Plasma Lithium Concentrations Research Articles

Lithium reduces ocular dominance plasticity in kitten visual cortex

Activity-dependent processes within the visual pathway play a crucial role in the expression of ocular dominance plasticity in immature visual cortex. The necessity of non-retinal, modulatory afferents to the regulation of ocular dominance plasticity has been recognized. Among a few chemically defined signaling systems, the noradrenaline-activated β-adrenoreceptors seem to have a prime role in this matter. The involvement of acetylcholine afferents was also proven. We looked for plausible molecular mechanisms which integrate the contribution of the two neuromodulator systems to ocular dominance plasticity. At the first step, based on the rich literature on psychotropic action of lithium and the recent advancement in understanding of its molecular mechanisms, we physiologically studied visual cortex of kittens which had been repeatedly injected with the lithium solution intraperitoneally or the cortex directly infused with it. We found (1) that ocular dominance plasticity was significantly reduced in lithium-injected kittens, (2) that the decrease was directly correlated with plasma concentrations of lithium (i.e. the higher the lithium concentration, the lower the plasticity), and (3) that the comparable decrease in the plasticity was obtained from kitten visual cortex which had been directly infused with the lithium solution. The present results suggest that lithium-sensitive processes, through most likely reduced production of second messengers, underlie the regulation of ocular dominance plasticity.

Lithium treatment reduces the renal kallikrein excretion rate

Lithium salts are widely used agents for the prophylactic treatment of affective disorders. Lithium salts may be associated with distal nephron dysfunction. Kallikrein is a protease which is generated by the distal nephron. We used an amidolytic assay of chromatographically purified enzyme to determine the urinary excretion rate of active kallikrein in relation to lithium treatment. All plasma lithium concentrations were within the therapeutic range (0.4 to 0.9 mmol/liter). In 15 patients the urinary excretion rate of active kallikrein was 267.4 +/- 65.6 mU/24 hrs before lithium treatment, and fell to 117.8 +/- 39.6 mU/24 hrs (P less than 0.05) on day 14 of lithium treatment. This reduction was associated with a decrease of immunoreactive kallikrein in the same urines by 66%. In another 15 patients who had undergone lithium therapy for an average period of 5.6 years, the urinary excretion rate of active kallikrein was 86.1 +/- 14.5 mU/24 hrs, while 21 age-matched healthy controls had an excretion rate of 364.1 +/- 58.4 mU/24 hrs (P less than 0.05). Measurements of immunoreactive kallikrein in the same urine samples demonstrated a reduction of kallikrein after long-term lithium treatment by 78%. These observations could not be attributed to changes in creatinine clearance, renal sodium or potassium excretion rates or plasma concentrations of aldosterone and vasopressin. Addition of lithium to the urine in vitro had no demonstrable effect on kallikrein measurement by amidolytic assay. We conclude that lithium in therapeutic plasma concentrations may directly suppress the secretion of kallikrein by renal connecting tubule cells.

Lithium distribution in mania: Single-dose pharmacokinetics and sympathoadrenal function

We examined lithium distribution after a single dose of 25 mEq in 14 drug-free manic patients. Lithium concentrations were measured in plasma, red blood cells, and urine. Maximum concentrations of lithium, times at which they were attained, and influx and efflux rate constants for extracellular fluid, red blood cell, and muscle-like compartments were estimated using a three-compartment pharmacokinetic model. Tissue lithium concentrations may continue to increase for hours after plasma lithium concentrations have peaked. Rate constants for absorption, excretion, and influx and efflux for the tissue compartments were similar to those previously reported for normal subjects. Rate constants for transport into and out of the tissue compartments correlated negatively with norepinephrine or epinephrine excretion and positively with the plasma/red cell Na + gradient. Rate constants for efflux from red blood cell and muscle compartments correlated with measures of adrenocortical function and were higher in dexamethasone nonsuppressors than in suppressors. These data show that distribution of lithium may be related to sympathodrenal activity and Na + distribution in manic patients.

Effects of lithium chloride on testicular steroidogenic and gametogenic functions in mature male albino rats

The present study was undertaken to evaluate the effects of lithium, an antimanic drug, on steroidogenic and gametogenic functions of testis in the laboratory rat. Adult male rats of Wistar strain maintained under standard laboratory conditions (L:D. 14h: 10h), were injected (S. C) with lithium chloride at the dose of 0.1 mg, 0.2 mg and 0.4 mg/100 g body weight/day for 21 days. All the treated animals along with the vehicle treated controls were sacrificed 24 hours after the last injections. Testicular steroidogenic activity was evaluated by measuring the activities of two steroidogenic key enzymes, Δ 5 −3 β hydroxysteroid dehydrogenase (Δ 5 −3 β -HSD) and 17β hydroxysteroid dehydrogenase (17 β −HSD). Gametogenic capacity was determined by counting the number of germ cells at stage VII of seminiferous cycle. Plasma levels of follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL) and testosterone (T) were measured by radioimmunoassay (RIA). Administration of lithium chloride at a dose of 0.1 mg/100g body wt. for 21 days led to insignifiant changes of plasma FSH, LH, PRL and T along with unaltered activities of testicular Δ5 −3β −HSD, 17 β−HSD activities and gametogenesis. In contrast, 0.2 mg of lithium treatment for 21 days causes a significant reduction of plasma FSH (P < 0.01), LH (P < 0.001), PRL (P < 0.001) and T (P < 0.001) along with inhibition of testicular Δ 5 −3 β −HSD activity (P < 0.01) and 17β −HSD activity (P < 0.001). Gametogenic activity does not exhibits any significant reduction in the number of preleptotene spermatocytes (PLSc) and midpachytene spermatocytes (mPSC) while significant reduction in the number of spermatogonia A (Asg) (P < 0.01) and Step 7 spermatids (7Sd) (P < 0.001) were observed at stage VII of seminiferous cycle when compared to control. The degree of detrimental effects of lithium on testicular activity became more prominent at the dose of 0.4 mg/100g body wt. The results of our experiments suggest that lithium administration might be associated with significant adverse effects on testicular activities. Furthermore, since hormonal changes and altered gametogenic activities were evident when plasma lithium concentration was below or within the therapeutic range, our data may have some potential clinical implications.

Does Lithium Affect Renal Sodium Handling and Renal Haemodynamics in Normal Man?

Renal haemodynamics, sodium excretion, and free-water clearance were evaluated at baseline and after acute frusemide administration in nine moderately volume-expanded healthy volunteers receiving a single administration of either 750 mg lithium carbonate or placebo. Lithium plasma concentration under 0.29 mmol/l exerted no significant effect on renal haemodynamics, on absolute, fractional, or cumulative sodium excretion, or on free-water and chloride clearances at baseline or after frusemide administration. Despite previous volume expansion and presumably depressed proximal reabsorption, frusemide decreased the fractional reabsorption of lithium significantly, suggesting that a small but significant part of lithium may be reabsorbed in the thick ascending limb of Henle's loop. By contrast, frusemide did not change renal haemodynamics or plasma renin activity. Using combined free-water and lithium clearances at baseline and after frusemide administration, fractional reabsorption of sodium in the (FRTAL) was calculated as delta CH2O/CLi, where delta CH2O, the difference in free water clearance before minus after frusemide, is taken as an index of sodium reabsorption in the thick ascending limb, and lithium clearance as an estimation of sodium delivery to the thick ascending limb. FRTAL was calculated in these volume-expanded subjects to lie from 11% to 20% depending on whether some lithium is assumed to be in the thick ascending limb.

Inter-organ relation between salivary gland and kidney in lithium excretion. II. Salivary, renal and systemic clearances of lithium under continuous stimulation of salivation in water loaded dogs.

This study was undertaken to investigate the effects of water loading on lithium clearance in dogs under the continuous stimulation of salivation as well as to clarify the mechanism of the inter-organ relation between salivary gland and kidney in lithium excretion. Dogs were given intravenously 0.145 meq/kg of lithium chloride followed by the continuous stimulation of salivation with citric acid solution. Fifty ml of water was loaded orally 7 times at 1-h intervals. Parotid and mandibular-sublingual salivas were collected separately by means of permanent fistulae. (1) Plasma concentrations of lithium were not significantly different from either those in the experiment with continuous stimulation under no water loading or those in the control experiment without continuous stimulation. (2) Salivary clearance of lithium was markedly increased compared with that in the control experiment. The urinary flow rate, which was decreased under the continuous stimulation of salivation without water loading, was restored by the water loading. The renal clearance of lithium, which was also decreased under the continuous stimulation, remained at the reduced level under the condition of this study. Consequently, the systemic clearance of lithium did not change from that in the experiment under the continuous stimulation without water loading or that in the control experiment. (3) It was suggested that the salivary and renal excretion mechanisms of lithium might be similar to those of potassium, since a similar interrelation between salivary and renal clearances was observed for potassium. (4) It was suggested that the reduction in the renal clearance of lithium under the continuous stimulation of salivation was attributed to the sodium loss caused by the excessive salivation.

Relationship between plasma concentration, saliva concentration and urinary excretion rate of lithium in man

The relationship between the plasma concentration, saliva concentration and urinary excretion rate of lithium was investigated and the possibility of using the saliva concentration or the urinary excretion rate for monitoring dosage was considered. The results in the present study support the idea that saliva concentration of lithium could be useful in monitoring dosage but, there are many difficulties to be overcome in using the urinary excretion rate of lithium due to inter-subject variation, intra-subject variation during the night and circadian variation in the renal excretion of lithium.

Lithium clearance during the paradoxical natriuresis of hypotonic expansion in man

Tubular sodium handling in humans undergoing hypotonic expansion due to the administration of antidiuretic hormone was studied using the clearance of lithium as an index of distal filtrate and sodium delivery. Clearance studies were performed in the morning in eight normal subjects before and on the fourth day of intranasal I-desamino-8-D-arginine vasopressin (dDAVP) administration. Fluid intake was kept constant at 25 ml/kg body weight. After dDAVP body weight increased (2.5 +/- 0.4 kg), plasma sodium fell (from 143 +/- 1 to 128 +/- 5 mmol/liter) and a progressive natriuresis developed. Sodium balance remained negative up to the second clearance study, when the cumulative sodium loss amounted to 148 +/- 96 mmol. Plasma renin activity fell significantly, but plasma aldosterone did not. Inulin clearance rose from 110 +/- 14 to 135 +/- 23 ml/min and lithium clearance from 30.9 +/- 7.6 to 48.9 +/- 15.1 ml/min. Fractional reabsorption of uric acid, phosphate and calcium decreased. Together these changes suggest that the negative sodium balance in hypotonic expansion with dDAVP results from increased filtered sodium load, decreased fractional reabsorption in the proximal tubules, and increased distal delivery. Estimated fractional reabsorption in the distal nephron remained unaltered. The plasma concentration of lithium, of which 10.8 mmol was ingested on the eve of the clearance studies, was not lower during the dDAVP-clearance study. This indicates that the tubular adaptations mentioned are present intermittently, in particular during daytime.

Effects of lithium on the pituitary-gonadal axis in the rat: Evidence for dose-dependent changes in plasma gonadotropin and testosterone levels

The purpose of the present study was to examine the effects of lithium, a drug which is now used rather widely in the treatment of acute mania and the prophylaxis of manic-depressive bipolar disorders, on the pituitary-gonadal function in the laboratory rat. Sexually adult male rats, maintained under standardized laboratory conditions (LD 14: 10; lights on at 06:00 h, CST),were injected (ip) with lithium chloride both acutely for 1 day and chronically for 5 days, and by utilizing a low and high dose. For the low dose, lithium was injected twice daily (at 10:00 and 15:00 h) at 2.5 meg/Kg for 1 and 5 days, whereas in the high dose groups, also receiving lithium twice daily and at the same hours, the dosages were 5 meg/Kg for 1 day and 3.5 meg/Kg for 5 days. Animals were sacrificed 4 hours after the last lithium (or saline) injections. Plasma and pituitary levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH), and plasma levels of testosterone (T) were measured by radioimunoassay (RIA). The administration of the low dose led to a significantly higher (P <0.001) plasma FSH, but unaltered plasma LH, levels after 5 days. In contrast, the high dose lithium led to significant suppressions of plasma LH (P <0.02; on day 5) and FSH (P <0.001; on both day 1 and 5) levels. The levels of plasma T also showed a significant reduction following the low dose (P <0.02; on day 5), as well as the high dose lithium treatment, as evident after both 1 (P <0.02) and 5 (P <0.02) days. Regardless of the dosage, or the duration of treatment, pituitary gonadotropin levels remained unaltered following lithium. The results of our present experiments suggest that lithium administration, either acutely or on a chronic basis, might be associated with significant adverse effects on the pituitary-testicular axis. Furthermore, since some of the hormonal changes were evident when plasma lithium concentration was within the therapeutic range, our data may have potential clinical implications.

Lithium distribution in mania: Plasma and red blood cell lithium, clinical state, and monoamine metabolites during lithium treatment

We examined red blood cell (RBC) and plasma lithium concentrations and RBC/plasma lithium ratios in 14 manic patients during lithium treatment as part of the National Institute of Mental Health's Collaborative Program on the Psychobiology of Depression, Biological Studies. All of the lithium measures increased during treament, especially RBC lithium. There were positive correlations between the RBC lithium concentration and the RBC/plasma lithium ratio and their maximal values in a single-dose pharmacokinetic experiment before treatment. After 5 and 16 days of treatment, patients with good subsequent outcome had higher RBC/plasma lithium ratios than did patients with poor outcome. Early in treatment, there was a negative correlation between lithium concentrations and severity of mania. During treatment, there was a negative correlation between RBC lithium and urinary MHPG excretion. There was a positive correlation between RBC or plasma lithium during the first few days of treatment and subsequent reduction in norepinephrine excertion during treatment. At 3 weeks, there were negative correlations between reductions in catecholamine measures and lithium concentrations. These data suggest that there are changes in the sensitivity of behavior and catecholamine function to lithium during treatment. RBC concentrations of lithium appear to be a potentially useful indicator of its behavioral and neurochemical effects.

The pharmacokinetic profile of lithium in rat and mouse; An important factor in psychopharmacological investigation of the drug

The pharmacokinetic characteristics of lithium and the profile of plasma lithium concentration at steady state in both the mouse and the rat have been determined. The half life of lithium in both rodents was shorter (3.5 h and 6 h) than that found during maintenance therapy in man. Following a loading dose (10 mmol/kg s.c.) and twice daily maintenance injections (3 mmol/kg s.c.) of lithium chloride the plasma concentration remained above the accepted human therapeutic minimum (0'4 mM) for 16 of every 24 h in the mouse and throughout the entire 24 h period in the rat. Maximum concentrations in both species were below the range at which toxic effects might be expected to occur.

Sodium-potassium, magnesium, and calcium ATPase activities in erythrocyte membranes from manic-depressive patients responding to lithium

Erythrocyte membrane Na + -K + adenosine triphosphatase (ATPase), Mg 2+ ATPase, and Ca 2 + ATPase activities were compared among 23 euthymic manic-depressive patients responding to lithium therapy and 24 healthy controls. The two groups were similar in age, sex composition, body mass index, and community background. No significant differences were noted in mean ATPase activities between the two groups. However, plasma lithium concentration correlated positively with Na + -K + ATPase and Mg 2+ ATPase activities within the patient group, and six patients with plasma lithium levels in the range of 0.85–1.2 m M had Na + -K + ATPase activities 62% greater than the control group mean. Possible biochemical mechanisms for the effects of lithium therapy on erythrocyte membrane functions are discussed .

Acute lithium treatment suppresses the proestrous LH surge in mice: chronic lithium leads to constant diestrus

Although the therapeutic usefulness of lithium in manic-depressive psychosis is now well-established, a number of basic and clinical studies in recent years have shown that the administration of this anti-manic drug produces a wide range of adverse endocrine and metabolic effects. The present study was undertaken in order to examine (a) what effects acute lithium administration might have on the preovulatory surge of luteinizing hormone (LH) during proestrus, and (b) whether chronic lithium administration has any adverse effect on the estrous cycle in C57BL/6 mice. Acute injections of lithium on the day of proestrus (at 10.00, 16.00 and 18.00 h; LD 14:10, lights on at 05.00 h CST) at a dosage of 5 mEq/kg b. wt. led to a significant ( P < 0.01) suppression of the LH surge that normally occurs in the evening of proestrus at 21.00 h. Chronic administration of lithium, on the other hand, resulted in a complete disruption in the regularity of the estrous cycle. This was characterized by an increasing number of mice showing a continuous diestrous vaginal smear during the first week of exposure to lithium, after which all of the lithium-treated mice completely stopped cycling and entered into constant diestrus. These results represent for the first time that lithium has significant adverse effects on the reproductive function in the female, especially in regard to the proestrous LH surge and estrous cyclicity in mice. Since these adverse effects were manifested under conditions when plasma lithium concentrations were within or around the therapeutic range, our results provide important conceptual information concerning possible adverse effects of lithium on the reproductive function in the human female.

An experimental study and computer simulation of the turnover of choline in erythrocytes of patients treated with lithium carbonate.

The mechanism by which choline accumulates in erythrocytes during treatment with lithium salts has been elucidated. A component of the study was a kinetic description of erythrocyte phospholipase-D, which catalyses the release of intracellular choline from phospholipids. Apparent steady-state kinetic parameters for calcium ions were determined: Km (+/- SD) = 0.6 +/- 0.3 mmol/l aqueous cell volume and Vmax (+/- SD) = 12 +/- 4 mumol/l packed red blood cells (RBC) min-1. Competitive inhibition of the phospholipase-D by barium ions was also observed. Other information concerning choline and lithium levels and red cell life-time was obtained from the literature. Details of the kinetics were used to develop a comprehensive dynamic model of choline metabolism by erythrocytes. The scheme is as follows; phosphatidylcholine associated with high density lipoproteins exchanges with the erythrocyte membrane phospholipids, the neutral phospholipids undergo two dimensional translational and rotational motion and also flip between each layer of the bilayer thus becoming exposed to an intracellularly-located phospholipase-D, whereupon the choline is hydrolysed and released into the intracellular milieu. A choline transport protein, which is able to be inhibited by lithium, mediates the influx and efflux of choline. The differential equations that describe reactant flux in this scheme were integrated numerically and the choline accumulation profiles under various conditions of transport and enzyme inhibition are presented. Computer solution of the model, by using as input values plasma lithium levels in the upper limit of the therapeutic range, required that the red cell life-time be reduced in order to explain the previously observed negative association between choline and increasing lithium levels. The results of the computer simulations under varying initial conditions of plasma and erythrocyte lithium and choline concentrations permit, for the first time, a comprehensive description of those factors affecting erythrocyte choline levels.

Short-term lithium administration enhances serotonergic neurotransmission: Electrophysiological evidence in the rat CNS

Rats received lithium-containing chow for 48 h. Brain and plasma lithium concentrations ranged from 0.4 to 1.0 mEq/1. A first series of experiments served to assess the responsiveness of CA 3 hippocampal pyramidal neurons to microiontophoretically applied serotonin (5-HT) and norepinephrine (NE). The response of the same neurons to electrical stimulation of the ventro-medial 5-HT pathway was measured after the lithium treatment. The responsiveness to 5-HT and NE was not modified whereas the effect of activation of the ascending 5-HT pathway was increased two-fold by the lithium treatment. These neurons were activated to their physiological firing rate by means of small ejection currents of acetylcholine. A pretreatment with the 5-HT neurotoxin 5,7-dihydroxytryptamine abolished the response to the electrical stimulation in lithium-treated rats. In a second series of experiments, unitary recordings of 5-HT neurons were obtained from the dorsal raphe nucleus. The lithium treatment modified neither the number of spontaneously active 5-HT neurons nor their mean firing rate. These results provide direct electrophysiological evidence for the enhancement of 5-HT neurotransmission by short-term lithium treatment through its presynaptic action on 5-HT terminals.

A pharmacokinetic approach to the study of cell membrane lithium transport in vivo.

Although many previous investigations have focused on in vitro studies of lithium transport by erythrocytes (RBCs) of psychiatric patients, the extent to which such studies actually reflect the transport of this drug by other types of cells in vivo is unknown. To study lithium transport in vivo, pharmacokinetic analysis of plasma lithium concentration data was performed in four subjects who were given single oral doses of lithium carbonate (600 mg). The data were analyzed according to a two-compartment model, consisting of a central compartment (extracellular, including plasma) and a peripheral (intracellular) compartment. Rate constants for the transfer of lithium into (ki) and out of (ko) the intracellular compartment were calculated. In RBCs from the same subjects, lithium transport in vitro was also directly measured. Rate constants were determined for phloretin-sensitive transport (ks), which corresponds to Na+-Li+ countertransport activity, and residual passive "leak" diffusion (kr). In RBCs, these two pathways account for major components of lithium efflux and influx, respectively. To compare the in vivo and in vitro rate constant data, the ratios ko/ki and ks/kr were also calculated. There was a significant correlation between these two rate-constant ratios (r = 0.96, p less than 0.05), although the values observed in vitro were higher than those found in vivo. Because the in vivo rate constants reflect lithium transport by many types of cells in the peripheral compartment, this finding supports the idea that the RBC may provide a useful model for studying lithium transport processes that are also operative in other types of cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence for bicarbonate-dependent lithium reabsorption in dog kidneys.

To examine whether lithium is reabsorbed along a transcellular or a paracellular route, experiments were performed in anesthetized volume-expanded dogs under conditions of constant glomerular filtration rate (GFR). Quabain, in doses inhibiting about 80% of Na, K-ATPase, and ethacrynic acid, another inhibitor of transcellular NaCl reabsorption, did not inhibit lithium or bicarbonate reabsorption. Lithium reabsorption increased in proportion to plasma concentration of lithium (PLi) up to 12 mM, suggesting a passive transport of lithium. During ouabain administration acetazolamide halved bicarbonate reabsorption, the main driving force for paracellular reabsorption, and halved the reabsorption of lithium. The reabsorbate concentration of lithium, calculated from data obtained before and after acetazolamide infusion, was almost equal to PLi. Mannitol, which reduces paracellular osmotic transport without affecting bicarbonate reabsorption, reduced lithium and chloride reabsorption in the same proportion as acetazolamide (r = 0.87). Combined acetazolamide and mannitol administration reduced fractional lithium reabsorption to 0.09 +/- 0.02. These data indicate that lithium is not actively transported but reabsorbed passively along a paracellular route by osmotic forces provided by transcellular NaHCO3 reabsorption.

Frusemide: A safe diuretic during lithium therapy?

This paper reports the effect of frusemide given in therapeutic doses for hypertension in patients receiving prophylactic lithium for affective disorders. It was found that frusemide had no significant effect on plasma lithium concentration in these patients who were studied over a 12-week period. It was concluded that frusemide is a safe diuretic to administer to patients receiving lithium therapy.

Lithium levels in white blood cells and their relationship to observed side effects.

A strong correlation was obtained between white blood cell (WBC) lithium concentrations and the severity of observed side effects in a group of 40 patients receiving prophylactic lithium therapy. However, there was no significant correlation between these levels and the specific side effect of hand tremor, although WBC concentrations were higher in patients with greater tremor. These results contrasted with those for plasma and red blood cell (RBC) lithium concentrations, which showed no relationship to side effects. This suggests that WBC lithium concentrations may be a more sensitive index of side effects than conventional plasma estimations.

Chronic lithium treatment and twenty-four hour rhythm of serum prolactin, growth hormone and melatonin in rats

This study was undertaken to extend the observations that lithium chloride has the ability to phase shift the 24-hour pattern of a large number of physiological parameters relative to the environmental lighting cycle. Adult male Wistar rats were housed individually in a temperature and sound controlled environment under a lighting schedule of 12 hours dark/12 hours light. Six point 24-hour maps were generated by taking measurements every four hours throughout 24 hours on separate groups of rats maintained for six weeks on ad lib water and one of three diets: 1) normal lab chow, 2) lab chow supplemented with 50 mM/kg of lithium chloride, 3) lab chow supplemented with 50 mM/kg of sodium chloride to control for the effects of a possible salt load. Variables measured included plasma and red blood cell lithium and sodium concentrations, serum prolactin, growth hormone and melatonin. Plasma lithium levels were 0.7–1.0 mEq/L. Plasma, but not red blood cell lithium levels deomonstrated a 24-hour rhythm with higher levels following the normal feeding period. Serum and red blood cell sodium levels did not differ among the diets and showed no 24-hour variation. The sodium diet had no significant effects on any of the variables measured. The 24-hour pattern of prolactin was not significantly affected by the diets, while growth hormone and melatonin levels differed in animals on the lithium diet. During the light hours when growth hormone levels are normally falling and melatonin levels are barely detectable, there were no differences on these measurements among the diets. However. during the dark hours when growth hormone and melatonin normally evidence a rise that peaks near the end of the dark phase, lithium fed animals evidence low unchanging levels of growth hormone, while melatonin levels reached peak values in the middle of the dark phase, four hours prior to the controls. The delay in peak values for growth hormone levels is in agreement with the pattern of phase shifting effects observed for many other physiological variables following lithium treatment, namely, a delay or shift to the right. However, the shifting of the melatonin peak to an earlier time In the 24-hour cycle is a unique finding. In rats, serum melatonin comes exclusively from the pineal. In view of the importance of this gland in biological rhythms, the unique shift to the left for melatonin following lithium treatment has important implications for the mechanisms, whereby lithium exerts its rhythm altering effects on biological systems.