Chronic Lithium Administration Research Articles

Patterns of ingestion of rats during chronic oral administration of lithium chloride

Chronic lithium administration to rodents is used to explore the potential neural mechanisms of mood stabilization, as well as to model the side effects of chronic lithium on multiple organ systems. Oral administration of lithium in the maintenance diet or drinking water is convenient, but lithium can acutely affect intake and it can mediate acquisition of conditioned taste aversions (CTA). We compared ad libitum food and fluid intake by male rats with LiCl or NaCl solutions as their sole source of fluid across 20 days, with a commonly used dosage of LiCl (24 mM: 1 g / L LiCl). To quantify the pattern of intake, rats were housed in cages equipped with lickometers to detect licks and infrared photobeams to detect food access with 6-s resolution. To determine if rats formed a CTA to LiCl, they were subsequently tested with access to NaCl. Rats showed an immediate avoidance of the LiCl solution, as seen on the first day of access by an increased latency to initiate drinking and a decreased size of drinking bouts. Rats showed a differential response to LiCl vs. NaCl after as few as 5 licks. Chronic consumption of LiCl solution led to significantly decreased food and fluid intake compared to baseline, with concomitant weight loss. The decreased intake was realized by marked changes in the pattern of drinking and feeding bouts: a decrease in per-lick volume and a decrease in licks per drinking bout, and an increase in feeding bout duration resulting in an overall decrease in eating rate. Conversely, chronic NaCl access led to an increase in drinking bout number and licks/bout. The avoidance of LiCl was likely a combination of toxic effects of ingested LiCl and rapid acquisition of a learned aversion to the taste of LiCl, as shown by an extinguishable generalized aversion to NaCl solution during subsequent NaCl test days. The marked effect of chronic oral LiCl on ingestion may impact the oral dosing of lithium as well as the rat's metabolic status.

Effects of lithium on locomotor activity and circadian rhythm of honey bees

Lithium has been considered a potential acaricidal agent against the honey bee (Apis mellifera) parasite Varroa. It is known that lithium suppresses elevated activity and regulates circadian rhythms and light response when administered to humans as a primary therapeutic chemical for bipolar disorder and to other bipolar syndrome model organisms, given the crucial role of timing in the bee's foraging activity and the alternating sunlight vs dark colony environment bees are exposed, we explored the influence of lithium on locomotor activity (LMA) and circadian rhythm of honey bees. We conducted acute and chronic lithium administration experiments, altering light conditions and lithium doses to assess LMA and circadian rhythm changes. We fed bees one time 10 μl sucrose solution with 0, 50, 150, and 450 mM LiCl in the acute application experiment and 0, 1, 5, and 10 mmol/kg LiCl ad libitum in bee candy in the chronic application experiment. Both acute and chronic lithium treatments significantly decreased the induced LMA under constant light. Chronic lithium treatment disrupted circadian rhythmicity in constant darkness. The circadian period was lengthened by lithium treatment under constant light. We discuss the results in the context of Varroa control and lithium's effect on bipolar disorder.

P-Tau Dephosphorylation Measurement on the Basis of Biomimetic Electrochemical-Polymerized Thin Film Modified Eqcm

Alzheimer’s disease (AD) is characterized by the abnormal protein deposit in the brain, as a most general neurodegenerative disorder in senior. Microtubule-associated tau protein was regarded as a critical biomarker for AD in recent years due to its post-translational modification, especially hyper-phosphorylated tau protein, which would render the protein aggregation and result in neuron degeneration and paired helical filaments (PHF) formation [1]. Unbalanced activities between kinase and phosphatase are the main reason of tau protein hyper-phosphorylation, including overexpression of kinase. Research has recorded that kinases inhibitor would reverse the hyper-phosphorylation induced pathology, showing the possible therapeutic strategy with adjusting the amount of phosphorylated sites. However, this indirect method is insufficient to reverse the neurofibrillary tangle and PHF aggregation [2]. A highly effective method of reversing hyper-phosphorylation need to be investigated. Furthermore, to control the phosphorylation of tau protein, a material with good interaction with biomolecules is required.In this study, polyaniline (PANI), as one of organic conducting polymers [3], was selected due to its fascinating properties and unparalleled multifunction, including good interaction with proteins, controllable electrical conductivity, ideal stability during electrochemical reactions, and changeable nanostructures, could meet above demands and offer further more bio-applications [4]. Through the electrochemical reaction-driven exchange of ions during oxidation and reduction, PANI mimics change in functional biological organs [5] and plays a key role to create a state-of-the-art biomimetic hippocampus.A new in vitro experimental architecture was developed based on electrical quartz crystal microbalance (EQCM). First, tau protein was adsorbed on PANI-modified electrodes by electrostatic interaction to mimic captured process on the hippocampus. Then, both the constant-potential method (current-time curve) and Cyclic Voltammetry (CV) were introduced to investigate the electrochemically-driven dephosphorylation-related process and mechanism following the found optimal potential and stimulation time.As the result, the feasibility of electrochemically-driven dephosphorylation was confirmed. By establishing the relationship between resonant frequency and mass change, this hippocampus-inspired biomimetic polymeric EQCM electrode could detect a trace amount of phosphate and whole protein adsorbed and desorbed to explore the possibility of a non-invasive therapeutic strategy for AD.[1]Alonso, A. D. C., Grundke-Iqbal, I., & Iqbal, K. "Alzheimer's disease hyperphosphorylated tau sequesters normal tau into tangles of filaments and disassembles microtubules," Nature medicine, 2(7), 783-787. (1996).[2]Engel, T., Goñi‐Oliver, P., Lucas, J. J., Avila, J., & Hernández, F., "Chronic lithium administration to FTDP-17 tau and GSK‐3β overexpressing mice prevents tau hyperphosphorylation and neurofibrillary tangle formation, but pre-formed neurofibrillary tangles do not revert," Journal of neurochemistry, 99(6), 1445-1455. (2006).[3]Higgins, M. J., Molino, P. J., Yue, Z., & Wallace, G. G. (2012). Organic conducting polymer–protein interactions. Chemistry of Materials, 24(5), 828-839.[4]Huang, L., Hu, J., Lang, L., Wang, X., Zhang, P., Jing, X., ... & Wei, Y. (2007). Synthesis and characterization of electroactive and biodegradable ABA block copolymer of polylactide and aniline pentamer. Biomaterials, 28(10), 1741-1751.[5] Higgins, M. J., Molino, P. J., Yue, Z., & Wallace, G. G. (2012). Organic conducting polymer–protein interactions. Chemistry of Materials, 24(5), 828-839. Figure 1

Differential expression profile between amygdala and blood during chronic lithium treatment in a rat model of depression – a pilot study

Lithium is a mood stabilizer widely used in the pharmacotherapy of bipolar disorder and treatment‑resistant depression. Taking into account dysregulated inflammatory activity in depression and the immunomodulatory role of lithium, we hypothesized that genes associated with inflammatory responses may be potential biomarkers of lithium action. We aimed to compare gene expression changes between the brain and the periphery after chronic lithium administration in an animal model of depression. Depressive behavior was induced by chronic mild stress protocol for 4 weeks. After 2 weeks, rats started to receive lithium (study group) or water (reference group). The control group were rats not exposed to stress. Amygdala, hippocampus, frontal cortex and peripheral blood were analyzed using whole transcriptome expression microarrays. Changes were confirmed with qPCR and ELISA assay. After 2 weeks of lithium administration, we observed significant changes in gene expression between amygdala and peripheral blood. Logistic regression analysis determined Alox15 expression as a predictor of lithium status, as its expression was tissue‑specific and increased in amygdala and decreased in blood. Analysis of serum ALOX15 protein revealed its upregulation after two‑week lithium administration. Our study suggests that lithium may have therapeutic potential in depressive behaviors. These results indicate immunomodulatory effect of lithium and that Alox15 may be a new potential marker of chronic lithium treatment.

Differential expression profile between amygdala and blood during chronic lithium treatment in a rat model of depression - a pilot study.

Lithium is a mood stabilizer widely used in the pharmacotherapy of bipolar disorder and treatment‑resistant depression. Taking into account dysregulated inflammatory activity in depression and the immunomodulatory role of lithium, we hypothesized that genes associated with inflammatory responses may be potential biomarkers of lithium action. We aimed to compare gene expression changes between the brain and the periphery after chronic lithium administration in an animal model of depression. Depressive behavior was induced by chronic mild stress protocol for 4 weeks. After 2 weeks, rats started to receive lithium (study group) or water (reference group). The control group were rats not exposed to stress. Amygdala, hippocampus, frontal cortex and peripheral blood were analyzed using whole transcriptome expression microarrays. Changes were confirmed with qPCR and ELISA assay. After 2 weeks of lithium administration, we observed significant changes in gene expression between amygdala and peripheral blood. Logistic regression analysis determined Alox15 expression as a predictor of lithium status, as its expression was tissue‑specific and increased in amygdala and decreased in blood. Analysis of serum ALOX15 protein revealed its upregulation after two‑week lithium administration. Our study suggests that lithium may have therapeutic potential in depressive behaviors. These results indicate immunomodulatory effect of lithium and that Alox15 may be a new potential marker of chronic lithium treatment.

Regulation of sensorimotor gating via Disc1/Huntingtin-mediated Bdnf transport in the cortico-striatal circuit.

Sensorimotor information processing underlies normal cognitive and behavioral traits and has classically been evaluated through prepulse inhibition (PPI) of a startle reflex. PPI is a behavioral dimension deregulated in several neurological and psychiatric disorders, yet the mechanisms underlying the cross-diagnostic nature of PPI deficits across these conditions remain to be understood. To identify circuitry mechanisms for PPI, we performed circuitry recording over the prefrontal cortex and striatum, two brain regions previously implicated in PPI, using wild-type (WT) mice compared to Disc1-locus-impairment (LI) mice, a model representing neuropsychiatric conditions. We demonstrated that the corticostriatal projection regulates neurophysiological responses during the PPI testing in WT, whereas these circuitry responses were disrupted in Disc1-LI mice. Because our biochemical analyses revealed attenuated brain-derived neurotrophic factor (Bdnf) transport along the corticostriatal circuit in Disc1-LI mice, we investigated the potential role of Bdnf in this circuitry for regulation of PPI. Virus-mediated delivery of Bdnf into the striatum rescued PPI deficits in Disc1-LI mice. Pharmacologically augmenting Bdnf transport by chronic lithium administration, partly via phosphorylation of Huntingtin (Htt) serine-421 and its integration into the motor machinery, restored striatal Bdnf levels and rescued PPI deficits in Disc1-LI mice. Furthermore, reducing the cortical Bdnf expression negated this rescuing effect of lithium, confirming the key role of Bdnf in lithium-mediated PPI rescuing. Collectively, the data suggest that striatal Bdnf supply, collaboratively regulated by Htt and Disc1 along the corticostriatal circuit, is involved in sensorimotor gating, highlighting the utility of dimensional approach in investigating pathophysiological mechanisms across neuropsychiatric disorders.

Chronic lithium administration in a mouse model for Krabbe disease.

Krabbe disease (KD; or globoid cell leukodystrophy) is an autosomal recessive lysosomal storage disorder caused by deficiency of the galactosylceramidase (GALC) enzyme. No cure is currently available for KD. Clinical applied treatments are supportive only. Recently, we demonstrated that two differently acting autophagy inducers (lithium and rapamycin) can improve some KD hallmarks in‐vitro, laying the foundation for their in‐vivo pre‐clinical testing. Here, we test lithium carbonate in‐vivo, in the spontaneous mouse model for KD, the Twitcher (TWI) mouse. The drug is administered ad libitum via drinking water (600 mg/L) starting from post natal day 20. We longitudinally monitor the mouse motor performance through the grip strength, the hanging wire and the rotarod tests, and a set of biochemical parameters related to the KD pathogenesis [i.e., GALC enzymatic activity, psychosine (PSY) accumulation and astrogliosis]. Additionally, we investigate the expression of some crucial markers related to the two pathways that could be altered by lithium: the autophagy and the β‐catenin‐dependent pathways. Results demonstrate that lithium has not a significant rescue effect on the TWI phenotype, although it can slightly and transiently improves muscle strength. We also show that lithium, with this administration protocol, is unable to stimulate autophagy in the TWI mice central nervous system, whereas results suggest that it can restore the β‐catenin activation status in the TWI sciatic nerve. Overall, these data provide intriguing inputs for further evaluations of lithium treatment in TWI mice.

Lithium toxicity. A case report

IntroductionLithium is widely used in the treatment of the bipolar disorder. Once introduced, it is necessary to carry out an adequate control of the therapeutic range, since it is potentially toxic, and can affect various organs.ObjectivesTo present the case of a patient suffering from lithium poisoning and to review the symptoms of lithium poisoning.MethodsA descriptive study of a clinical case and review of the literatureResults49-year-old woman, married. Diagnosed with bipolar disorder. She went to the emergency room due to a low level of consciousness, kidney failure, trembling of the limbs, hyperthermia and leukocytosis. In the last two weeks, the patient has reduced her intake of food, not water, finding herself more and more shaky and less reactive. Lithium in blood at admission 1.71, so conventional dialysis was performed with a progressive decrease into 0.65. On examination, he is practically mutist, bradypsychia with a significant response latency. Clinical judgment: Accidental lithium poisoning.ConclusionsThe primary site of toxicity is the central nervous system and clinical manifestations vary from asymptomatic supratherapeutic drug concentrations to clinical toxicity such as confusion, ataxia, or seizures. Severe lithium neurotoxicity occurs almost exclusively in the context of chronic therapeutic administration of lithium and rarely results from acute ingestion of lithium, even in patients currently taking lithium. As such it is an iatrogenic illness, occurring in patients who have identifiable clinical risk factors: nephrogenic diabetes insipidus, older age, abnormal thyroid function and impaired renal function.DisclosureNo significant relationships.

Chronic Lithium Neurotoxicity Presenting as Dementia: A Case Report

<h3>Introduction</h3> Treatment with Lithium can be associated with a continuum of neurological side effects, ranging from benign tremors to early reversible lithium neurotoxicity, to chronic irreversible lithium neurotoxicity. Among chronic systemic adverse effects of Lithium, neurotoxicity has been reported to be the most common, followed by renal and cardiovascular toxicity (Sunn et al). Data on lithium toxicity in the elderly is limited but available data indicates that adverse effects occur more commonly in the context of chronic therapeutic administration of lithium rather than instances of overdose (Oakly et al). EEG and nerve conduction studies show notable changes that correlate with the increased duration of Li therapy (Fountoulakis et al). Older adults are more susceptible to side effects even with "normal" lithium levels for reasons such as declined renal function, reduced volume of distribution, medical comorbidities, concomitant medications, and drug interactions. Here we present a case of an elderly man with chronic lithium neurotoxicity associated with significant cognitive changes and severe disability. This will be followed by a review of literature of chronic lithium neurotoxicity in the geriatric population. <h3>Methods</h3> Case of Mr. A: We present the case of a 72 year old man who presented to the Memory Clinic with a diagnosis of Alzheimer's disease (AD) since the age of 55. His presentation was also notable for progressive aphasia and he had a PEG tube placed for feeding. His cognitive deficits were most significant in the domains of executive and visuospatial functioning, memory, and language. Physical exam findings were notable for mild left hand tremor, difficulties with balance, slow gait with short steps and a decreased arm swing, limited vertical gaze, and dysphagia. He was independent with his ADLs but dependent on IADLs due to aforementioned cognitive and physical findings. Other psychiatric diagnoses included Bipolar Disorder, Substance Use Disorder in remission. At the time of his evaluation, Mr. A had been on Lithium for over 20 years with records for the past three years showing therapeutic levels .5-1.1mmol/L. Although the patient had been previously diagnosed with AD, his relatively stable neuropsychological profile over the last 15 years called the diagnosis of AD into question and this was confirmed by negative amyloid imaging. The patient had yearly therapeutic levels of Lithium until his wife's concern for further insidious cognitive decline in the domains of language and memory, along with worsening gait and tremor prompted checking a Lithium level which was 1.8. Patient was subsequently weaned off Lithium over several months. At the time of this writing this abstract, Mr. A's cognition and motor function are significantly improving, to the extent of no longer requiring PEG for dysphagia. Electronic searches of The Cochrane Central Register of Controlled Trials and the standard bibliographic databases PubMed, MEDLINE, EMBASE, and PsycINFO will be performed for papers focusing on chronic lithium neurotoxicity in older adults. Keywords include "lithium" and "adverse effects" or neurotoxicity" or "neurological manifestations." Original research, case reports, and reviews will be included. Data focusing on older adults will be extracted and presented. <h3>Results</h3> Initial search for literature focusing on chronic lithium neurotoxicity yielded 4 papers. Data from these papers will be extracted. The range of neurological adverse effects, both physical and mental, will be described. This will be followed by a discussion of risk and precipitating factors for lithium neurotoxicity. Association with lithium doses, duration of treatment, and serum lithium levels will be elucidated. Lastly, diagnosis and treatment considerations will be highlighted. <h3>Conclusions</h3> Chronic lithium Neurotoxicity is more common in the elderly and can occur at normal to even sub therapeutic doses. It is imperative to have an optimal index of suspicion if an individual on chronic lithium therapy presents with cognitive deficits. <h3>Funding</h3> not applicable

Transcriptome Changes in Three Brain Regions during Chronic Lithium Administration in the Rat Models of Mania and Depression.

Lithium has been the most important mood stabilizer used for the treatment of bipolar disorder and prophylaxis of manic and depressive episodes. Despite long use in clinical practice, the exact molecular mechanisms of lithium are still not well identified. Previous experimental studies produced inconsistent results due to different duration of lithium treatment and using animals without manic-like or depressive-like symptoms. Therefore, we aimed to analyze the gene expression profile in three brain regions (amygdala, frontal cortex and hippocampus) in the rat model of mania and depression during chronic lithium administration (2 and 4 weeks). Behavioral changes were verified by the forced swim test, open field test and elevated maze test. After the experiment, nucleic acid was extracted from the frontal cortex, hippocampus and amygdala. Gene expression profile was done using SurePrint G3 Rat Gene Expression whole transcriptome microarrays. Data were analyzed using Gene Spring 14.9 software. We found that chronic lithium treatment significantly influenced gene expression profile in both mania and depression models. In manic rats, chronic lithium treatment significantly influenced the expression of the genes enriched in olfactory and taste transduction pathway and long non-coding RNAs in all three brain regions. We report here for the first time that genes regulating olfactory and taste receptor pathways and long non-coding RNAs may be targeted by chronic lithium treatment in the animal model of mania.

Beneficial effects of low-dose lithium on cognitive ability and pathological alteration of Alzheimer's disease transgenic mice model.

Lithium has been shown to delay the progression of Alzheimer's disease to reduce the prevalence of dementia. However, its narrow therapeutic index and numerous toxic effects at conventional dosage limited its long-term use to older subjects. Here, we tested the effect of low-dose lithium on cognitive impairment and pathology alterations in a mouse model of Alzheimer's disease, the amyloid precursor protein/presenilin-1 (APP/PS1) transgenic mouse. We found that both chronic and acute administration of lithium dose-dependently increased in blood and brain tissues. Long-term administration of low-dose lithium does not affect the body weight of APP/PS1 mice, but can significantly improve spatial memory of APP/PS1 mice. Pathologically, it also reduced β-amyloid plague and p-tau levels. Therefore, our results show that long-term low-dose lithium can ameliorate cognitive dysfunction and pathological alterations of Alzheimer's disease transgenic mice, and provide a theoretical basis for the further application of low-dose lithium in Alzheimer's disease clinical treatment.

Mesocortical BDNF signaling mediates antidepressive-like effects of lithium.

Lithium has been used to treat major depressive disorder, yet the neural circuit mechanisms underlying this therapeutic effect remain unknown. Here, we demonstrated that the ventral tegmental area (VTA) dopamine (DA) neurons that project to the medial prefrontal cortex (mPFC), but not to nucleus accumbens (NAc), contributed to the antidepressive-like effects of lithium. Projection-specific electrophysiological recordings revealed that high concentrations of lithium increased firing rates in mPFC-, but not NAc-, projecting VTA DA neurons in mice treated with chronic unpredictable mild stress (CMS). In parallel, chronic administration of high-dose lithium in CMS mice restored the firing properties of mPFC-projecting DA neurons, and also rescued CMS-induced depressive-like behaviors. Nevertheless, chronic lithium treatment was insufficient to change the basal firing rates in NAc-projecting VTA DA neurons. Furthermore, chemogenetic activation of mPFC-, but not NAc-, projecting VTA DA neurons mimicked the antidepressive-like effects of lithium in CMS mice. Chemogenetic downregulation of VTA-mPFC DA neurons' firing activity abolished the antidepressive-like effects of lithium in CMS mice. Finally, we found that the antidepressant-like effects induced by high-dose lithium were mediated by BNDF signaling in the mesocortical DA circuit. Together, these results demonstrated the role of mesocortical DA projection in antidepressive-like effects of lithium and established a circuit foundation for lithium-based antidepressive treatment.

Questioning the predictive validity of the amphetamine-induced hyperactivity model for screening mood stabilizing drugs

Animal models are critical for the study of disease mechanisms and the screening of potential novel treatments. In the context of bipolar disorder, amphetamine-induced hyperactivity (AIH) is a frequently used screening model for antimanic effects. Yet, the utility of screening models depends on their predictive (or pharmacological) validity and it is expected that such models will respond to effective treatments. Lithium is the prototypic mood stabilizer but previous data regarding the effects of lithium in the AIH model are not clear and most data comes from studies using acute lithium administration that is not relevant to the therapeutic regimen in patients. To evaluate the pharmacological validity of AIH as a model for mania-like behavior we tested the interaction between chronic oral administration of lithium and amphetamine in ICR (CD-1®) mice and in black Swiss mice. We conducted 4 different experiments where chronic lithium was followed by an acute injection of amphetamine and one experiment where chronic amphetamine was combined with chronic lithium. The results show that amphetamine result in hyperactivity (experiments 1–4) and that lithium has no effects. Moreover, chronic amphetamine (experiment 5) result in sensitization that is not attenuated by lithium. The results clearly show that the predictive validity of the AIH model in ICR or black Swiss mice is problematic and possibly cast doubt on the utilization of the AIH as a screening model for novel mood stabilizers in other strains of mice.

Genetic Deletion of P2Y2 Receptor Offers Long-Term (5 Months) Protection Against Lithium-Induced Polyuria, Natriuresis, Kaliuresis, and Collecting Duct Remodeling and Cell Proliferation.

Chronic lithium administration for the treatment of bipolar disorder leads to nephrogenic diabetes insipidus (NDI), characterized by polyuria, natriuresis, kaliuresis, and collecting duct remodeling and cell proliferation among other features. Previously, using a 2-week lithium-induced NDI model, we reported that P2Y2 receptor (R) knockout mice are significantly resistant to polyuria, natriuresis, kaliuresis, and decrease in AQP2 protein abundance in the kidney relative to wild type mice. Here we show this protection is long-lasting, and is also associated with significant amelioration of lithium-induced collecting duct remodeling and cell proliferation. Age-matched wild type and knockout mice were fed regular (n = 5/genotype) or lithium-added (40 mmol/kg chow; n = 10/genotype) diet for 5 months and euthanized. Water intake, urine output and osmolality were monitored once in every month. Salt blocks were provided to mice on lithium-diet to prevent sodium loss. At the end of 5 months mice were euthanized and serum and kidney samples were analyzed. There was a steady increase in lithium-induced polyuria, natriuresis and kaliuresis in wild type mice over the 5-month period. Increases in these urinary parameters were very low in lithium-fed knockout mice, resulting in significantly widening differences between the wild type and knockout mice. Terminal AQP2 and NKCC2 protein abundances in the kidney were significantly higher in lithium-fed knockout vs. wild type mice. There were no significant differences in terminal serum lithium or sodium levels between the wild type and knockout mice. Confocal immunofluorescence microscopy revealed that lithium-induced marked remodeling of collecting duct with significantly increased proportion of [H+]-ATPase-positive intercalated cells and decreased proportion of AQP2-positive principal cells in the wild type, but not in knockout mice. Lithium-induced collecting duct cell proliferation (indicated by Ki67 labeling), was significantly lower in knockout vs. wild type mice. This is the first piece of evidence that purinergic signaling is potentially involved in lithium-induced collecting duct remodeling and cell proliferation. Our results demonstrate that genetic deletion of P2Y2-R protects against the key structural and functional alterations in Li-induced NDI, and underscore the potential utility of targeting this receptor for the treatment of NDI in bipolar patients on chronic lithium therapy.

Altered Sensory Phenomena Experienced in Bipolar Disorder.

Altered Sensory Phenomena Experienced in Bipolar Disorder.

Face and predictive validity of the ClockΔ19 mouse as an animal model for bipolar disorder: a systematic review.

Mice carrying the circadian locomotor output cycles Kaput delta 19 N-ethyl-N-nitrosoure (ENU) mutation (ClockΔ19) are used as an animal model for bipolar disorder (BD). We aimed to systematically review the face validity (phenotypical and pathophysiological resemblance with BD) and predictive validity (responsiveness to treatments used in BD) of this model in adherence with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. We carried out a systematic search of the databases PubMed and Embase, combining search terms covering BD and ClockΔ19. The 22 studies included in the review (from a total of 1281 identified records) show that the behavioral phenotype of the ClockΔ19 mouse is characterized by hyperactivity, decreased anxiety-like behavior, decreased depression-like behavior and increased preference for rewarding stimuli. This is highly consistent with mania in humans. Moreover, the ClockΔ19 mouse exhibits rapid mood cycling (a manic-like phenotype during the day followed by euthymia at night), which is consistent with BD. Chronic administration of lithium, a drug with well established mood-stabilizing effect in humans with BD, reverses the majority of the bipolar-like traits and most of the neurobiological abnormalities observed in the ClockΔ19 mouse. In conclusion, the ClockΔ19 mouse has substantial face validity as an animal model for BD. The predictive validity of the ClockΔ19 mouse has primarily been investigated via studies using lithium challenge. Therefore, further studies are needed to determine how the ClockΔ19 mouse responds to other mood-stabilizing treatments of BD such as valproate, lamotrigine, carbamazepine, oxcarbazepine, antipsychotics, electroconvulsive therapy and various light interventions.

Polyuria: A Pathophysiologic Approach

Polyuria: A Pathophysiologic Approach

Genetic Deletion of Akt3 Induces an Endophenotype Reminiscent of Psychiatric Manifestations in Mice.

The protein kinase B (PKB/Akt), found in three distinctive isoforms (PKBα/Akt1, PKBβ/Akt2, PKBγ/Akt3), is implicated in a variety of cellular processes such as cell development, growth and survival. Although Akt3 is the most expressed isoform in the brain, its role in cerebral functions is still unclear. In the present study, we investigated the behavioral, electrophysiological and biochemical consequences of Akt3 deletion in mice. Motor abilities, spatial navigation, recognition memory and LTP are intact in the Akt3 knockout (KO) mice. However, the prepulse inhibition, three-chamber social, forced swim, tail suspension, open field, elevated plus maze and light-dark transition tests revealed an endophenotype reminiscent of psychiatric manifestations such as schizophrenia, anxiety and depression. Biochemical investigations revealed that Akt3 deletion was associated with reduced levels of phosphorylated GSK3α/β at serine 21/9 in several brain regions, although Akt1 and Akt2 levels were unaffected. Notably, chronic administration of lithium, a mood stabilizer, restored the decreased phosphorylated GSK3α/β levels and rescued the depressive and anxiety-like behaviors in the Akt3 KO mice. Collectively, our data suggest that Akt3 might be a critical molecule underlying psychiatric-related behaviors in mice.

Blood metabolomics analysis identifies abnormalities in the citric acid cycle, urea cycle, and amino acid metabolism in bipolar disorder

BackgroundBipolar disorder (BD) is a severe and debilitating psychiatric disorder. However, the precise biological basis remains unknown, hampering the search for novel biomarkers. We performed a metabolomics analysis to discover novel peripheral biomarkers for BD. MethodsWe quantified serum levels of 116 metabolites in mood-stabilized male BD patients (n=54) and age-matched male healthy controls (n=39). ResultsAfter multivariate logistic regression, serum levels of pyruvate, N-acetylglutamic acid, α-ketoglutarate, and arginine were significantly higher in BD patients than in healthy controls. Conversely, serum levels of β-alanine, and serine were significantly lower in BD patients than in healthy controls. Chronic (4-weeks) administration of lithium or valproic acid to adult male rats did not alter serum levels of pyruvate, N-acetylglutamic acid, β-alanine, serine, or arginine, but lithium administration significantly increased serum levels of α-ketoglutarate. ConclusionsThe metabolomics analysis demonstrated altered serum levels of pyruvate, N-acetylglutamic acid, β-alanine, serine, and arginine in BD patients. General significanceThe present findings suggest that abnormalities in the citric acid cycle, urea cycle, and amino acid metabolism play a role in the pathogenesis of BD.

Neuroprotective Effects of Lithium in Patients with Bipolar Disorder

Background: Lithium has been considered the "gold standard" in the management of bipolar disorder, being the agent compared with "new mood stabilizer". It has also shown effect in the reduction of suicidal thoughts. Among the known mechanisms of action of lithium it has been described the inhibition in inositol monophosphatase (IMP) as resulting in non-competitive inhibition of IMP, resulting in a decrease of inositol in the central nervous system leading to a decrease in the synthesis of inositol triphosphate, affecting the transmission and translation of signals. Added to this, lithium inhibits kinase glycogen synthase enzyme (GSK) 3-β; it’s regulated by different signaling pathways and its dysfunction has been related to the pathophysiology of mood disorders, schizophrenia, diabetes and Alzheimer's disease. The neuroprotective effects have been shown of lithium in preclinical studies. The chronic administration of lithium enhances the proliferation of progenitor cells and inhibits cell loss induced by glutamate and glucocorticoids. In addition to a neurotrophic and neuroprotective role, lithium can also exert beneficial effect through its ability to improve mitochondrial function. Objective: Our aim was to explore the current information on the findings relating to lithium as a substance with possible neuroprotector effect in patients with diagnosis of bipolar disorder, as well as other conditions. Method: We performed a literature review regarding the use of Lithium and its potential neuroprotective effect in patients Conclusion: There is enough evidence that lithium may slow the progression of neurocognitive impairment in long term treatment patients, suggesting a potential use for the treatment of neurodegenerative diseases. Keywords: Bipolar disorder, mood disorders, lithium, neuroprotection, neurodegenerative, mood stabilizer.