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PubMed2004

Lithium spectroscopic imaging of rat brain at therapeutic doses.

Since the discovery that lithium (Li) is efficacious for the treatment of manic depressive illness, the brain Li distribution of mammals treated with lithium has been of interest. However, the spatial relationship of lithium in the brain regions to its function remains largely unknown. Knowledge of Li distribution in the brain is necessary to localize its action in the brain. Both the therapeutic and neurotoxic side effects of Li are centered mainly in the central nervous system and hence there is considerable interest in understanding the extent of lithium penetration into the central nervous system. The mechanism by which neurotoxic side effects are generated is not known and may, in part, be related to the particular distribution of lithium in the brain. The regional specificity in lithium's brain distribution could underlie important steps on its action. Li levels in various brain regions for autopsied rats and humans have been reported. However, many results are conflicting due to ion redistribution at death or during sample preparation. A direct nondestructive measurement of Li levels in the brain where the drug exerts its effects is certainly desirable. Because magnetic resonance technique can be used to observe Li, it can be an appropriate method to monitor and map the distribution in the brain. The application of MR technology to rat brain regions has provided information on lithium distribution in a non-invasive manner. The earlier development work at lower field strengths provided brain lithium information at high dose of Li administration. Here we demonstrate the feasibility of quantitative spectroscopic imaging on rat brain under therapeutic doses.

Animals↗
PubMed2004

Increased inositol-monophosphatase activity by lithium treatment in bipolar patients.

Inhibition of inositol monophosphatase (IMPase) enzyme is the target mechanism of action of lithium. However, increased activity of mRNA levels by lithium has been reported. These two diverse effects were shown after relatively short periods of lithium administration. The aim of this study was to observe the effect of prolonged use of lithium on IMPase activity. The authors investigated IMPase activities in fresh erythrocytes and leukocytes in 63 bipolar patients (42 euthymic, 8 depressive, 13 manic episodes) and 16 control subjects. We found that erythrocyte IMPase activity was higher in lithium treated euthymic patients than non-lithium treated patients. The duration of lithium use was positively correlated with leukocyte IMPase activity. Increased IMPase activity by chronic lithium use suggests an up-regulation of the enzyme activity.

Adult↗
PubMed2005

Lithium increases body weight of rats: relation to thymolysis.

Lithium treatment of patients and laboratory animals causes increased body weight. Lithium also elevates the plasma corticosterone levels of rats. Our purpose was to correlate the gain of body weight with the effects of lithium on the thymus gland, the organ most susceptible to stress and to elevated corticosterone levels. Toward this end, it was also necessary to establish a reliable and reproducible model by use of an inbred strain of rats. Female rats of the inbred Lewis strain were injected subcutaneously with lithium chloride or saline for an 18-day period. Necropsies were performed one day after the last treatment or at intervals during the treatment period. Lithium increased body weight gain compared to controls in all the experiments on Lewis rats. Contrary to the body as a whole, lithium caused loss of weight of the thymus gland. The spleen lost less weight than the thymus. Both lithium and nonspecific stress elevate plasma corticosterone and cause thymolysis. Mild nonspecific stress is known to cause increased weight gain in rats as well as in humans. Our data suggest that lithium acts like nonspecific stress to increase weight gain as a consequence of elevated glucocorticoids, manifested in our experiments by thymolysis. This mechanism has not been proposed previously.

Animals↗
PubMed2004

GSK-3beta inhibition by lithium confers resistance to chemotherapy-induced apoptosis through the repression of CD95 (Fas/APO-1) expression.

Lithium exerts neuroprotective actions that involve the inhibition of glycogen synthase kinase-3beta (GSK-3beta). Otherwise, recent studies suggest that sustained GSK-3beta inhibition is a hallmark of tumorigenesis. In this context, the present study was undertaken to examine whether lithium modulated cancer cell sensitivity to apoptosis induced by chemotherapy agents. We observed that, in different human cancer cell lines, lithium significantly reduced etoposide- and camptothecin-induced apoptosis. In HepG2 cells, lithium repressed drug induction of CD95 expression and clustering at the cell surface as well as caspase-8 activation. Lithium acted through deregulation of GSK-3beta signaling since (1) it provoked a rapid and sustained phosphorylation of GSK-3beta on the inhibitory serine 9 residue; (2) the GSK-3beta inhibitor SB-415286 mimicked lithium effects by repressing drug-induced apoptosis and CD95 membrane expression; and (3) lithium promoted the disruption of nuclear GSK-3beta/p53 complexes. Moreover, the overexpression of an inactivated GSK-3beta mutant counteracted the stimulatory effects of etoposide and camptothecin on a luciferase reporter plasmid driven by a p53-responsive sequence from the CD95 gene. In conclusion, we provide the first evidence that lithium confers resistance to apoptosis in cancer cells through GSK-3beta inhibition and subsequent repression of CD95 gene expression. Our study also highlights the concerted action of GSK-3beta and p53 on CD95 gene expression.

Apoptosis↗
PubMed1997

Lithium treatment in amiodarone-induced thyrotoxicosis.

PURPOSE: Amiodarone hydrochloride is an iodine-rich drug effective in the control of various tachyarrhythmias. It is known to cause refractory to thyrotoxicosis, which usually does not respond to regular antithyroid drugs. Lithium bicarbonate is a medication used to treat psychiatric disorders; it also influences thyroid production and release of hormones. We tried it in combination with propylthiouracil (PTU) for the treatment of amiodarone-induced thyrotoxicosis. PATIENTS AND METHODS: Twenty-one patients were studied. The first group (n = 5) was treated by amiodarone withdrawal only. The second group (n = 7) received PTU (300 to 600 mg), and the third (n = 9) PTU (300 mg) and lithium (900 to 1350 mg) daily. Patient selection was not randomized. The PTU + lithium group had more severe symptoms and signs of thyrotoxicosis, as well as thyroxine levels at least 50% above the upper limit of normal. They also had been on a longer course of amiodarone treatment (34.3 +/- 11.9 months) than the PTU-only (11.4 +/- 7.5) and the no-treatment (7.8 +/- 4.2) groups. RESULTS: While there was no difference between the first two groups in time until recovery (10.6 +/- 4.0 versus 11.6 +/- 0.5 weeks, respectively), the group receiving lithium normalized their thyroid function tests in only 4.3 +/- 0.5 weeks (P < 0.01 versus both other groups). T3 levels normalized even earlier-by 3 weeks of lithium treatment. No adverse effects of lithium were encountered, and the medication was stopped 4 to 6 weeks after achieving a normal clinical and biochemical state. CONCLUSIONS: We conclude that lithium is a useful and safe medication for treatment of iodine-induced thyrotoxicosis caused by amiodarone. We would reserve this treatment for severe cases only. Further studies are needed to find out whether in patients with this troublesome complication lithium therapy could permit continuation of amiodarone treatment.

Amiodarone↗
PubMed2000

Lithium regulation of aldolase A expression in the rat frontal cortex: identification by differential display.

BACKGROUND: Substantial evidence indicates that lithium may exert its therapeutic effects through progressive adaptive changes at the level of gene expression; however, the study of lithium-regulated genes has been primarily undertaken with the "candidate gene" approach based on a specific testable hypothesis. The aim of our study was to identify lithium-regulated genes that would not be predicted a priori by the candidate gene approach. METHODS: Differential display polymerase chain reaction was used to isolate and identify messenger RNAs (mRNAs) that are differentially expressed in the frontal cortex of rats given lithium for 5 weeks to achieve plasma lithium concentrations of 0.6 to 0.9 mmol/L. RESULTS: A putative lithium-regulated complementary DNA fragment (LRG1) was identified. Northern blot analysis revealed that 5 weeks of lithium treatment, but not 1 week, significantly reduced LRG1 mRNA levels. LRG1 mRNA levels were similarly reduced by 5 weeks of carbamazepine, but not valproate administration. Sequence analysis and search of the GenBank database revealed that LRG1 is analogous to the sequence of the gene for rat aldolase A. CONCLUSIONS: These results demonstrate that chronic administration of lithium, but not short-term administration, down regulates the levels of aldolase A mRNA, suggesting this effect may play a role in mediating the therapeutic action of this agent.

Animals↗
PubMed2001

The effects of lithium on ex vivo cytokine production.

BACKGROUND: Studies suggest that lithium may have profound immunomodulatory effects in animal models as well as in humans. METHODS: In this study, whole blood cultures from normal control subjects were established for 5 days and the effects of lithium on cytokine production were investigated. Because many of lithium's actions have been postulated to be modulated through phosphoinositide (PI), protein kinase C (PKC) and cyclic adenosine monophosphate (c-AMP) signaling pathways, the effects of myo-inositol and prostaglandin E(2), alone or in combination with lithium, were also investigated. RESULTS: We found that lithium caused an increase in interleukin-4 and interleukin-10 levels, traditionally classified as T-helper lymphocyte type-2 cytokines, and a decrease in interleukin-2 and interferon-gamma levels, traditionally classified as T-helper lymphocyte type-1 (TH-1) cytokines. This shift cannot be fully explained by lithium's actions on the PI, PKC, or c-AMP messenger systems. CONCLUSIONS: Monocytes exposed to lithium in the presence of a mitogen for 5 days produced a shift toward the production of TH-2 cytokines and away from the production of TH-1 cytokines. The study suggests that lithium may have complex time-dependent effects on immune function.

Adult↗
PubMed1997

Relationship between prophylactic effect of lithium therapy and family history of affective disorders.

Lithium therapy response and age of onset (AOO) were studied in 98 patients with bipolar affective disorder (BPAD) who were divided into subgroups depending on type of family history of affective disorders. The highest (33.0 years) and lowest (25.5 years) age of onset were found in nonfamilial patients and in familial patients with a first-degree relative of BPAD, respectively. Nonfamilial patients showed the best response to lithium. There were 0.9 episodes/year off lithium compared to 0.3 episodes/year on lithium (an 88% decrease). A poorer response (a 71% decrease; a reduction from 1.39 episodes per year off lithium to 0.65 on lithium) was found in familial patients with a first-degree relative of BPAD. Differences in serum lithium values between the groups could not explain the observed differences. Thus, familial patients showed a more severe manifestation of the disease with an earlier AOO and a lower prophylactic effect of lithium.

Age of Onset↗
PubMed1999

Vitamin B12 and folate levels and lithium administration in patients with affective disorders.

BACKGROUND: It is unclear whether there is a relationship between lithium administration and vitamin B12 metabolism. METHODS: We compared serum B12, serum folate, and red blood cell folate concentrations in patients receiving and not receiving lithium at two Mood Disorders Clinics. As the two centers differed in vitamin assay methods, data were first analyzed separately and then combined. To rule out an in vitro effect of lithium on the assays, we also added varying amounts of lithium to lithium-free blood samples and measured vitamin concentrations. RESULTS: Mean serum B12 concentrations were approximately 20% lower in the lithium than in the nonlithium group at each center. This difference was statistically significant for each center and on combination (two-tailed p = .017, .021, and .0009). The parametric effect size for each center and the combined weighted mean effect size were moderate in magnitude (.605, .523, and .565). There was a nonsignificant trend toward an increased prevalence of assay-defined B12 deficiency in the lithium group at one center only, with no cases in either group at the other center and a nonsignificant combined relative risk. CONCLUSIONS: Our data may represent a lithium-associated decrease in serum B12 concentration. The clinical significance of these findings is not yet clear.

Adult↗
PubMed2002

Lithium ions modulate the expression of VMAT2 in rat brain.

Recent work has indicated that lithium (at 1 mM, a concentration that is efficacious in the treatment of manic-depressive disorders) modulates the level of vesicular monoamine transporter 1 (VMAT1) mRNA in PC12 cells as a function of the differentiation status of these cells. To ascertain whether VMAT expression in neurons is sensitive to lithium, in vivo, rats were fed a lithium-supplemented diet for 21 days (which raised serum lithium to 0.98+/-0.1 mM). Northern analysis revealed an overall increase (199+/-27%) of the neuronal VMAT isoform (VMAT2) in rat brain after lithium. However, in situ hybridization analysis revealed regional differences in the effects of lithium. Thus, VMAT2 mRNA increased by 50-100% over control in the raphe nuclei, ventral tegmental area, and substantia nigra of rats fed the lithium diet. Concomitantly, VMAT2 mRNA declined by about 50% in the locus coeruleus. Because VMAT2 is expressed in neurons that are strongly implicated in regulating mood and behavior, these data support the hypothesis that alterations of VMAT2 expression contribute to the therapeutic effects of lithium in psychiatric disorders.

Animals↗
PubMed1997

Effects of chronic lithium treatment on ornithine decarboxylase induction and excitotoxic neuropathology in the rat.

Young adult rats were chronically treated with lithium (2.5 mmol/kg/day) for 16 days. The day after the last lithium administration, rats were injected s.c. with the excitotoxic convulsant kainic acid (10 mg/kg). As compared to saline controls, lithium-treated rats had no apparent attenuation of convulsions. Furthermore, the induction of brain ornithine decarboxylase and the consequent increase of putrescine levels, an index related to the convulsant effects of kainic acid, were similar in saline- and lithium-treated rats. Other rats were unilaterally injected with ibotenic acid into the nucleus basalis magnocellularis: no differences were measured in cortical choline acetyltransferase (ChAT) decrease among saline- and lithium-treated rats. In both the above experiments, apoptotic cell death was monitored in relevant brain regions of saline- or lithium-treated rats through a specific in situ labeling method for fragmented DNA. Whilst morphological evidence for a reduced damage in the olfactory cortex and hippocampus of kainic acid-injected rats was not obtained, lithium-treated rats showed a lower decrease of specific neurochemical markers: [3H]D-aspartate uptake and glutamate decarboxylase. This result suggests that mechanisms of recovery, absent in saline-treated animals, are elicited by the excitotoxic insult in lithium-treated rats.

Animals↗
PubMed2001

Lithium does not synergize the peripheral action of cholinomimetics as seen in the central nervous system.

Lithium is known to synergize the action of cholinomimetics in the CNS such that pilocarpine induces seizures in low concentration (1/13th of per se dose) in rats. The present study was undertaken to see if lithium priming also enhances the peripheral effects of acetylcholine and pilocarpine i.e. change in blood pressure in rats and contractions of the isolated guinea pig ileum. In anaesthetized rats the blood pressure was recorded from cannulated carotid artery connected through the pressure transducer to Coulbourn polygraph. The blood pressure response of pilocarpine was not different either in magnitude or in duration when administered 1, 2 and 4 h after lithium chloride (3 meq/kg) pretreatment as compared to the control. Similarly acetylcholine effect remained unchanged after lithium chloride priming. In the isolated guinea pig ileum experiments, ileum was incubated for 1 h in different concentrations of lithium chloride and effect on acetylcholine induced contractions were observed. Lithium in concentration of 2.8 x 10(-3) M had no effect on acetylcholine induced contractions while incubation with higher concentrations of 1.4 x 10(-2) M and 2.8 x 10(-2) M significant inhibition of acetylcholine contractions were observed. At this concentration, histamine induced contractions were also inhibited. The results indicate that lithium does not synergize the action of cholinomimetics in the periphery as that seen in the CNS. The inhibition of acetylcholine and histamine induced contractions in guinea pig ileum at high concentration of lithium seems to be non-specific effect.

Acetylcholine↗
PubMed1999

Lithium administration affects gene expression of thyroid hormone receptors in rat brain.

Even though lithium has received wide attention in the treatment of manic depressive illness, the mechanisms underlying its mood stabilizing effects are not understood. Lithium is known to interact with the thyroid axis and causes hypothyroidism in a subgroup of patients, which compromises its mood stabilizing effects. Since lithium was recently reported to alter thyroid hormone metabolism in the rat brain, the present study investigated whether these effects were mediated through regulation of thyroid hormone receptor (THR) gene expression. Adult male euthyroid rats were either given a diet containing 0.25% lithium or one without lithium for 14 days. Rats were sacrificed in the evening and RNA was isolated from different brain regions to quantitate the isoform specific mRNAs of THRs. Following 14 days of lithium treatment, THR alpha1 mRNA levels were increased in the cortex and decreased in hypothalamus; THR alpha2 mRNA levels were increased in the cortex and THR beta mRNA levels were decreased in the hypothalamus. No significant difference in the expression of these THR isoforms was observed in the hippocampus or cerebellum. Thus, chronic lithium treatment appeared to regulate THR gene expression in a subtype and region specific manner in the rat brain. It remains to be determined whether the observed effects of lithium on THR gene expression are related to its therapeutic efficacy in the treatment of bipolar disorder.

Animals↗
PubMed1999

Effects of lithium on receptor-mediated activation of G proteins in rat brain cortical membranes.

The underlying molecular mechanism of action of lithium in the treatment of manic-depressive illness is not clear. The effect of chronic lithium on GTP-binding and toxin-mediated ADP-ribosylation of specific G proteins in brain cortical membranes was examined. Incubation of cortical membranes with 5-HT increased [35S]GTPgammaS binding to Galphas, Galphai, Galphao and Galphaq proteins. Six weeks but not 1 week of lithium treatment reduced the increases in [35S]GTPgammaS binding to Galphas, Galphai and Galphao which are produced by 5-HT by 75-85%, whereas 5-HT stimulated [35S]GTPgammaS binding to Galphaq was reduced by 38%. No changes in membrane levels of Galpha and Gbeta proteins were noted in lithium-treated rats. Pertussis toxin (PTX)-mediated ADP-ribosylation of Galphai/o was increased by 60% in cortical membranes of chronically treated rats. Lithium treatment did not affect cholera toxin-mediated ribosylation of Galphas. Increases in [35S]GTPgammaS binding to Galpha proteins evoked by 5-HT were also inhibited by 0.5-2.0 mM lithium chloride added in vitro to the assay mixture. Rubidium and cesium did not change 5-HT-stimulated G protein activation. ADP-ribosylation of Galphai/o catalyzed by PTX was not changed by in vitro LiCl. The inhibitions of 5-HT-stimulated increases in [35S]GTPgammaS-binding to Galphas and Galphaq were completely suppressed by 2.4 mM MgCl2 this concentration of MgCl2 inhibited the effect of lithium on Galphai and Galphao by 50%. Similar findings were also noted when [alpha-32P]GTP was used in the binding assay. The results suggest that lithium interferes with receptor-G protein coupling via a Mg2+-sensitive mechanism. This action of the drug is more effective for Gs, Gi and Go than for Gq and may result from its interference with the recycling of trimeric G proteins.

Animals↗
PubMed1998

The effect of prophylactic lithium treatment on mortality and suicidal behavior: a review for clinicians.

Prophylactic lithium treatment lowers the frequency of recurrences in manic depressive illness. Does it also reduce mortality and suicidal behavior? In this paper all relevant publications were reviewed. The mortality of lithium-treated patients was compared with the mortality in the general population, and the patients' suicidal behavior when they were on lithium was compared with their behavior when they were not. The mortality of manic depressive patients is two to three times higher than that of the general population, a highly significant difference. In the studies reviewed here the patients' mortality during lithium treatment was not significantly higher or only moderately higher than in the general population. After discontinuation of lithium the mortality was again significantly higher. The number of patients attempting suicide was 6-15 times lower and the number of patients completing suicide was 3-17 times lower when they were on lithium than they were not. Similar observations have not been reported for prophylactic treatment with other mood stabilizers. For methodological reasons explained in the introduction, these observations cannot prove that lithium treatment has a mortality-lowering, antisuicidal effect. But they are compatible with such an assumption. It must be the duty of psychiatrists to keep the possibility of an antisuicidal action of lithium in mind when they choose prophylactic treatment for patients with severe depressions or suicidal thoughts or suicide attempts in the past or combinations of these.

Bipolar Disorder↗
PubMed2001

Oxytocin mediates the inhibitory action of acute lithium on the morphine dependence in rats.

The role of central oxytocin in inhibitory action of lithium on the development of morphine dependence was behavioral investigated in rats. Acute lithium could enhance the morphine-induced analgesia in rats with or without chronic morphine treatment; this effect could be inhibited by intraventricular injection of oxytocin antagonist d (CH(2))(5)-Tyr (Me)-[Orn(8)]-Vasotocin (OVT). Lithium could attenuate naloxone-precipitated withdrawal signs in morphine dependent rats. The reduction of the expression of naloxone-precipitated withdrawal signs by lithium was reversed by ICV of OVT. The lithium significantly inhibited the conditioned place preference (CPP) induced by morphine, which inhibitory action of lithium could also reverse by ICV injection of OVT. These results suggested that lithium might inhibit the physical dependence on morphine as well as psychological dependence in rats, and that this inhibitory effect of lithium on the development of morphine dependence might be associated with oxytocin systems in the central nervous system.

Analgesics, Opioid↗
PubMed1991

Whole-bowel irrigation as a treatment for acute lithium overdose.

STUDY OBJECTIVE: To determine if gastrointestinal decontamination using whole-bowel irrigation (WBI) was an effective treatment for acute ingestion of sustained-release lithium. METHODS: In a two-phase, crossover protocol, ten normal volunteers ingested in each phase 0.80 mEq/kg sustained-release lithium carbonate. In the second phase, WBI was begun one hour after lithium ingestion, and 10 L of polyethylene glycol solution were administered over five hours. Serum samples were collected every half hour for six hours, every hour for an additional six hours, and then every 24 hours for as long as 72 hours after ingestion. These samples were analyzed for lithium concentration. The area under the lithium serum concentration-versus-time curve was calculated for each phase. RESULTS: The average area under the lithium serum concentration-versus-time curve in the WBI phase was 67% +/- 11% less than that in the control phase (P less than .0005 using a two-tailed Student's t test). The mean serum lithium concentration was significantly decreased (P = .03) within one hour of beginning WBI. CONCLUSION: WBI is an effective treatment for acute ingestion of sustained-release lithium. We recommend it as the decontaminant procedure of choice in this situation.

Adolescent↗
PubMed1999

Lithium modulates desensitization of the glutamate receptor subtype gluR3 in Xenopus oocytes.

Analysis of splice variants and site-directed mutants of the AMPA receptor GluR3 expressed in Xenopus oocytes has shown that lithium produces a large potentiation of the GluR3 flop splice variant and suggested that lithium might inhibit rapid desensitization, which is characteristic of this receptor (Karkanias, N. and Papke, R., Subtype-specific effects of lithium on glutamate receptor function. J. Neurophysiol., 81 (1999) 1506-1512). We now show that mutation of the 769R/ G desensitization site (Lomeli, H.M.J., Melcher, T., Hoger, T., Geiger, J.R., Kuner, T., Monyer, H., Higuchi, M.B.A. and Seeburg, P.H, Control of kinetic properties of AMPA receptor channels by nuclear RNA editing. Science, 9(266) (1994) 1709-1713) greatly attenuates the lithium-induced potentiation of GluR3. Additionally, experiments with the non-desensitizing site-directed mutant GluR3(L507Y) (Stern-Bach, Y., Russo, S., Neuman, M. and Rosenmund, C., A point mutation in the glutamate binding site blocks desensitization of AMPA receptors. Neuron, 21 (1998) 907-918) further confirms that lithium enhances GluR3 responses by reducing desensitization, since lithium's effects are reversed in this mutant. Lithium's effects on GluR3 desensitization are distinct from the effects of aniracetam on desensitization. Specifically, aniracetam, which potentiates wild-type AMPA receptors, is ineffective on the non-desensitizing GluR3(L507Y) mutant, but has synergistic effects with lithium on wild-type receptors.

Animals↗