Chronic Lithium Treatment Research Articles

Chronic lithium treatment up-regulates cell surface Na V1.7 sodium channels via inhibition of glycogen synthase kinase-3 in adrenal chromaffin cells: Enhancement of Na + influx, Ca 2+ influx and catecholamine secretion after lithium withdrawal

In cultured bovine adrenal chromaffin cells expressing Na V1.7 isoform of voltage-dependent Na + channels, we have previously reported that lithium chloride (LiCl) inhibits function of Na + channels independent of glycogen synthase kinase-3 (GSK-3) (Yanagita et al., 2007). Here, we further examined the effects of chronic lithium treatment on Na + channels. LiCl treatment (1–30 mM, ≥12 h) increased cell surface [ 3H]saxitoxin ([ 3H]STX) binding by ∼32% without altering the affinity of [ 3H]STX binding. This increase was prevented by cycloheximide and actinomycin D. SB216763 and SB415286 (GSK-3 inhibitors) also increased cell surface [ 3H]STX binding by ∼31%. Simultaneous treatment with LiCl and SB216763 or SB415286 did not produce an increased effect on [ 3H]STX binding compared with either treatment alone. LiCl increased Na + channel α-subunit mRNA level by 32% at 24 h. LiCl accelerated α-subunit gene transcription by 35% without altering α-subunit mRNA stability. In LiCl-treated cells, LiCl inhibited veratridine-induced 22Na + influx as in untreated cells. However, washout of LiCl after chronic treatment enhanced veratridine-induced 22Na + influx, 45Ca 2+ influx and catecholamine secretion by ∼30%. Washout of LiCl after 24 h treatment shifted concentration–response curve of veratridine upon 22Na + influx upward, without altering its EC 50 value. Ptychodiscus brevis toxin-3 allosterically enhanced veratridine-induced 22Na + influx by two-fold in untreated and LiCl-treated cells. Whole-cell patch-clamp analysis indicated that I– V curve and steady-state inactivation/activation curves were comparable between untreated and LiCl-treated cells. Thus, GSK-3 inhibition by LiCl up-regulated cell surface Na V1.7 via acceleration of α-subunit gene transcription, enhancing veratridine-induced Na + influx, Ca 2+ influx and catecholamine secretion.

Differential modulation of intracellular Ca2+ responses in B lymphoblasts by mood stabilizers

Irregularities of intracellular calcium (Ca2+) homeostasis have been implicated in the pathophysiology of bipolar disorder (BD). Findings that chronic ex-vivo treatment with lithium modifies lysophosphatidic acid (LPA)-stimulated Ca2+ responses in B lymphoblast cell lines (BLCLs) from BD-I patients and healthy controls, and differentially decreases levels of the type-3 canonical transient receptor potential Ca2+-permeable channel in BLCLs from BD-I patients, support the view that the amelioration of these abnormalities is important in the therapeutic action of lithium. To determine whether other clinically efficacious mood stabilizers share these effects, LPA (100 mum)- and thapsigargin (TG, 200 nm)-stimulated Ca2+ responses were determined in BLCLs from BD-I patients and healthy controls treated acutely (24 h) and chronically (7 d) ex vivo with therapeutically relevant concentrations of lithium (0.75 mm), valproate (0.5 mm), lamotrigine (15 mum) or respective vehicles. Chronic treatment with valproate significantly attenuated LPA-stimulated Ca2+ responses ([downward arrow]8%: F's=9.1-9.4, d.f.=1, 9, p's<0.05) compared to vehicle in BLCLs from BD-I patients and healthy controls, similar to chronic lithium treatment ([downward arrow]8%: F=6.2, d.f.=1, 21, p<0.05), but also attenuated TG-evoked Ca2+ responses ([downward arrow]10% to [downward arrow]19%: F's=5.5-15.5, d.f.=1, 12, p's<0.05). However, chronic lamotrigine treatment did not affect LPA- or TG-stimulated Ca2+ responses. These results suggest that chronic lithium and valproate treatments act differently from lamotrigine in respect of modulation of receptor- and/or capacitance-mediated Ca2+ flux. These differential effects on Ca2+ responses may be relevant to the distinctive clinical profiles of these mood stabilizers.

Chronic lithium treatment decreases NG2 cell proliferation in rat dentate hilus, amygdala and corpus callosum

An increasing number of investigations suggest volumetric changes and glial pathology in several brain regions of patients with bipolar disorder. Lithium, used in the treatment of this disorder, has been reported to be neuroprotective and increase brain volume. Here we investigate the effect of lithium on the proliferation and survival of glial cells positive for the chondroitin sulphate proteoglycan NG2 (NG2 cells); a continuously dividing cell type implicated in remyelination and suggested to be involved in regulation of neuronal signaling and axonal outgrowth. Adult male rats were treated with lithium for four weeks and injected with the proliferation marker bromodeoxyuridine (BrdU) before or at the end of the treatment period. Immunohistochemical analysis of brain sections was performed to estimate the number of newly born (BrdU-labeled) NG2 cells and oligodendrocytes in hippocampus, basolateral nuclei of amygdala and corpus callosum. Lithium significantly decreased the proliferation of NG2 cells in dentate hilus of hippocampus, amygdala and corpus callosum, but not in the molecular layer or the cornu ammonis (CA) regions of hippocampus. The effect was more pronounced in the corpus callosum. No effect of lithium on the survival of newborn cells or the number of newly generated oligodendrocytes could be detected. Our results demonstrate that in both white and gray matter brain regions implicated in the pathophysiology of bipolar disorder, chronic lithium treatment significantly decreases the proliferation rate of NG2 cells; the major proliferating cell type of the adult brain.

A role for nitrergic system in the antidepressant-like effects of chronic lithium treatment in the mouse forced swimming test

In the present study we evaluated the involvement of nitric oxide (NO) system in the antidepressant-like effects of chronic lithium administration in the mouse forced swimming test (FST). Administration of lithium chloride (300 mg/L in drinking water for 21 days) had no effect on the immobility of mice in the FST, whereas 600 mg/L lithium caused a significant ( P < 0.001) decrease in the immobility time compared with control animals. Administration of the NO synthase inhibitor N G-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg, daily for a week, i.p.) had no significant effect on the immobility time of either control or lithium (300 mg/L)-treated mice, whereas acute administration of non-effective dose of L-NAME (30 mg/kg, i.p.) caused a robust decrease ( P < 0.01) in the immobility time of lithium (300 mg/L)-treated animals in the FST. Moreover, chronic administration of low dose of the NO precursor L-arginine (200 mg/kg, daily for a week, i.p.) prevented ( P < 0.001) the antidepressant-like effects of lithium treatment (600 mg/L) in the FST. Acute treatment with L-arginine (200 mg/kg, i.p.) increased ( P < 0.05) the immobility time of lithium (600 mg/L)-treated mice in the FST. Chronic lithium treatment (600 mg/L but not 300 mg/L) caused a significant ( P < 0.05) decrease in the serum NO X levels in mice compared with controls. Our data suggested that the NO system could be involved in the antidepressant-like effect of chronic lithium treatment in the FST.

The influence of chronic lithium administration on deafferentation-induced cellular changes in the chick cochlear nucleus

The avian brainstem serves as a useful model system to address the question of how afferent activity influences viability of target neurons. Approximately 20–30% of neurons in the chick cochlear nucleus, nucleus magnocellularis (NM) die following deafferentation (i.e. deafness produced by cochlea removal). Previous studies have identified cellular events that occur within hours following cochlea removal, which are thought to lead to the ultimate death of NM neurons. We have recently shown that chronic lithium treatment increases neuronal survival following deafferentation. To assess where in the cell death cascade lithium is having its effect, we evaluated some of the early deafferentation-induced cellular changes in NM neurons. Lithium did not affect deafferentation-induced changes that occur across the entire population of NM neurons. There were still deafferentation-induced increases in intracellular calcium concentrations and early changes in the ribosomes, as indicated by Y10b immunolabeling. Lithium did, however, affect changes that are believed to be indicative of the subpopulation of NM neurons that will eventually die. Ribosomes recovered in all of the deafferented NM neurons (as assessed by Y10b labeling) by 10 h following cochlea removal in subjects pretreated with lithium, while a subpopulation of the NM neurons in saline-treated subjects showed dramatic reduction in Y10b labeling at that time. Lithium treatment also prevented the robust upregulation of b cell leukemia/lymphoma-2 (Bcl-2) mRNA that is observed in a subpopulation of deafferented NM neurons 6 h following cochlea removal.

Lithium may be useful in the prevention of Alzheimer’s disease in individuals at risk of presenile familial Alzheimer’s disease

Alzheimer's disease (AD) is the most common form of dementia among older people. Presenile familial AD (FAD) and sporadic Alzheimer's disease (SAD) have identical brain lesions, containing senile plaques with beta-amyloid (Abeta) peptide and neurofibrillary tangles formed by hyperphosphorylation of a microtubule-associated protein known as tau. However, FAD and SAD differ in onset and genetic transmission. Unlike SAD, presenile FAD is transmitted as a pure autosomal dominant trait. The authors suggest that lithium could be used for AD prevention, particularly in individuals at risk of presenile FAD, which has early onset. Evidence supporting this hypothesis suggests that lithium decreases Abeta peptide production and inhibits the activity of glycogen synthase kinase-3 which induces aggregation of tau protein into tangles, and tau hyperphosphorylation. Prevalence of AD is lower in patients with chronic lithium treatment, which also increases brain-derived neurotrophic factor activity, so might prevent onset in patients at risk for AD. Several considerations are suggested for prevention trials: the effect of lithium could be evaluated in young animal models that express presenile FAD mutant genes; the time, dose, duration and monitoring of lithium therapy are considered; early phenotypes could be monitored for treatment effect; and some other agents, like valproic acid, could also be candidates for prevention.

O1-04-06: Glycogen synthase kinase-3β and the p25 activator of cyclin-dependent kinase-5 regulate axoplasmic transport of mitochondria by increasing their stationary behavior

testing, a lithium chow diet was used. We also assessed the effect of the lithium diet on LTP of pyramidal cells in area CA1 of hippocampal slices, an area strongly implicated in the pathophysiology of Alzheimer’s disease. Socially housed rats were given continual access to lithium chow or to a control chow diet for four weeks prior to, and throughout all learning assessments. After four weeks access to their designated chow diet, rats began conditioning in the holeboard spatial discrimination or t-maze delayed alternation task. They immediately began conditioning in the opposite task once completing the first. This was then followed with social place-preference conditioning, after 24-hours isolation from their homecage social partner. Results: Results showed that chronic lithium magnified learning in all three paradigms, regardless of the reward received. Both food and social interaction supported enhanced learning. Furthermore, four weeks exposure to the lithium diet also enhanced LTP in area CA1 of hippocampal slices prepared from the rats fed with the lithium chow. This enhancement was shown under clinically relevant serum levels at the time of testing (0.70 0.03 mEq/l). Conclusions: These findings suggest that chronic lithium treatment may improve cognitive function in Alzheimer’s disease by enhancing mechanisms involved in basal learning and memory formation, such as hippocampal LTP.

O1-04-05: Chronic lithium treatment magnifies learning and enhances LTP in area CA1 of the hippocampus

O1-04-05: Chronic lithium treatment magnifies learning and enhances LTP in area CA1 of the hippocampus

Neuroprotective effect of chronic lithium treatment against hypoxia in specific brain regions with upregulation of cAMP response element binding protein and brain‐derived neurotrophic factor but not nerve growth factor: comparison with acute lithium treatment

We evaluated the neuroprotective effect of chronically or acutely administered lithium against hypoxia in several brain regions. Furthermore, we investigated the contribution of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and cAMP response element binding protein (CREB) to the neuroprotective effect of lithium. Brain slices were prepared from rats that had been treated chronically or acutely with lithium. The cerebral glucose metabolic rate (CMRglc) before and after hypoxia loading to brain slices was measured using the dynamic positron autoradiography technique with [(18)F]2-fluoro-2-deoxy-D-glucose. The changes of expression of proteins were investigated using Western blot analysis. Before hypoxia loading, the CMRglc did not differ between the lithium-treated and untreated groups. After hypoxia loading, the CMRglc of the untreated group was significantly lower than that before hypoxia loading. However, the CMRglc of the chronic lithium treatment group recovered in the frontal cortex, caudate putamen, hippocampus and cerebellum, but not in the thalamus. In contrast, the CMRglc of the acute lithium treatment group did not recover in any analyzed brain regions. After chronic lithium treatment, the levels of expression of BDNF and phospho-CREB were higher than those of untreated rats in the frontal cortex, but not in the thalamus. However, the expression of NGF did not change in the frontal cortex and thalamus. These results demonstrated that lithium was neuroprotective against hypoxia only after chronic treatment and only in specific brain regions, and that CREB and BDNF might contribute to this effect.

Elektroenzephalographische und psychoexperimentelle Untersuchungen mit Lithium an gesunden Probanden

In previous experiments with lithium on normal volunteers, in whom plasma levels of 0.8 mmol/l after acute and 0.5-0.6 mmol/l during steady state after two weeks of lithium administration were obtained, we found slight effects on the awake EEG and psychological performance tests which could be interpreted as a decrease in vigilance and activation. The present study was designed to replicate these results with slightly higher plasma levels: 1 mval/l (acute), an 0.7-0.9 mval/l during steady state, in normal subjects selected according to strict EEG criteria. Besides quantitative pharmaco-EEG, the Zerssen scale for mood (Bf-S) and psychosomatic complaints (B-L) were applied; furthermore, subjective time estimation, the digit symbol test, flicker fusion frequency, and the pursuit rotor test were performed. After acute administration only a slight increase in psychosomatic complaints and a tendency towards increase in xxx-power in the EEG could be observed. Under chronic lithium treatment a significant increase in xxx-power and decrease in flicker fusion frequency in comparison to placebo were found. Tendencies for a decrease in performance were obtained by the digit symbol test and by the pursuit rotor test. The subjective time estimation 17 seconds as well as mood and psychosomatic complaints as measured by Bf-S and B-L did not change. The results of this trial confirm that lithium has negative effects on vigilance and activation. However, despite of higher plasma levels, the changes found in comparison to placebo were slight and discrete. Thus, in the routine test battery designed to describe and classify acute effects of classic psychotropic drugs such as 10 mg diazepam, 75 mg chlorpromazinc, 75 mg imipramine, or 20 mg dextroamphetamine, lithium does not induce unambiguous effects. Other test models are required to demonstrate specific psychic effects of lithium. In this context, appropriate criteria for selection of lithium sensitive subjects play an important role.

Evidence for the involvement of the kainate receptor subunit GluR6 (GRIK2) in mediating behavioral displays related to behavioral symptoms of mania.

The glutamate receptor 6 (GluR6 or GRIK2, one of the kainate receptors) gene resides in a genetic linkage region (6q21) associated with bipolar disorder (BPD), but its function in affective regulation is unknown. Compared with wild-type (WT) and GluR5 knockout (KO) mice, GluR6 KO mice were more active in multiple tests and super responsive to amphetamine. In a battery of specific tests, GluR6 KO mice also exhibited less anxious or more risk-taking type behavior and less despair-type manifestations, and they also had more aggressive displays. Chronic treatment with lithium, a classic antimanic mood stabilizer, reduced hyperactivity, aggressive displays and some risk-taking type behavior in GluR6 KO mice. Hippocampal and prefrontal cortical membrane levels of GluR5 and KA-2 receptors were decreased in GluR6 KO mice, and chronic lithium treatment did not affect these decreases. The membrane levels of other glutamatergic receptors were not significantly altered by GluR6 ablation or chronic lithium treatment. Together, these biochemical and behavioral results suggest a unique role for GluR6 in controlling abnormalities related to the behavioral symptoms of mania, such as hyperactivity or psychomotor agitation, aggressiveness, driven or increased goal-directed pursuits, risk taking and supersensitivity to psychostimulants. Whether GluR6 perturbation is involved in the mood elevation or thought disturbance of mania and the cyclicity of BPD are unknown. The molecular mechanism underlying the behavioral effects of lithium in GluR6 KO mice remains to be elucidated.

The nonadrenergic noncholinergic-mediated relaxation of corpus cavernosum was impaired in chronic lithium-treated rats: Improvement with l-arginine

One-third of lithium-treated men complain from sexual dysfunction, although the exact mechanisms of which are not yet known. In this study we investigated the effect of chronic lithium (LiCl, 600 mg/l for 30 days) administration on the neurogenic relaxation of isolated rat corpus cavernosum. The corporal strips were precontracted with phenylephrine and electrical field stimulation (EFS) was applied to obtain relaxation. Relaxation to EFS was significantly ( P < 0.001) impaired in LiCl-treated rats. The nitric oxide (NO) synthase inhibitor N ω -nitro- l-arginine methyl ester ( l-NAME; 100 µM) inhibited the relaxation to EFS in both LiCl-treated and control rats. The NO precursor l-arginine, at per se noneffective concentration (0.1 mM), significantly ( P < 0.001) enhanced the EFS-induced relaxation of LiCl-treated corporal strips. The relaxation responses to the NO donor sodium nitroprusside were similar between two groups. These data demonstrate that chronic lithium treatment could impair the NO-mediated neurogenic relaxation of rat corpus cavernosum which could be prevented by l-arginine.

Rarely seen cardiotoxicity of lithium overdose: Complete heart block

Introduction Serious cardiac toxicity due to lithium toxicity is uncommon and generally only occurs in individuals with underlying heart disease. Cardiac impairment may result in dysrhythmias, including sinus bradycardia, sinoatrial block, and first-degree atrioventricular block. This paper describes a patient with complete AV block in the course of chronic lithium treatment. Case report Fifty-seven year-old female was brought into the emergency department (ED) due to altered mental status and malaise by ambulance from hospice. She had hypertension, type-II diabetes mellitus, and depression. The caregivers told that she had been fine yesterday, had taken regular medications (lysinopril, furosemid, acetyl salicylic acid, oral antidiabetic tablets and lithium (300 mg tb/day)). Her vital signs were; blood pressure: 70/45 mmHg, pulse: 37 bpm, respiratory rate: 22 bpm, and oxygen saturation 86%. She was confused and unresponsive to verbal stimulation. Her EKG revealed total atrioventricular block. Initial biochemical results were unremarkable except for a lithium level of 2.2 mmol/l (therapeutic range 0.5–0.8 mmol/l) and an increased creatinine of 2.11 mg/dl. A transvenous pacing electrode was introduced into the right ventricle, which allowed rapid restoration of haemodynamic and neurological status. Her neurologic examination was completely normal in the follow-up period and she was discharged without sequelae. Conclusion In conclusion, emergency physicians should bear in mind that complete AV block can ensue in the course of lithium toxicity and it is an entity that should be included in the differential diagnosis.

Functional MRI of Delayed Chronic Lithium Treatment in Rat Focal Cerebral Ischemia

The use of lithium as a neuroprotective agent has been demonstrated using various models in which improvements in infarct size, DNA damage, and neurological function were reported. We further investigated neurohemodynamic aspects of the treatment-associated recovery by assessing the therapeutic efficacy of delayed chronic lithium treatment using functional MRI. Ipsilesional functional MRI activations in the somatosensory cortex, acquired 2 weeks after the 90-minute transient middle cerebral artery occlusion, were compared between lithium- and saline-treated rats. Specifically, MRI signal changes based on blood oxygenation level dependence and functional cerebral blood volume responses were examined using electrical stimulation of forelimbs. Additional immunohistochemical assays were performed. The ratio of ipsilesional to contralesional blood oxygenation level dependence response magnitudes significantly improved with lithium treatments. In contrast, the increase of the functional cerebral blood volume response magnitude ratio was not statistically significant. Nonetheless, the lithium treatment induced significant enhancements of total functional MRI activation (defined as a product of activation volume and response magnitude) for both blood oxygenation level dependence and functional cerebral blood volume methods. Increased cerebral blood volume in periinfarct tissues suggests a possible stroke-induced vascular transformation in both saline- and lithium-treated rats; however, other MRI-derived vascular parameters (vascular size index and microvascular volume) and immunohistochemical staining (CD31, glia fibrillary-associated protein, and matrix metalloproteinase-9) may imply that the neoformation of vasculature was differently affected by the lithium treatment. The delayed chronic lithium treatment enhanced the blood oxygenation level dependence functional MRI response magnitude in the absence of neurological improvement and influenced vascular formation in poststroke animal models.

Chronic Lithium Salt Treatment Reduces CRE/CREB-Directed Gene Transcription and Reverses Its Upregulation by Chronic Psychosocial Stress in Transgenic Reporter Gene Mice

The molecular mechanism of action of the mood stabilizer lithium is assumed to involve changes in gene expression leading to neuronal adaptation. The transcription factor CREB (cAMP-responsive element binding protein) regulates the expression of many genes and has been implicated in important brain functions and the action of psychogenic agents. We here investigated the effect of lithium on cAMP-responsive element (CRE)/CREB-mediated gene transcription in the brain, using transgenic reporter mice that express the luciferase reporter gene under the control of four copies of the rat somatostatin gene promoter CRE. Chronic (21 days) but not acute (24 h) treatment with lithium (7.5 mmol/kg) significantly decreased CRE/CREB-directed gene expression in hippocampus, cortex, hypothalamus, and striatum to 60-70%, and likewise reduced CREB phosphorylation. As bipolar disorder is also considered as a stress-related disorder, the effect of lithium was determined in mice submitted to a paradigm for chronic psychosocial stress. As shown before, stress for 25 days significantly increased CRE/CREB-directed gene expression in several brain regions by 100-150%. Treatment of stressed mice with lithium decreased stress-induced CRE/CREB-directed gene expression to control levels in nearly all brain regions and likewise reduced CREB phosphorylation. Chronic lithium treatment induced beta-catenin accumulation and decreased cAMP levels, indicating an inhibitory effect of lithium on glycogen synthase kinase 3 and the adenylate cyclase/protein kinase A signalling cascade, which are known to modulate CREB activity. We here for the first time show that lithium regulates CRE/CREB-directed gene transcription in vivo and suggest CREB as a putative mediator of the neuronal adaptation after chronic lithium treatment.

The effect of mood stabilizer lithium on expression and activity of glutathione s-transferase isoenzymes

Chronic treatment with the mood stabilizer lithium is required to generate its mood stabilizing effect in the treatment of bipolar disorder. Our recent studies have shown that chronic lithium treatment increases mRNA and protein levels of the cytosolic glutathione s-transferase (GST) M1 isoenzyme. Cytosolic GST encompasses a family of detoxification enzymes that include four main classes: alpha (A), mu (M), pi (P) and theta (T). The purpose of this study is to examine the effect of lithium on GST isoenzymes that are expressed in brain, and determine the role of GST in the neuroprotective effects of lithium against oxidative stress. We found in primary cultured rat cerebral cortical cells that chronic lithium treatment not only increased GST M1 mRNA levels, but also increased GST M3, M5 and A4 mRNA levels. Chronic lithium treatment increased GST enzyme activity when 1-chloro-2, 4-dinitrobenzene and 4-hydroxynonenal were used as substrates. In addition, we found that chronic lithium treatment inhibited reactive oxygen metabolite H 2O 2-induced cell death and DNA fragmentation in primary cultured rat cerebral cortical cells, while GST inhibitor ethacrynic acid reduced the neuroprotective effect of lithium against H 2O 2-induced cell death and DNA fragmentation. Since GST conjugates glutathione, the major antioxidant in brain, with a variety of oxidized products to form nontoxic products, and plays an important role in cellular protection against oxidative stress, our findings suggest that lithium selectively targets GST isoenzymes in order to produce neuroprotective effects against oxidative stress.

Deciphering the lithium transcriptome: Microarray profiling of lithium-modulated gene expression in human neuronal cells

The mechanisms underlying lithium’s therapeutic efficacy in the chronic treatment of bipolar disorder are not clearly understood. Useful insights can be obtained by identifying genes that are differentially regulated during chronic lithium treatment. Toward this end, we have used microarray technology to identify mRNAs that are differentially expressed in a human neuronal cell line that has been continuously maintained in therapeutic levels of lithium for 33 days. Significantly, unlike other transcriptomes where predominantly rodent cells were used and a limited number of genes probed, we have used human cells probed with more extensive 44,000 gene microarrays. A total of 671 differentially regulated transcripts, after correcting for false discovery rates, were identified, of which 347 and 324, respectively, were found to be up- and downregulated. Peroxiredoxin 2 (PRDX2), an antioxidant enzyme, was the most upregulated while tribbles homolog 3 (TRB3), a pro-apoptotic protein, was the most downregulated, implying a beneficial effect of lithium on neuronal cells. Several of the most highly regulated genes are novel, uncharacterized and encode proteins of unknown function. Differentially expressed genes associated with phosphoinositide metabolism include those encoding phosphatidyl inositol 4-phosphate 5-kinase type II α (PIP5K2A), WD repeat domain, phosphoinositide interacting 1 protein (WIPI49), tribbles homolog 3 (TRB3) and sorting nexin 14 (SNX14). A protein interactome using some of the saliently regulated genes identified protein kinase C (PKC) as a major target for lithium action while a global analysis of all 671 differentially expressed genes identified the mitogen-activated protein kinase pathway as the most regulated. The list of highly regulated genes, besides encoding putative targets for antimanic agents, should prove useful in defining novel pathways, or to better understand the mechanisms, underlying the mood stabilization process.

Neurocognitive Impairment and Dementia in Mood Disorders

Neurocognitive Impairment and Dementia in Mood Disorders

Effect of chronic lithium treatment on D 2/3 autoreceptor regulation of dopaminergic function in the rat

Dysregulation of mesolimbic dopamine (DA) neurotransmission has been implicated in bipolar disorder. DA release in the nucleus accumbens is reduced in rats treated chronically with the mood stabiliser lithium, and this effect is maintained for 3 days after withdrawal from the lithium treatment. We tested whether this decrease in DA release is due to an increase in D 2/3 autoreceptor sensitivity. In vivo microdialysis studies showed that in the shell of the nucleus accumbens, dialysate DA was decreased following chronic lithium treatment and 3 days after withdrawal from lithium treatment. The elevation of dialysate DA induced by local blockade of the terminal D 2/3 receptor was reduced in both lithium treated and lithium withdrawn groups. In vitro electrophysiology studies showed that chronic lithium treatment (and lithium withdrawal) did not alter either basal firing rate of DA neurones in the ventral tegmental area, or somatodendritic D 2/3 autoreceptor-mediated inhibition of firing. D 2 mRNA expression in the ventral tegmental area was unchanged by lithium treatment and lithium withdrawal. Our data suggest that the decrease in dopamine release in the nucleus accumbens induced by chronic lithium treatment is not the result of increased terminal or somatodendritic autoreceptor sensitivity or decreased firing rate of DA neurones.

Chronic lithium treatment magnifies learning in rats

Recent electrophysiological work shows that chronic lithium treatment increases long-term potentiation (LTP) in neurons of the hippocampus, and LTP is thought to be the major neurophysiological basis for the development of learning and memory. This suggests that lithium might enhance learning and memory. Available studies have mainly assessed memory using aversive conditioning paradigms, but very little is available on the effect of lithium on learning. Since lithium may diminish anxiety or negative affect in adult rats, which would hinder aversive learning, the present study used three different positive reinforcement spatial cognitive tasks to determine whether chronic lithium affects learning. Each task differed in complexity, in the type of learning required, and in the reward received. For 4 weeks prior to, and throughout all learning assessments, rats had continual access to lithium chow or to a control chow diet. After 4 weeks’ access to their designated chow diet, rats began conditioning in the hole-board spatial discrimination or T-maze delayed alternation tasks in a counterbalanced fashion. They immediately began conditioning in the opposite task once completing the first. This was then followed with social place-preference conditioning, after 24-h isolation from their home-cage social partner. Chronic lithium increased learning in all three paradigms, regardless of the reward received. Indeed, both food and social interaction supported enhanced learning. Thus the learning effect was not merely due to an effect of lithium on food palatability. Importantly, clinically relevant serum lithium levels were evidenced at the time of testing. Lithium also marginally enhanced memory as well. Thus chronic lithium treatment may improve learning and memory in Alzheimer’s disease, and do so not only by blocking the formation of beta-amyloid and neurofibrillary tangles as suggested by previous research, but also by enhancing mechanisms involved in basal learning and memory formation, such as hippocampal synaptic plasticity.