High Doses Of Lithium Research Articles

Impact of Lithium on the Immune System: An Investigation of T-Cell Subpopulations and Cytokine Responses in Rats.

The aim of this study was to investigate the dose-dependent adverse effects of long-term dietary lithium administration on specific aspects of the defense system in rats. Additionally, the study aimed to explore the inflammatory activities of lithium beyond its recognized anti-inflammatory properties. Forty Wistar Albino rats were involved, which were randomly allocated into the control and four treatment groups. The control group received standard rat feed, and the experimental groups' diet was added 1g/kg, 1.4g/kg, 1.8g/kg, and 2.2g/kg lithium bicarbonate, respectively. CD4+, CD8+, and CD161 + cells were assessed by flow cytometry. TNF-α, IFN-γ, IL-1β, and IL-2 and IL-4, IL-6, and IL-10 levels were measured. The proportion of CD4 + cells and the CD4+/CD8 + ratio (P = 0.005 and P = 0.038, respectively) were reduced with the highest dose of lithium compared to the control group. The data regarding pro-inflammatory cytokines showed a dose-dependent increase in serum TNF-α and IFN-γ levels (P = 0.023 and P = 0.001, respectively). On the other hand, serum IL-1β and IL-2 levels were decreased in a dose-dependent manner (P = 0. 001 and P = 0. 001, respectively). As for anti-inflammatory cytokines, a dose-dependent decrease was determined in serum IL-4 level (P = 0.002), while no significant changes were noted in IL-6 and IL-10 levels (P = 0.507 and P = 0.732, respectively). In conclusion, lithium adversely impacted the cellular defense system. Furthermore, apart from its anti-inflammatory properties, lithium exhibited cytokine-mediated inflammatory activities. Therefore, lithium's potential adverse effects on the immune system should be considered in immunodeficient patients and those with an inflammatory status treated with high doses of lithium.

Folic acid supplementation improved cognitive deficits associated with lithium administration during pregnancy in rat offspring.

The present study aimed to analyse both neurobehavioural and biochemical results of neonates born of mothers exposed to different doses of lithium along with the groups that received lithium at the highest dose with folic acid as a preventive treatment. Male and female rats were mated in separate cages, and pregnant rats were divided into eight first group as (1) vehicle; (2) propylthiouracil (PTU)-induced hypothyroidism; (3-4) received two different doses of lithium carbonate (15 and 30 mg/kg); (5-7) the highest doses of lithium (30 mg/kg) plus three different doses of folic acid (5, 10 and 15 mg/kg); and (8) received just folic acid (15 mg/kg). All treatments were dissolved in drinking water and continued until delivery, followed by returning to a regular diet without treatment. Lithium (30 mg/kg) disrupts both behavioural and biochemical markers, including TSH, T3 and T4 as measuring indicators to assess thyroid function, IL-10 and TNF-α as anti-inflammatory and inflammatory agents, respectively, malondialdehyde as an oxidative stress marker, alongside SOD, and catalase activity as antioxidant indicators. Besides, folic acid, almost at the highest dose (15 mg/kg), attenuated memory impairement and anxiety-like behaviour caused by lithium. Moreover, the groups treated with folic acid alone in comparison with vehicles demonstrated higher levels of antioxidant and anti-inflammatory indicators. According to the results, prenatal exposure to a high dose of lithium (30 mg/kg) leads to foetal neurodevelopmental disorder and growth restriction through various mechanisms more likely attributed to hypothyroidism, which means it should be either prohibited or prescribed cautiously during pregnancy.

Synergistic but not additive effect between ACPA and lithium in the dorsal hippocampal region on spatial learning and memory in rats: Isobolographic analyses

Lithium and cannabinoids can disrupt learning and memory performance. The goal of the present study is to investigate the additive or synergistic effect of lithium and cannabinoid combination doses on spatial learning and memory in rats by isobolographic analyses. Although several studies have suggested synergistic effects of cannabinoids or lithium in response to other compounds, in most of them isobolographic analyses were not used; Thus, there is a need for more detailed studies using isobolographic analyses. In this study, spatial memory was evaluated in the Morris Water Maze (MWM) apparatus by eight trials in the training day and one trial in the test day. Lithium was injected intraperitoneal and ACPA (cannabinoid type 1 receptor agonist) was injected into the dorsal hippocampal region (intra-CA1). For the isobolographic analyses, the ED50 of lithium (2.5 mg/kg) and ACPA (0.5 μg/rat) was measured by linear regression analysis, considering the doses were tested in our previous research. The results showed that, combinations of low, medium and high doses of lithium (0.312 mg/kg, 0.625 mg/kg and 1.25 mg/kg, respectively) and ACPA (0.0625 μg/rat, 0.125 μg/rat and 0.25 μg/rat, respectively) had synergistic but not additive effect on spatial learning and spatial memory. In conclusion, we suggest that combination doses of lithium and ACPA have synergistic but not additive effect on spatial learning and memory in the rat's dorsal hippocampal region.

Low dose lithium supplementation activates Wnt/β-catenin signalling and increases bone OPG/RANKL ratio in mice

Lithium, a well-known inhibitor of glycogen synthase kinase-3β (GSK3β), can improve bone formation by activating the Wnt/β-catenin signalling pathway. However, most studies have used higher doses of lithium, which potentially have adverse effects. Herein, we report that low dose lithium supplementation (10 mg/kg/d for 6 weeks) in mice results in a serum lithium concentration of 0.02 mM significantly inhibiting GSK3β while activating Wnt/β-catenin in bone. In turn, we observed a significant increase in the expression of osteoprotegerin (OPG), with unaltered expression of nuclear-factor kβ ligand (RANKL), ultimately leading to a significant increase in the OPG/RANKL ratio. Altogether, our findings provide initial evidence that low dose lithium supplementation can promote the signalling pathways associated with bone formation.

Biological Mechanisms of Lithium separately and in combination with Caffeine in Palatogenesis in Albino Rat

Purpose: The purpose of this study was to evaluate the Biological Mechanisms of Lithium separately and in combination with Caffeine in Palatogenesis in Albino Rat Materials and Methods: Thirty six adult rats were used in this study, twenty four female and twelve male rats, after mating procedures and confirmation of pregnancy the pregnant rats were divided into 3 groups :group1(control) , which consists of six pregnant rats and were not receive any medication during gestation, group2’ Which consists of nine pregnant rats and were received prianil (lithium carbonate) 200mg/kg intragasteric During the period of ( 6th to 15th ) day of gestation &group 3: Which consists of nine pregnant rats and were received prianil (lithium carbonate) 200mg/kg rat and caffeine 18mg/kg rat intragasteric durig the same period. The fetuses were obtained from mother were decapitated and the heads were fixed in buffered formaline for at least 3 hours. The specimens were collected, prepared and examined by routine haematoxylin &eosin and immunostained by (Ki-67) marker. Results: at 16, 18 and 21 days of gestation, the greatest mean value was recorded in group II, followed by group III, with the least value recorded in group I. Both group I and III revealed a decrease in area percent of (Ki-67) throughout the study, whereas in group II revealed an increase. Conclusions: The study offers a clear evidence that lithium during pregnancy causing cleft palate in fetus and caffeine could efficiently antagonize the teratogenicity of high doses of lithium on palate when both administrated.

Simultaneous triple therapy for the treatment of status epilepticus

Early maladaptive internalization of synaptic GABAA receptors (GABAAR) and externalization of NMDA receptors (NMDAR) may explain the time-dependent loss of potency of standard anti-epileptic drugs (AED) in refractory status epilepticus (SE). We hypothesized that correcting the effects of changes in GABAAR and NMDAR would terminate SE, even when treatment is delayed 40 minutes. SE was induced in adult Sprague-Dawley rats with a high dose of lithium and pilocarpine. The GABAAR agonist midazolam, the NMDAR antagonist ketamine and the AED valproate were injected 40 min after SE onset in combination or as monotherapy. The midazolam-ketamine-valproate combination was more efficient than triple-dose midazolam, ketamine or valproate monotherapy or higher-dose dual therapy in reducing several parameters of SE severity. Triple therapy also reduced SE-induced acute neuronal injury and spatial memory deficits. In addition, simultaneous triple therapy was more efficient than sequential triple therapy: giving the three drugs simultaneously was more efficient at stopping seizures than the standard practice of giving them sequentially. Furthermore, midazolam-ketamine-valproate therapy suppressed seizures far better than the midazolam-fosphenytoin-valproate therapy, which follows evidence-based AES guidelines. These results show that a treatment aimed at correcting maladaptive GABAAR and NMDAR trafficking can reduce the severity of SE and its long-term consequences.

Midazolam-ketamine dual therapy stops cholinergic status epilepticus and reduces Morris water maze deficits.

Pharmacoresistance remains an unsolved therapeutic challenge in status epilepticus (SE) and in cholinergic SE induced by nerve agent intoxication. SE triggers a rapid internalization of synaptic γ-aminobutyric acid A (GABAA ) receptors and externalization of N-methyl-d-aspartate (NMDA) receptors that may explain the loss of potency of standard antiepileptic drugs (AEDs). We hypothesized that a drug combination aimed at correcting the consequences of receptor trafficking would reduce SE severity and its long-term consequences. A severe model of SE was induced in adult Sprague-Dawley rats with a high dose of lithium and pilocarpine. The GABAA receptor agonist midazolam, the NMDA receptor antagonist ketamine, and/or the AED valproate were injected 40 min after SE onset in combination or as monotherapy. Measures of SE severity were the primary outcome. Secondary outcomes were acute neuronal injury, spontaneous recurrent seizures (SRS), and Morris water maze (MWM) deficits. Midazolam-ketamine dual therapy was more efficient than double-dose midazolam or ketamine monotherapy or than valproate-midazolam or valproate-ketamine dual therapy in reducing several parameters of SE severity, suggesting a synergistic mechanism. In addition, midazolam-ketamine dual therapy reduced SE-induced acute neuronal injury, epileptogenesis, and MWM deficits. This study showed that a treatment aimed at correcting maladaptive GABAA receptor and NMDA receptor trafficking can stop SE and reduce its long-term consequences. Early midazolam-ketamine dual therapy may be superior to monotherapy in the treatment of benzodiazepine-refractory SE.

Neurotrophic effects of lithium stimulate the reduction of ischemic and neurodegenerative brain damage

For over 60 years, high doses of lithium (hundreds of milligrams of elemental lithium) have being used to treat bipolar disorder. However, only during the past 20 years the relevant basic and clinical studies have shown that neuroprotective and neurotrophic effects of lithium are possible in much smaller doses ( hundreds of micrograms of elemental lithium). These data indicate a significant potential for the clinical applications of lithium-based drugs in modern neurology for the purposes of prevention and treatment of neurodegenerative and ischemic pathologies. Pharmacological and molecular biology studies indicated that the inhibition of glycogen synthase kinase-syntentase-3 (GSK-3) and induction of brain-derived neurotrophic factors are the main mechanisms of neurotropic actions of lithium. Also, by inhibiting the NMDA receptors, lithium regulates the calcium homeostasis and inhibits the activation of calcium-dependent apotosis. These and other molecular mechanisms of lithium action protect neurons from ischemia and neurodegeneration thus contributing to a significant reduction of neurological deficit in various models of stroke and neurodegenerative diseases.

Distressing cutaneous lesion among bipolar affective disorder patients on lithium therapy: A retrospective cross-sectional study.

Aim:To assess the incidence of cutaneous lesion in bipolar affective disorder (BPAD) patients on lithium therapy. To evaluate the relationship between duration of lithium therapy, dosage of lithium, serum lithium level, and cutaneous lesions. To assess whether reduction/stoppage of dose of lithium has any change in the course of cutaneous side effects. To look for a relationship between addition of isotretinoin and the course of mood disorder.Methodology:We retrospectively collected hospital case records of 125 consecutive BPAD patients initiated lithium therapy, assessed with inclusion and exclusion criteria. We follow up them for 2½ years for the assessment of above said aims.Results:The prevalence of skin reaction in BPAD patients with lithium therapy was 19.8%. Among patients on lithium therapy, cutaneous lesion emerged in initial 6 months and later after 1 year of treatment. Nearly 55% of patients on higher doses of lithium (1200 mg) had a cutaneous lesion. Patient on therapeutic serum level of lithium had a higher incidence of skin lesion. Out of six patients in whom dosage of lithium was reduced, three of them had reduced lesions (P = 0.6), in two patients, skin lesion increased, and one patient had no change. Among 11 patients treated with isotretinoin, only two patients had emergence of depressive symptoms.Conclusion:Lithium continues to increase the incidence of multiple cutaneous lesions among BPAD patients on lithium therapy. Incidence of cutaneous side effects directly correlates with the dose of lithium and therapeutic range of serum lithium level. Altering the dose of lithium does not statistically influence the cutaneous lesion.

PTEN Overexpression Cooperates With Lithium to Reduce the Malignancy and to Increase Cell Death by Apoptosis via PI3K/Akt Suppression in Colorectal Cancer Cells.

Lithium is a well-established non-competitive inhibitor of glycogen synthase kinase-3β (GSK-3β), a kinase that is involved in several cellular processes related to cancer progression. GSK-3β is regulated upstream by PI3K/Akt, which is negatively modulated by PTEN. The role that lithium plays in cancer is controversial because lithium can activate or inhibit survival signaling pathways depending on the cell type. In this study, we analyzed the mechanisms by which lithium can modulate events related to colorectal cancer (CRC) progression and evaluated the role that survival signaling pathways such as PI3K/Akt and PTEN play in this context. We show that the administration of lithium decreased the proliferative potential of CRC cells in a GSK-3β-independent manner but induced the accumulation of cells in G2/M phase. Furthermore, high doses of lithium increased apoptosis, which was accompanied by decreased proteins levels of Akt and PTEN. Then, cells that were induced to overexpress PTEN were treated with lithium; we observed that low doses of lithium strongly increased apoptosis. Additionally, PTEN overexpression reduced proliferation, but this effect was minor compared with that in cells treated with lithium alone. Furthermore, we demonstrated that PTEN overexpression and lithium treatment separately reduced cell migration, colony formation, and invasion, and these effects were enhanced when lithium treatment and PTEN overexpression were combined. In conclusion, our findings indicate that PTEN overexpression and lithium treatment cooperate to reduce the malignancy of CRC cells and highlight lithium and PTEN as potential candidates for studies to identify new therapeutic approaches for CRC treatment.

Lithium Toxicity Precipitated by Thyrotoxicosis Due to Silent Thyroiditis: Cardiac Arrest, Quadriplegia, and Coma

Lithium is widely used to treat bipolar disorders. Lithium toxicity is generally caused by inappropriately high doses of lithium or impaired lithium excretion. Most lithium is eliminated via the kidneys and, since thyroid hormone increases tubular reabsorption of lithium, thyrotoxicosis could contribute to the development of lithium toxicity. We report a case of severe lithium toxicity that was apparently precipitated by the onset of thyrotoxicosis resulting from silent thyroiditis and dehydration. The patient was a 64-year-old woman who was admitted for muscle weakness in the lower extremities, diarrhea, and palpitations. She had bipolar disorder and was being treated with lithium carbonate, which she discontinued one week before admission. Her circulating lithium levels had been monitored yearly. Early in her admission she was dehydrated and had febrile episodes, paroxysmal atrial fibrillation, and muscle weakness. Initially, fluid therapy was started, but she lost consciousness and had a cardiac arrest for 2 minutes due to prolonged sinus arrest. Chest compression and manual artificial ventilation were performed, and body surface pacing was started. Serum lithium was markedly elevated to 3.81 mEq/L (therapeutic range, 0.4-1.0 mEq/L), and thyroid hormone levels were increased (free triiodothyronine, 8.12 pg/mL; free thyroxine, 4.45 ng/dL), while thyrotropin (TSH) was suppressed (<0.01 μIU/mL). Hemodialysis was performed, and a temporary pacemaker was inserted for severe sinus bradycardia. The serum thyroglobulin was 4680 ng/mL (reference range, <32.7 ng/mL). A TSH receptor antibody test was negative. Glucocorticoid therapy and inorganic iodine (100 mg) were administered and continued until day 11. However, her neurological symptoms deteriorated with floppy quadriplegia and deep coma. She gradually recovered. On day 36, she was discharged without any neurological symptoms or thyrotoxicosis. A 64-year-old woman taking lithium for bipolar disorder developed lithium toxicity in the setting of what seemed likely to be a recent onset of thyrotoxicosis due to silent thyroiditis. Thyrotoxicosis may be a contributing cause of lithium toxicity, particularly if it is abrupt in onset and even with cessation of lithium therapy if renal function is compromised. Thyroid function should be assessed immediately in patients with suspected lithium toxicity.

Stutter Exacerbated by Lithium in a Pediatric Patient with Bipolar Disorder

To report the first known case of a lithium-exacerbated stutter in a pediatric patient. A 10-year-old male with a history of developmental stuttering, bipolar disorder not otherwise specified (NOS), attention-deficit/hyperactivity disorder, and conduct disorder was admitted to the psychiatric hospital because of recurrent suicidal ideations and increased physical aggression toward staff at his residential facility. The patient was being treated with lithium at initial dose of 150 mg/day at bedtime for bipolar disorder NOS. When the lithium dose was increased to 900 mg twice daily to better control the bipolar symptoms, his developmental stutter worsened intensely. When the lithium dose was reduced to 600 mg in the morning and 900 mg at night, the stutter returned to baseline. No other medication changes were made during this interval. His serum lithium concentration was 0.62 mEq/L at baseline, 1.24 mEq/L during the height of his exacerbated stutter, and returned to 0.64 mEq/L after dose reduction. To our knowledge, only 1 case of lithium-exacerbated stutter has been reported in the literature, and this was in an adult. The developmental stutter of our pediatric patient worsened when he was treated with higher doses of lithium. He was on stable doses of his other medications during the adjustments to the lithium dose, making it less likely that the stutter was due to one of these medications. However, it is possible that the exacerbation involved an interaction between lithium and one or several of the other medications. Based on the Naranjo probability scale, this case represents a probable adverse drug reaction. Clinicians should be aware that an additional adverse effect of lithium may be an exacerbation of stutter.

Lithium induces mortality in medulloblastoma cell lines

Lithium is the main therapeutic agent for the treatment of bipolar disorders but nerve cells are not the sole target of this drug. Indeed, lithium has been reported to target numerous cell types and to affect cell proliferation, differentiation and death. Lithium targets a variety of enzymes among which there is GSK-3beta and a number of cell responses elicited by lithium are mediated by the Wnt pathway that is involved in medulloblastoma (MB) pathogenesis. We studied the in vitro effects of lithium on two different MB cell lines: D283MED and DAOY. High doses of lithium inhibited GSK3-beta, decreased cell proliferation and induced non-apoptotic cell death in both cell lines independently by intracellular levels of beta-catenin that is consistently high only in D283MED. At clinical doses, the anti-neoplastic effects were observed only in this cell line, highlighting the importance of a specific molecular background in determining the target therapy response. In conclusion, lithium could be a promising drug in MB, but an accurate molecular profile predictive of drug response still needs to be clarified.

Effectiveness of Normal Saline Diuresis in Treating Lithium Overdose

Lithium carbonate is a common treatment for mood disorders, but it has a very narrow therapeutic index and can be toxic to multiple organ systems. Unfortunately, many patients suffer toxic effects through the course of their therapy. We describe a patient with toxic effects from a high dose of lithium who was successfully treated with normal saline diuresis. We discuss the properties that make lithium susceptible to normal saline diuresis and explore alternative options for treatment of lithium toxicity.

Role of Nitric Oxide and Prostaglandin Systems in Lithium Modulation of Acetylcholine Vasodilation

The mechanism of lithium action, an effective treatment for bipolar disease, is still unknown. The present study examined the role of nitric oxide (NO) and prostaglandin systems in lithium modulation of acetylcholine in mesenteric vascular bed of rats by cannulating superior mesenteric artery. Acetylcholine (ACh) or sodium nitroprusside was injected under constant controlled flow induced by phenylephrine; therefore, changes in perfusion pressure reflect changes in resistance. Although 0.5 mM or 1 mM lithium-pretreatment of vascular bed causes reduction in ACh-response, 1.5 mM lithium induced no changes and 2 and 2.5 mM lithium potentiated ACh-induced mesenteric vascular bed relaxation compared to control group. Pretreatment of vascular bed with L-NAME or indomethacin decreased ACh-induced relaxation in 2 concentrations of 0.5 and 2 mM of lithium. The vasorelaxation response to sodium nitroprusside, the NO donor, was not different among lithium groups (0.5 and 2 mM) and controls. In conclusion, there is a dual modulation of endothelium-dependent relaxation, including an inhibitory effect at lower dose and a stimulating effect at higher dose of lithium in rat mesenteric vascular bed. NO synthesis or cyclooxygenase inhibition decreased vasorelaxation in both lower and higher doses of lithium, suggesting a role for NO and prostaglandin in this effect.

Exposure to a context previously associated with nausea elicits conditioned gaping in rats: A model of anticipatory nausea

Following one or more chemotherapy treatments, many patients report that they experience anticipatory nausea. This phase of nausea has been interpreted as a classically conditioned response where a conditional association develops between the contextual clinic cues and the nausea and/or vomiting that developed following treatment. Although rats do not vomit, they display a distinctive gaping reaction when exposed a flavored solution previously paired with a toxin. Here we report that, even in the absence of a flavored solution, rats display conditioned gaping reactions during exposure to a distinctive context previously paired with a high dose of lithium (Experiment 1 with a distinctive odor and Experiment 3 without a distinctive odor), a low dose of lithium (Experiment 2) or provocative vestibular stimulation (Experiment 2). These results suggest that the conditioned gaping reaction in rats is selectively elicited by nausea-paired contextual stimuli, as well as flavors. This rat model of anticipatory nausea may serve as a valuable preclinical tool to evaluate the effectiveness of anti-nausea treatments and the side effect of nausea produced by newly developed pharmaceutical compounds intended for other clinical treatments.

Lithium has no direct effect on cardiac function in the isolated, perfused rat heart.

To determine if lithium exerts direct cardiac toxicity, using an isolated, perfused rat heart model, paced and unpaced beating rat hearts were perfused with Krebs-Henseleit bicarbonate solution and left ventricular pressures were measured via a balloon-tipped catheter positioned in the left ventricle via the mitral valve. Following a stabilization period, hearts were then perfused with Krebs-Henseleit bicarbonate solution containing 1, 10, and 100 mM ionized lithium chloride or lithium carbonate in an antecedent dose-response protocol and perfused for 10 min. at each dose. To control for the possibility of osmotic effects from the high dose of lithium, an additional group was studied in which hearts were perfused with Krebs-Henseleit bicarbonate solution for an initial stabilization period, then perfused for an additional 20 min. with Krebs-Henseleit bicarbonate solution alone, and finally with Krebs-Henseleit bicarbonate solution containing mannitol (200 mOsm/l) for 10 min. Lithium did not have any effect on left ventricular peak systolic pressure, left ventricular end diastolic pressure, heart rate or coronary haemodynamics at concentrations of 1 or 10 mM. At 100 mM LiCl and Li2CO3, left ventricular peak systolic pressure decreased transiently during the first minute of lithium infusion, but recovered significant function by 10 min. Heart rate decreased significantly by 10 min. of infusion. These effects were also seen in the osmotic controls and thus do not appear to be a direct effect of lithium. At the doses tested, lithium had no direct effect on cardiac function which could not be explained by an osmotic effect.

Tolerability of combined treatment with lithium and fluoxetine: 14 cases treated under open conditions.

Fourteen cases of depression resistant to multiple treatments were treated by lithium augmentation of fluoxetine. Tolerability of the treatment was poor. Lithium and fluoxetine may be a possible treatment for resistant depression but there is caution regarding tolerability and toxicity with the relatively high doses of lithium used in this series.

Lithium effects on inositol phospholipids and inositol phosphates: evaluation of an in vivo model for assessing polyphosphoinositide turnover in brain.

Administration of lithium chloride to rats injected intracerebrally with [3H]inositol led to time- and dose-dependent increases in levels of labeled inositol monophosphates in brain. Quantitative analysis of the inositol phosphates by ion chromatography revealed 37- and 20-fold increases in the mass of myo-inositol 1-phosphate and 4-phosphate, respectively, at 4 h intraperitoneal after injections of 6 mEq/kg of lithium chloride. Albeit to a much lesser extent, lithium administration also resulted in an increase in the level of myo-inositol, 1,4-bisphosphate in brain. The lithium-induced increase in content of labeled inositol monophosphates was marked by a concomitant decrease in content of labeled inositol, and after injections of high doses of lithium, e.g., 10 mEq/kg, this was followed by a general decrease in labeling of the inositol phospholipids. In general, animals injected with [3H]inositol but not lithium did not reveal obvious differences in labeling of inositol monophosphates on stimulation by mecamylamine or pilocarpine. However, when animals were injected with [3H]inositol and then lithium, there were large increases in the levels of labeled inositol monophosphates on administration of these compounds. Administration of atropine to the lithium-treated mice led to a partial reduction in the amount of labeled inositol monophosphates accumulated due to the administration of lithium alone. Furthermore, atropine was able to block the pilocarpine-induced increase in level of labeled inositol monophosphates. These results demonstrate the suitable use of the radiotracer technique together with lithium administration for assessing the effects of drugs and receptor agonists on the signaling system involving polyphosphoinositide turnover in brain.

Diurnal variations in serum lithium and renal lithium clearance in rats given lithium as a single small dose or as multiple high doses.

Clearance determinations were carried out in three groups of rats: A high lithium group given food to which 70 mmol/kg of lithium were added for 4-6 weeks leading to a mean serum lithium concentration of 0.85 mmol/l, a low lithium group given food to which 15 mmol/kg of lithium were added for two days before the clearance period leading to a mean serum lithium concentration of 0.22 mmol/l, and a group given the same food without lithium. The sodium and potassium contents of the food were kept high in order to avoid lithium-induced development of negative sodium balance and excessive polyuria. The rats were housed in four rooms with 6-hour displaced 24-hour light-dark cycles. The results showed that high doses of lithium led to a significant increase of the lithium clearance and the urine flow. Small amounts of lithium influenced neither the clearance values nor the urine flow. All renal variables were increased by about 50-100% during the dark period. The serum lithium concentration was least influenced by the diurnal rhythm. It is concluded that serum lithium concentrations measured at any time of the day are fairly representative of the 24 hours. A lithium clearance measured during daytime is valid for this period only. Long-term lithium treatment leads to an increase of the renal lithium clearance but does not diminish the normal diurnal rhythm of the kidney function.