Indian J. Psychiat. (1982), 24(4), 329—337
PINEAL RESPONSE TO LITHIUM1
S. PARVATHI DEVI* A. VENKOBA RAO>
PINEAL FUNCTION AND BEHAVIOUR—A until Crowther demonstrated from his REVIEW autopsy studies that pineal calcification The pineal gland in ma.i is an active had nothing to do with mental derange endocrine gland throughout life (Wurtman ment. et al., 1964 ; Tapp & Huxley, 1972 ; Interest in the pineal gland lay dormant Cardinali, 1974 ; Reiter et al., 1975 ; Reiter, and the gland was relegated to be a ves- 1978). It elaborates several hormones with tigeal organ until the endocrine nature precise rhythmicity. The chronobiological of the gland was suggested following des aspects of the mammalian pineal gland have criptions of pineal tumours associated with been clearly brought out by Reiler (198!) precocious puberty (Kitay, 1954). The defining the circadian rhythms in indole idea of a special relation of pineal gland to metabolism within the pineal of mammals. mind was revived in reports of experiments The two major classes of pineal hormones— with pineal extracts in the treatment of pineal indoles (melatonin, serotonin and schizophrenia (Becker, 1920 ; Eldered et the tryptophols) and the polypeptides are al., 196U; Kitay & Altschule, 1954). The known to influence several physiological isolation and characterisation of the pineal systems including the central nervous system hormone melatonin was a turning point (Cardinali, 1974 and Anton Tay, 1974). in pineal research (Lerner et al., 1958). The association of pineal gland with be Since then the pineal gland has been a haviour and mental illness can be traced to focus of intense scientific enquiry revealing Alexandrian school of thought (Herophilus it to be an endocrine gland capable of c. 300 B.C.). that the pineal is a sphincter affecting brain and behaviour. which regulates the flow of thought. Among the early observations on the Descartes (1650) located the soul, the influence of pineal gland on the brain are origin of all thought in the pineal gland these of Quay (1965) on the inability of (quoted in Hunter and Macalpine, 1963). pinealectomised rats to maintain their cere The first recorded post mortem at Bethletn bral potassium content. A slowing of brain Hospital by Thomas Allen in 1976 revealed maturation, particularly myelination was that the pineal gland was "turned into a reported after pinealcetomy in animals bladder of water" (Hunter and Macal (Relkin et al., 1973 ; Relkin & Schneck, pine, 1963). King (1686) observed that a 1975). mentally deranged patient, had a petrified Pinealectomy is accompanied by a pineal. Gunz (1753) suggested that con general increase in neural excitability (Nir cretions of pineal might be the cause of et al., 1969) and in stimulus-induced hippo- mania. This was supported by Morgagni campal potentials with convulsive patterns (1769) and Arnold (1786). Assertions of a (Bindoni and Rizzo, 1965). Frank con link between the pineal and insanity con vulsions have been noted after pinealectomy tinued to appear in the eighteenth century in previously thyroparathyroidectomised ani-
1 The Authors would like to name the response as "Tilak Effect". 2 Director & Professor, Institute of Physiology, Madurai Medical College, Madurai-625020. 3 Professor & Head, Institute of Psychiatry, Madurai Medical College & Govt. Rajaji Hospital, Madurai- * 625020, 330 S. PARVATHI DEVI & A. VENKOBA RAO mals (Reiter and Morgan, 1972 ; Reiter rescence in the rat pineal gland, signifying et al., 1972a). The convulsions result from hyper activity (Parvathi Devi et al., 1978). changes in brain electrolytes and nore Above all these facts, it has been found pinephrine content (Reiter et al., 1972 ; that plasma melatonin concentrations are Reiter, 1977). high at night and low or absent during the Administration of pineal extracts in day both in animals and men (Rollag & duces EEG activation (Quay and Renzoni, Niswender, 1976 ; Arendt et al., 1977 ; 1963 ; Roldan and Anton-Tay, 1968). Smith et al., 1977 ; Kennaway et al., 1977). Melatonin has powerful sedative effects In several recent studies of the temporal on animals (Marceynski et al., 1964 ; organization of melatonin concentrations Barchas et al., 1967 ; Hishikawa et al., during 24-hour periods in normal men, 1969). In human volunteers and in epi Weinberg et al. and Weitzman et al. have leptics receiving melatonin an increase in shown that although melatonin values are alpha activity, EEG synchronisaiton and significantly higher at night during sleep, shep, dreams, REM cycles, visual imageries episodic secretion exists during the waking and feelings of well-being have been ob daytime period (Weinberg et al., 1973 ; served (Anton Tay, 1971 ; 1972 ; Cramer and Weitzman et al., 1978). et al., 1976). In epileptics the paroxysmal Lewy et al., (1979), who used a new discharges were suppressed by injections mass spectroscopic assay, have found that of melatonin (Anton-Tay et al., 1971). the nocturnal secretion of melatonin from Therapeutic benefits have been claimed the pineal gland was substantially reduced with melatonin as an oral anticonvulsant during depressive phases compared to manic (Anton Tay, 1974). phases in bipolar cases. Since beta-adr A well substantiated behavioural effect energic and serotonergic mechanisms me of melatonin is its ability to induce sleep diate melatonin secretion, these observations (Barchas et al., 1967; Marczynski et al., could implicate disturbances in these neuro 1964). Melatonin decreases the latency of transmitter systems. sleep onset, of stages 3 and 4 and of REM Recent studies suggest that certain sleep. The pattern of sleep induced strik depressed patients may have an altered ingly resembles natural sleep (Cramer et biological rhythm. Alterations have been al., 1974, 1976). It facilitates barbiturate found in the sleep waking pattern timing of induced sleep (Martini, 1971). Koella activity levels, diurnal mood variation and (1969) has suggested that normal sleep in the daily secretion of pituitary hormones may involve leakage of pineal hormones as well as in other biological variables and their hyper-synchronising action via (Hawkins & Mendels, 1966 ; and Sachar, the area postrema, tractus solitarius and 1976). Since derangements of biological upper brainstem. Pineal arginine vasotocin rhythm function have been linked with (AVT) is reported to suppress REM sleep depression we considered it of interest to (Pavel et al., 1977). investigate the temporal organization of Following pinealectomy, dissociation melatonin secretion in patients with uni develops between the nycthemeral varia polar and bipolar depression. The likely tions of REM and slow-wave sleep. REM central nervous influence on melatonin sleep decreases during the high phase of secretion in man, its possible reflection of the cycle and increases during the dark brain beta-receptor sensitivity (Hanssen, phase (Anton Tay, 1972). In our studies, 1977) and the resemblance of its annual it was observed that following a 48-hour secretion pattern to that of hospital admis selective REM sleep deprivation, there sion for depression (Eastwood and was an increase in the NE and 5-HT fluo Peacocke, 1976) lead to the suggestion that PINEAL RESPONSE TO LITHIUM 331 the study of rhythmic human melatonin less abundant in the earth's crust than secretion may prove to be of importance in Sodium and Potassium it is known to be diagnostic, prophylactic and therapeutic far more abundant than silver and Gold. psychiatry. Of major importance in psy Industrial and technological (textiles, cera chiatry are schizophrenia and manic-de- mics, electronics, batteries, air-conditioners, pressive disease which also for other reasons enamel and glasses, aluminium) applica have been linked to a possible disturbance tions of Lithium exceed diose of its medical in pineal function (Allschule, 1975 ; and use. Carman et al., 1976). Watterberg, (1978) Lithium was introduced to Medicine pointing disturbances in melatonin meta by Lipowitz in 1841 and by Garrod in bolism in schizophrenic and depressed 1859 and to Psychiatry as an antimanic patients and has suggested the possible use agent by Cade in 1949. After a period of of melatonin excretion pattern as a pre lull, the Aarhus group of investigators in dictive tool in the evaluation and outcome Denmark led by Schou added considerable when treating depressed patients with sleep knowledge of i(s use to make lithium one deprivation therapy. Mendlewicz et al. of the most important rediscoveries in (1980) noting the 24 hour pattern of plasma psychiatric therapies. melatonin in depressed patients before and The exact mechanism of action of after treatment indicated that the nocturnal lithium is not yet satisfactorily known. melatonin increase found in normal sub In the earlier days of its application, atten jects was essentially absent in 3 of the 4 tion was directed to its effects upon electro depressed patients suggesting an altered lyte balance. Lithium can never act as pineal rhythm. The functional significance a substrate for sodium though it replaces of the pineal in behaviour becomes very it and hence a failure in sodium pump evident. mechanism occurs. The neuronal mem brane is unable to maintain the polarization LITHIUM—ITS MODES OF ACTION—A and conduct action potentials. However REVIEW this is not likely in the clinical concen Lithium sulfate was identified in 1817 tration of lithium in the blood. It was also by Arvedson, a young Swedish student advanced that lithium might correct a of Chemistry and his celebrated teacher tendency for the intracellular concentration Berzelius. The elemental Lithium was of sodium to increase in manic depressive isolated in 1855. Lithium is a soft white psychosis as was proposed by Coppen and alkaline metal related to Sodium and Shaw (1969). This theory appears un Potassium. It is the lighetst metal that can tenable since the postulate that sodium is float in gasoline (Atomic number ; 3, abnormally retained has not been estab Atomic weight, 6.941, density; 0.531 g/cra.). lished. In keeping with the monoamine The size of Lithium ions is larger than hypothesis of affective disorders, lithium those of Sodium and Potassium but same has been known to improve the manic as those of Magnesium. Chemically very episodes by preventing the release of NE reactive it never occurs in a free state in (Katz et al., 1968) and also to improve nature. There are two major source of the reuptake (Coburn et al., 1969). It also Lithium, namely, the pegmatite and the interferes with the development of super brine deposits. Spodumene is the Lithium sensitivity of dopamine receptors in patients bearing ore in the pegmatite. The major on chronic treatment with neuroleptics mining operations are carried out in Kings (Bunney, 1978). Lithium fails to offer Mountains and Bessemer city, North Caro support to die biogenic monoamine hypo lina, United States. Though Lithium is thesis of affective disorders with its uni- 332 S. PARVATHIDBVI ft A. VKNKOBA RAO directional amine effect and bidirectional logical changes of hyperactivity (Harihara- clinical benefit. Lithium has been known subramanian et al., 1976). Increased NE to inierfere with the action of the hormones and 5-HT fluorescence in the rat pineal including the transmitters on the adenyl gland was also evident. These effects were cyclase in the receptor functionl, it is parti seen both in normal and adrenalectomised cularly so in case of the thyroid. Lithium rats and were not abolished by exposure has been found to be antimanic and anti " to constant illumination (Parvathi Devi thyroid, its antithyroid effect being a part etal., 1976, 1977a, 1978a, 1978c and 1979). of the antimanic effect (Whybrow, 1980). Lithium, like melatonin stabilises excit Wolpert (1975) emphasized the physio ability of the brain (Johnson et al., 1970 J logical factors in the genesis of recurrent Small et al., 1971) stimulates uptake of affective disorders attributing mania to amines in the brain (Mendels and Frazer, an excess of physiological energy, and its 1974) and inhibits locomotor activity. It lack causing depression. Wolpert attributes is suggested that the pineal hormones may Ac benefits of lithium to its normalizing mediate therapeutic and other systemic effects upon the energy systemY Other effects of lithium. - minor actions like the uptake and utiliza It is of interest to note that lithium tion of glucose, its action on magnesium and melatonin have similar actions on have been resorted to explain its action both the central nervous system and endo- (Frizel et al., 1969 ; Carney et al., 1973 ; crines. Both stimulate uptake of biogenic and Srinivasan et al., 1977). amines in the brain (Mendels and Fraeer, Thus the role of lithium in the treat 1974), inhibit stimulus induced release of ment of affective disorders has been ex amines and induce EEG synchronization tensively studied, its effects on ionic balance, and sleep (Anton Tay et al., 1971 ; Johnson on neurotransmitter dynamics and \e ;:--^. .. > ry T, -.:•-;! H Ue fWractfve Kef"*' C«liTft,< LITHIUM TREATED HYPERACTIVE ANEAL ^ LITHIU1UMH TRIREAT£I > 1NCJ^e^SEj ) UHEAU h.UOR£SCfcNCe $34 $• PARVATHI DEVI & A. VENKOBA RAO light, which also inhibits the pineal The stimulatory response of the pineal gland enzyme hydroxy indole-O-methyl transferase to lithium is christened "Tilak Effect." (HIOMT). HIOMT is responsible for the Effects similar to "Tilak Effect" have conversion of serotonin into melatonin. been under study with other psychoactive Constant lighting thus renders the pineal drugs (Parvathi Devi, 1982 ; Ffarihara- hypoactive. subramanian, 1982 and Srinivasan, 1982— The authors noted that the lithium- unpublished observations). mediated pineal stimulation resulted in an Melatonin levels before and after increased sertonergic fluorescence within lithium therapy in depressives are being the pincals of normal and adrenalectomised studied and the value of the observations rats on lithium administration, indicative of are being assessed for their therapeutic pineal responding to altered electrolyte significance (Venkoba Rao et «/., 1982 balance. The pineals of lithium-treated and Parvathi Devi et al., 1982)—(under rats alto manifested increased serotonin publication). content, the presence of serotonin being ACKNOWLEDGEMENTS indicated by the development of yellowish- green 5-HT fluorophores. The authors The authors acknowledge the help also observed that the pineal hypo-activity of Dr. N. Hariharasubramanian, M.D., induced by constant light was prevented Ph.D., and Dr. V. Srinivasan, M.Sc., when lithium was simultaneously adminis Ph.D., Assistant Professors of Physiology, tered an pineal hyperactivity was noted. Institute of Physiology, Madurai Medical This observation serves as an evidence of College, Madurai, who have been with the pineal stimulatory response to lithium. them throughout the decade of this study. Pineal responses to lithium point to an Thanks are recorded to Mr. N. Rama- increased melatonin output. swami, Technical Assistant, Institute of Physiology, Madurai Medical College, Pineal stimulatory response to lithium : ' TILAK Madurai. EFFECT' The authors thank Dr. S. Gnanadesikan, Director of Medical Education, Government A decade ago the idea that lithium of Tamil Nadu, Madras and Dr. K. B. could probably mediate pineal activity Kalyanasundaram, Dean, Madurai Medical emerged (Parvathi Devi, 1972). Work in College, M adurai for their kind permission the direction of observing the effects of to publish the paper. lithium on the pineal gland began. The findings evoked interest in several quarters. In July 1977 at the First British Lithium REFERENCE Congress at Lancaster, the authors had th° ALTSCHULE, M. D. (1975). Frontiers of Pineal opportunity to present the paper entitled Physiology, London : MIT Press. "Lithium - Pineal - Adrcno - cortical Axis." ANTON-TAY, F. (1971). Pineal-brain relationships, The late John F. Cade of Australia and In : Eds. 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