J 1986; 292 : 1170.

51. Armstrong SM. Melatonin. The Internal Zeitgeberof Mammals ? Pineal Researcb Reviews 1989; 7: 157-202.

52. Lieberman HR. Behaviour, Sleep and melatonin. InMelatonin in Humans. Eds, Wurtman. R.] andWaldhauser. F: Proceeding of the I-st InternationalConference on Melatonin in Humans. Vienna Austria N01J.7-9. 1985; 209-17.

53. Marczynski T]. Yamaguchi N, Ling GM, GrodzinskaL. Sleep indeed by the administration of melatonin(5-methoxy-Macetyl tryptamine) to the hypothalamusin unrestrained cats. Experientia 1964; 20 : 435-37.

54. Cramer H, Rudolph], Consbruch U, Kendel K. Onthe effect. of sleep and behaviour in man. Ado BioehemBehan 198\: II : 187-91.

55. Vollr oth L, Semm P, Gammel G Sleep induction byintranasal application of melatonin. Advances in Bio-sciences 1981; 29: 327-29.

56. Birkeland A]. Plasma melatonin levels and nocturnaltransitiom between sleep and wakefulness. Neuroendo-crinology 1982; 34 : 126-31.

57. Halberg F. Physiologic considerations underlyingrhythmicit y with special reference to emotional illness.In cycles biologigues et psychiatric. eds. JDe Ajuriaguena.1968: pp, 73-78.

58. Watterberg L, Beck Fr irs ], Aperia B, Petterson U.Melatonin/cortisol ratio in depression. Lancet 1979; ii1361.

59. Venkobarao A, Parvathi Devi S, Srinivasan V. Urinarymelatonin in depression Ind J Phychiat 1983; 167·72.

Ind.]. Physio!. Pharmac., Volume 33, Number 4, 19B9

60. Wetterberg L. The Pineal hormone melatonin as amarker for a subgroup of depression. Medicographica1986; 8: 4-7.

61. Srinivasan V, Parvathi Devi S, Venkobarao A. Pinealmediation of Psychoactive drug effects. Paper read atthe XVth International Congress of the ISPNE KTOTOApril 14-IB : 1985.

62. Murphy DL, Garrick NA, Tamarkin-L, Taylor PL,Markey SP. Effects of Antidepressants and otherpsychotrophic drugs on melatonin release and Pmealgland function. J Neural Transm 1986; 21 : 291-309.

63. Srinivasan V. Imipramine and Pineal gland. Neuro-endocrinology Letters 1987,9 : 223.

64. Srinivasan V. Psychoactive drugs, Pineal glandAffective : disorders. Progs Neuro-Psychopharn.acot andBio/ Psychiat 1989, 13: 653-64.

65. Thompson C, Mezey G, Corn T, Franey C, English],Arendt], Check ley SA. The effect of desipramine uponmelatonin and cortisol secretion in depressed and normalsubjects. BritJ Psychiat 1985; 147: 3l:lY-93.

66. Srinivasan V, Venkobarao A, Parvathi Devi S. Mela-tonin levels in Endogenous depressives and on imipramineTherapy. Abstract of the XVth International Congressof the ISPNE Vienna]uly 15-19 1984; 117.

67. Golden RN. Markey SP, Risby ED, Rudorder MV,Cowdry R W, Potter WZ. Antidepressants reduce wholebody Norepinephr ir.e turnover while enhancing 6hydroxy melatonin output Arch gen Psychiat 1988; 45:150-54.

68. Rosenthal NE, Sack DA. Gillin C, Lewy C, Lewy A],Goodwin FK, Davenport Y, MuelJer PS, Newsome DA,Wehr TA. Seasonal Affective disorder. A descriptionof the syndrome and preliminary findings with lighttherapy. Arch Gen Psychiat 1984; 41 : 72-80.

69. Rosenthal NE, ]ackobson FM, Sack DA, Arendt],James SP, Parry BL, Wehr TA. Atenolol in seasonalAffective disorder. A Test of Melatonin Hypothesis.Amer J Psychiat 1988; 145: 52-56.

70. Blask DE The Pineal : an Oncostatic rgland. InPineal gland Ed R] Reiter New Tork Raven Press 1984;pp. ;153-84.

71. Blask DE, Hill SM. Effects of melatonin on Cancer:studies on MCF Human Breast Cancer cells in cultureIn Melatonin in Humans Eds R.]. Wurtman and F.Waldhauser. Proceedings of the first Interna nonalConference on Melatonin in Humans. Vimna Austria.Nov. 7-9 1985; 403-20.

72. Reiter R]. Pineal gland Cellular proliferation andNeoplastic growth. An historical account. In ThePineal gland and Cancer. Eds. D Gupta and AAttanasio and R] Reiter. Brain Research PromotionTubingen 198-,; pp. 41 64.

73. Par vat hi Devi S, Harihara Subramanian N, SrinivasanV and Krishnan V. The Pieneal gland responses tovarious stressors. Quart J Surgical Sciences 1977; 13:181-95.

74. Lynch H]. Deng MH. Pineal response to stress. JNeural Trans 1986; 21 : 461-73.

75. Lehrer S. Pineal effect on longevity. J Chron Dis 1979;32 : 411-12.

76. Binkely S. Pineal gland Biorhythms: N. acetyl trans-ferase in chickens and rats. Fed Pr oc 1976; 35 : 2347-52.