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PubMed1975

Modifications by lithium of behavioral responses to methamphetamine and tetrabenazine.

Different groups of mice were injected s.c. daily with lithium chloride in three doses(0.52, 1.58 and 4.72meg/kg) or with saline for a period of 3 weeks. Lithium administered acutely or chronically did not affect spontaneous locomotor activities. However, methamphetamine-induced hyper-locomotor activities were inhibited in the lithium groups as compared with those in the saline group, while the hyper-locomotor activities induced by tetrabenazine in the nialamide-pretreated animals were reduced to some extent but not significantly by lithium. Tetrabenazine brought about an initial transient increase followed by a decrease of spontaneous locomotor activities in the lithium groups, whereas it induced only a decrease of the activities in the saline group. In addition, jumping and vertical jumping behaviors, which were not observed in the saline group, occurred 30-60 min after tetrabenazine in the lithium groups. These effects of lithium tended to increase with an increase of the doses administered and with a prolongation of its daily administration. The results demonstrate that lithium modifies behavioral responses to methamphetamine and tetrabenazine.

Animals↗
PubMed1976

Lithium effects on serum calcium, magnesium and phosphate, in rats.

LiCl was injected daily to rats in a dose of 3 mmol/kg. The rats were, in different experiments, unoperated rats, parathyroidectomized rats and thyroparathyroidectomized rats. Serum concentrations of calcium, magnesium, and phosphate were measured 2 h after a lithium injection. Serum calcium was unaffected by lithium in unoperated and parathyroidectomized rats. In thyroparathyroidectomized rats lithium increased the serum calcium concentration. Serum magnesium was increased by lithium in all 3 groups of rats. Serum phosphate was slightly decreased by lithium in all 3 groups of rats. It is concluded that lithium increases both serum calcium and magnesium, but in the intact organism only a slight or no increase in serum calcium is seem after lithium due to physiological control mechanisms. After removal of the calcitonin producing C-cells in the thyroid gland the organism is unable to produce a fast decrease in serum calcium, and lithium is then able to increase the serum calcium concentration.

Animals↗
PubMed1984

Lithium does not interact with haloperidol in the dopaminergic pathways of the rat brain.

Prophylactic treatment with lithium has been reported to prevent haloperidol-induced dopamine (DA) receptor supersensitivity. If such an effect exists, then lithium may be useful in the prevention of tardive dyskinesia, which is related to the neuroleptic-induced DA hyperfunction. In the experiments reported here chronic lithium administration had no effect on DA synthesis or utilization in the nigrostriatal, mesolimbic, or mesocortical DA pathways in the rat brain. Similarly, lithium had no effect on the increase in DA metabolism induced by the acute administration of haloperidol. Also, chronic lithium treatment failed to modify the biochemical tolerance which developed after prolonged administration of the neuroleptic drug. Supersensitivity of the presynaptic DA receptors, which was induced by prolonged exposure to haloperidol, likewise was unaffected by prophylactic lithium treatment. We conclude that lithium does not affect changes in DA metabolism or receptor supersensitivity induced by haloperidol. These results do not support the use of lithium in neurological disorders that may be related to neuroleptic-induced DA receptor supersensitivity.

Animals↗
PubMed1979

Serotonergic function in mouse head twitches induced by lithium and reserpine.

We examined the relationship between lithium-induced head twitches and serotonergic neurons. Head twitches were elicited by combined treatment with lithium chloride (2 or 5 mEq/kg x 5, s.c. administered hourly) and rauwolfia alkaloids, i.e., reserpine (5 mg/kg, s.c.), tetrabenazine (20 mg/kg, s.c.), and syrosingopine (10 mg/kg, s.c.). Neither lithium nor the alkaloid alone induced the twitches; nor did combined administration of lithium with methamphetamine or p-chloroamphetamine. The head twitches induced by lithium in combination with reserpine were strongly inhibited by antiserotonin drugs, methysergide and cyproheptadine, and also by a serotonin synthesis inhibitor, p-chlorophenylalanine (PCPA), when administered between lithium and reserpine. When PCPA was administered before lithium for 3 days, the head twitches were potentiated. In addition, the head twitches were potentiated by a serotonin receptor stimulant, 5-methoxy-N,N-dimethyltryptamine. The results imply that lithium can induce head twitches in the presence of rauwolfia alkaloids and may exert its effect in part by acting on the serotonergic neuron system.

Acetylcholine↗
PubMed1982

Acute and chronic effects of lithium in therapeutically relevant concentrations on potassium uptake into astrocytes.

Potassium uptake into astrocytes in primary cultures was measured by the aid of 42K. Acute application of lithium in concentrations of 1 and 5 mM, but not 0.5 und 0.25 mM, exerted a significant inhibition of the potassium uptake rates. This effect is due to a partial impairment of the ouabain-sensitive part of the uptake into the cells caused by a lithium interaction with the extracellular K+-activated site of the Na+, K+-ATPase. After 14 days of exposure of the astrocytes to 1 mM lithium, the potassium uptake remained lower in the presence of lithium than in its absence. However, the cells had adjusted to the chronic presence of lithium by increasing their potassium uptake to such an extent that, during the exposure to 1 mM lithium, it was indistinguishable from that in cultures from the same batches grown in the absence of lithium and measured in the absence of this compound. The interference by lithium with potassium uptake into astrocytes may well be related to the inhibition of potassium clearance in the CNS described in the literature.

Astrocytes↗
PubMed1989

Lithium inhibition of protein kinase C activation-induced serotonin release.

The effect of lithium on protein kinase C (PKC) stimulation-induced serotonin and norepinephrine release facilitation was examined in [3H]5-HT and [3H]NE preloaded superfused rat brain slices. The facilitation of K+-evoked [3H]5-HT release elicited by the active phorbol esters PMA and PDBu was inhibited by 4 mM but not by 1 mM in vitro lithium. In experiments performed in cortical, hippocampal and hypothalamic slices obtained from animals treated for 3 weeks with lithium-containing diet, PMA-induced facilitation of K+-elicited [3H]5-HT release was found to be inhibited by the treatment (serum lithium less than 1 mEq/l). Basal [3H]5-HT efflux, which was enhanced by PMA in control animals, was also inhibited by lithium treatment. In parietal cortical slices, PMA elicited increase in K+-evoked [3H]NE release was prevented in slices taken from lithium-treated (3 weeks) animals. Lithium treatment did not affect the activity and distribution of protein kinase C in cortical tissue. However, 3 weeks of treatment reduced the PMA-induced translocation of the enzyme. These results suggest that lithium treatment interferes with serotonin and norepinephrine release facilitation which results from the stimulation of PKC by phorbol esters. These actions of the ion may be mediated by its ability to inhibit PMA induced PKC translocation.

Animals↗
PubMed1990

Chronic lithium administration enhances serotonin release in the lateral hypothalamus but not in the hippocampus in rats. A microdialysis study.

Chronic administration of lithium displays therapeutic and prophylactic effects in bipolar affective disorders, but its mechanism of action remains unknown. Several studies in animals and humans strongly suggest that central serotonergic neurons might be involved in lithium effects. In the experiments reported here microdialysis with removable probes and high pressure liquid chromatography and electrochemical detection were used to assess the amphetamine-induced release of serotonin (5-HT) and the 5-hydroxy-indoleacetic acid (5-HIAA) levels in the perifornical hypothalamus (PFH) and hippocampus (HP) of freely moving rats before and after chronic lithium chloride administration (2 meq/kg, as intragastric daily injections for 14 days). The serum lithium levels were 0.66 +/- 0.08 meq/l. After lithium treatment, the amphetamine-induced 5-HT release was significantly enhanced in the PFH but not so in the HP. Basal levels of 5-HIAA in the control group decreased but remained unchanged in the lithium group in the PFH. No change of basal levels of 5-HIAA was observed in the HP. The effect of lithium on the PFH could be related to the improvement of the autonomic and cyclic symptoms of patients with manic depressive disorders undergoing lithium therapy.

Amphetamine↗
PubMed1993

Chronic lithium treatment enhances the postsynaptic 5-HT1A receptor-mediated 5-HT behavioral syndrome induced by 8-OH-DPAT in rats via catecholaminergic systems.

The effects of antimanic agents, including lithium, carbamazepine, clonazepam and zotepine, on the postsynaptic 5-HT1A receptor-mediated behavioral and hypothermic responses induced by 8-OH-DPAT in rats, and on [3H]8-OH-DPAT binding to 5-HT1A receptors in the rat hippocampus were examined. Treatment with lithium (3 mEq/kg, IP) for 14 days enhanced forepaw treading, one component of the 5-HT behavioral syndrome induced by 8-OH-DPAT, and this enhancement by lithium was abolished by catecholamine depletion with reserpine or alpha-methyl-p-tyrosine, but not by 5-HT depletion with p-chlorophenylalanine. These data suggest that lithium enhances 5-HT1A-mediated behavior via catecholaminergic systems. In contrast, chronic lithium treatment did not alter the hypothermic response to 8-OH-DPAT in untreated rats, as well as in rats treated with reserpine. These findings strengthen the suggestion that lithium has no direct influence on the postsynaptic 5-HT1A-mediated response. Other antimanic agents had no effect on either forepaw treading or hypothermia induced by 8-OH-DPAT. Radioligand binding studies using [3H]-8-OH-DPAT demonstrated that chronic lithium treatment, but not other antimanic agents, caused 5-HT1A receptor down-regulation in rat hippocampus. A discrepancy therefore exists between 5-HT1A receptor down-regulation and unaltered 5-HT1A-mediated behavioral and hypothermic responses in catecholamine-depleted rats after chronic lithium treatment.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1996

Chronic lithium attenuates dopamine D1-receptor mediated increases in acetylcholine release in rat frontal cortex.

The effects of chronic lithium treatment on methylphenidate-, D1 dopamine receptor agonist (A-77636)-, and tactile stimulation-induced increases in frontal cortical acetylcholine release were studied in the rat using in vivo brain microdialysis. Cortical acetylcholine release in control rats was maximally stimulated by methylphenidate (1.25 and 2.5 mg/kg) to 173% and 212% above baseline, respectively. The effect of methylphenidate (2.5 mg/kg) was blocked by pretreatment with the dopamine D1 receptor antagonist SCH 23390 (0.3 mg/kg). Chronic treatment with lithium chloride (3-4 weeks) produced plasma lithium concentrations of 0.45 +/- 0.02 meq/l. Chronic lithium significantly reduced increases in cortical acetylcholine release produced by methylphenidate. Stimulation of dopamine D1 receptors with the full D1 receptor agonist A-77636 (0.73 mg/kg) increased cortical acetylcholine release. Chronic lithium significantly reduced this effect of A-77636. In contrast, lithium failed to influence the increases of cortical acetylcholine release produced by tactile stimulation. These results suggest that while lithium does not influence normal, arousal-related increase in cortical acetylcholine release, this ion selectively attenuates dopamine mediated increases and/or abnormally large increases, which in the present circumstances were pharmacologically induced. The relevance of these findings to the antimanic actions of lithium is discussed.

Acetylcholine↗
PubMedDate not supplied

Clinical features and management of lithium poisoning.

Lithium salts, in particular the carbonate and citrate, were formerly in widespread use, forming part of alkaline salt mixtures which were used for treatment of the many disorders belonging to the uric acid diathesis. Among these disorders were mania, depression, acute mania, acute melancholia and periodic depression. Satisfactory prophylactic effects on periodic depression were directly claimed. Daily doses of 3 to 26 mmol of lithium were recommended as standards. Only slight or moderate symptoms of poisoning were reported in a very few cases during the period in question (1860 to 1930), when the popularity of these lithium-containing prophylactic drugs with a favourable therapeutic index was at its peak. Lithium intoxication was not a serious clinical problem until 1949 when Cade introduced his fortuitously effective, but nevertheless high, dosage regimen which was continued until signs of recovery from mania appeared. For the maintenance dose, Cade in principle recommended, but seldom adhered to, 17 mmol/day. Chronic lithium intoxication starts insidiously with silent affliction of the kidneys followed by 'prodromal' symptoms, and when moderate severity has been reached, an accelerating renal vicious circle with decreasing kidney function is imminent. After this point the chronic intoxication resembles acute intoxication. Active detoxification at this, or an earlier stage, leaves the patient with a good chance of recovery. At a later stage, with the occurrence of oliguria, semi-coma or coma, and latent convulsive movement, recovery is less certain. There is no specific antidote for the toxic effects of lithium. Haemodialysis is the most effective treatment for acute lithium poisoning. For patients with impaired, or potentially impaired renal function, peritoneal dialysis may be an alternative, but less effective, treatment. Forced diuresis demands unimpaired renal function, and is little more effective than withdrawal of treatment, supplemented with correction of water and electrolyte balance. Sodium overloading is not recommended. Patients on lithium prophylaxis are treated on an outpatient basis. Prevention of intoxication depends on cooperation between patient and clinician, and possibly on the use of smaller, low risk dosages in most patients.

Humans↗
PubMed2000

Effects of lithium on platelet membrane phosphoinositides in bipolar disorder patients: a pilot study.

RATIONALE: In vitro and in vivo animal studies suggest that the intracellular phosphatidylinositol (PI) pathway is an important target for the effects of lithium. OBJECTIVES: We conducted a preliminary study to examine the in vivo effects of lithium treatment on platelet membrane phosphoinositides in bipolar disorder subjects, in an attempt to examine further the hypothesis that lithium has significant in vivo effects on the PI pathway in these patients. METHODS: We quantitated PI, phosphatidylinositol-4-phosphate (PIP), and phosphatidylinositol-4,5-bisphosphate (PIP2) in platelet membranes of seven subjects (five male, two female; mean age= 27.9+/-5.7 years), initially while they were unmedicated, and a second time after at least 21 days of lithium treatment (mean+/-SD=28.7+/-7.1 days). RESULTS: The mean+/-SD values for PI were 5.63+/-2.25% and 5.21+/-1.06%; for PIP 0.68+/-0.20% and 0.55+/-0.11%; and for PIP2 0.60+/-0.21% and 0.38+/-0.15%, before and after lithium treatment, respectively. The decrease in PIP2 values after lithium treatment was statistically significant (Wilcoxon signed ranks test, Z=-2.37, P=0.02). CONCLUSION: This longitudinal study suggests that therapeutic doses of lithium significantly decrease platelet membrane PIP2 levels in vivo in bipolar disorder subjects, which may be related to lithium's mechanism of action in bipolar disorder.

Adult↗
PubMed2003

Lithium in the acute treatment of bipolar disorders-a stocktaking.

Before the rise of atypical antipsychotics, lithium used to be the most frequently investigated substance in the acute treatment of bipolar disorders, although studies are not always of the highest methodological standard. Due to the doubt about a sufficient efficacy of lithium expressed in recent years from various sides, and the simultaneous availability of newer treatment alternatives, this paper attempts to make a critical stocktaking of our knowledge about lithium in the acute treatment of bipolar disorders. Aspects concerning the changed disorder concept through the broadening of the bipolar spectrum, together with the available results from controlled and open studies with lithium, are presented and appraised. This shows that lithium should still be seen as an essential, but not the only corner stone in the differentiated treatment of bipolar patients. Provided that it is taken reliably and well-tolerated, lithium represents a first choice treatment, particularly for a classical course of manic-depressive illness (Bipolar I disorder), especially for mild to moderate manic syndromes.However, as antidepressive treatment, lithium should rather not be applied as a monotherapy, particularly in severe bipolar depression, since with the new generation of antidepressants and anticonvulsants well-tolerated and very effective alternatives are available. In combination treatment, lithium should be applied particularly when it has already shown good prophylactic efficacy and/or in patients for whom a high suicide risk must be presumed.

Antimanic Agents↗
PubMed2006

Non-convulsive status epilepticus during lithium treatment at therapeutic doses.

The purpose of this study is to report the case of a patient with normal lithium serum levels who developed non-convulsive status epilepticus (NCSE). A 52-year-old woman with bipolar disorder type I (DSM-IV) treated with lithium experienced bradypsychism and episodes of confusion and spatial disorientation without signs or symptoms of lithium intoxication. Lithium serum levels were in the normal range. A brain MR scan was negative; the electroencephalogram (EEG) revealed a background 3-4 Hz delta rhythm and diffuse spike discharges. Prompt EEG and clinical response to intravenous diazepam therapy was observed. Based on these findings, a diagnosis of NCSE was made and lithium therapy was withdrawn, resulting in symptom remission and EEG normalization. The treatment was resumed after two months to test the correlation between NCSE and lithium therapy. Resumption of therapeutic range lithium induced the same clinical symptoms and EEG patterns; the therapy was thus definitively discontinued. The present data-signalling the temporal correlation of clinical and EEG changes with drug administration and withdrawal-suggest that even in the therapeutic range lithium treatment may trigger NCSE onset in predisposed subjects.

Bipolar Disorder↗
PubMed1995

Dietary potassium effects on lithium concentration and toxicity in hamsters.

Lithium can be toxic in rodents and human patients at concentrations within the therapeutic range for treatment of affective disorders. Diet containing supplemental potassium reduced lithium-induced weight loss in hamsters following daily injections of 3 mmol LiCl/kg for 7-10 days. Potassium supplementation also decreased lithium concentrations in peripheral tissues; but not in brain, after repeated lithium administration. Repeated lithium injection lowered the concentration of potassium in peripheral tissues, but tissue potassium was not restored by dietary potassium supplementation. Toxic effects of single injections of 1-10 mmol LiCl/kg were unaffected by dietary potassium. Lithium concentrations in plasma, brain, or peripheral tissues 6-hr after injection of 5 mmol LiCl/kg were also not altered by potassium diet. These data suggest that interactions between lithium and potassium diet differ in peripheral tissues compared to the central nervous system, and after acute versus chronic lithium administration.

Animals↗
PubMed1989

Dorsalization of mesoderm induction by lithium.

Lithium dorsalizes the body plan of Xenopus embryos when administered at the 32-cell stage (K.R. Kao and R.P. Elinson, 1988, Dev. Biol. 127, 64-77). In this paper, we have attempted to determine the effects of lithium on mesoderm induction, in order to localize the target of action of lithium. In the 32-cell embryo, the vegetal-most tier 4 cells are able to induce dorsal development in the overlying, equatorial tier 3 cells (R.L. Gimlich and J.C. Gerhart, 1984, Dev. Biol. 104, 117-130). Our experiments show that microinjection of lithium into either tier 3 or tier 4 cells of ultraviolet-irradiated, dorsoanterior-deficient embryos rescues normal development. Lineage tracer studies show that only tier 3-injected cells contribute progeny to dorsal axial structures while tier 4-injected cells contribute progeny to endoderm. Sandwich explants between animal caps and ventral vegetal cells cause induction of large amounts of muscle in the explants if either caps or vegetal cells are pretreated with lithium. Similarly, fibroblast growth factor-mediated mesoderm induction is also modified by lithium so that muscle is induced instead of ventral mesoderm. We conclude that lithium dorsalizes the response of animal cells to mesoderm induction signals, while not acting directly as a mesoderm inducer itself. The target of action of lithium is likely the third tier of cells of the 32-cell embryo.

Animals↗
PubMed1981

Lithium treatment decreases blood pressure in genetically hypertensive rats.

Chronic lithium treatment was examined for effects on the blood pressure of spontaneously hypertensive rats (SHRs). Treated rats were allowed continuous access to a pelleted lithium diet (1.7 g LiCl (40 mmol)/kg diet) for 21 days. Control SHRs were fed a similar diet lacking the lithium. Two groups of control rats were examined. One group had continuous access to control diet (ad lib controls); a second group was pair-fed a daily ration of control diet such that their mean body weight remained similar to the lithium treated group (pair-fed controls). Heart rate, systolic, diastolic and mean arterial blood pressures were recorded on day 21 from freely moving conscious rats. Systolic, diastolic and mean arterial blood pressure was significantly lower (approximately 15 mmHg) in the lithium treated SHRs as compared to either control group; the pair-fed and ad lib controls had similar blood pressures at the end of the treatment periods. Heart rate was increased in the lithium treated animals. All rats gained weight during the 21 days of treatment, although the lithium treated group and the pair-fed control group did not gain weight as much or as rapidly as the control group that had continuous access to control diet. Plasma and brain lithium levels were in the moderate range (0.3--0.4 meq/l) and all rats appeared healthy at the end of the experiment. These results suggest that chronic treatment may have clinically relevant effects on blood pressure.

Animals↗
PubMed1986

Effects of bipolar affective disorder and lithium administration on the cholinergic system in human blood.

Several processes relating to the cholinergic system that are present in human blood were measured in samples obtained from patients with bipolar affective disorder, both before and during treatment with lithium, and from controls. The biochemical measurements include RBC and plasma choline concentrations, the kinetics of RBC choline uptake, plasma non-specific cholinesterase and RBC and plasma acetylcholinesterase. The RBC choline level is increased and the Vmax of the RBC choline uptake system is decreased in samples from lithium-free bipolar patients during manic episodes. There are no differences from control in the plasma choline levels or in the acetylcholinesterase enzyme activities in blood samples from the lithium-free or lithium-treated patients. Plasma non-specific cholinesterase is below control levels in all patients. Lithium treatment increases the RBC choline concentration to more than ten-times control levels and reduces the Vmax and the affinity for choline of the RBC choline transport system. In vitro addition of lithium does not replicate the effects of in vivo administration of lithium. Possible mechanisms for these effects of lithium are discussed.

Acetylcholinesterase↗
PubMed1986

Behavioral and receptor binding studies of phencyclidine (PCP) and lithium interaction in the rat.

Three groups of female Sprague-Dawley rats (n = 4) were conditioned to drink water during a daily 2 hr session. The water was then changed to a solution of 1.0 mg/ml lithium chloride producing average doses between 62.9 and 72.1 mg/kg/day for Groups I and II. These rats were challenged with 4 mg/kg PCP i.p. before and during lithium treatment. Group I was tested for spontaneous locomotor activity in the open field apparatus. Lithium alone did not affect activity. After 1, 2, and 3 weeks of chronic lithium, PCP-induced activity increased 2.1, 1.7, and 2.8 fold, respectively, relative to PCP-induced activity during limited access to water only. Whole brain homogenates from Group II, after one week of chronic lithium, were used for receptor binding experiments using [3H] PCP; Group III served as water controls. The Kd (nM +/- S.E.M.) was not different in untreated (146.39 +/- 18.95) and lithium-treated (181.22 +/- 14.35) rats. The Bmax (pmole/mg protein +/- S.E.M.), however, was increased 48% (p less than 0.01) from 1.50 +/- 0.08 to 2.22 +/- 0.10 after lithium. These preliminary results suggest that chronic administration of lithium modifies the behavioral effects of PCP possibly via alterations at the receptor level.

Animals↗