Endophenotypes in Bipolar Disorder

American Journal of Medical Genetics. May, 2002  |  Pubmed ID: 11992561

The search for genes in bipolar disorder has provided numerous genetic loci that have been linked to susceptibility to developing the disorder. However, because of the genetic heterogeneity inherent in bipolar disorder, additional strategies may need to be employed to fully dissect the genetic underpinnings. One such strategy involves reducing complex behaviors into their component parts (endophenotypes). Abnormal neurophysiological, biochemical, endocrinological, neuroanatomical, cognitive, and neuropsychological findings are characteristics that often accompany psychiatric illness. It is possible that some of these may eventually be useful in subdefining complex genetic disorders, allowing for improvements in diagnostic assessment, genetic linkage studies, and development of animal models. Findings in patients with bipolar disorder that may eventually be useful as endophenotypes include abnormal regulation of circadian rhythms (the sleep/wake cycle, hormonal rhythms, etc.), response to sleep deprivation, P300 event-related potentials, behavioral responses to psychostimulants and other medications, response to cholinergics, increase in white matter hyperintensities (WHIs), and biochemical observations in peripheral mononuclear cells. Targeting circadian rhythm abnormalities may be a particularly useful strategy because circadian cycles appear to be an inherent evolutionarily conserved function in all organisms and have been implicated in the pathophysiology of bipolar disorder. Furthermore, lithium has been shown to regulate circadian cycles in diverse species, including humans, possibly through inhibition of glycogen synthase kinase 3-beta (GSK-3beta), a known target of lithium.

Signaling Networks in the Pathophysiology and Treatment of Mood Disorders

Journal of Psychosomatic Research. Aug, 2002  |  Pubmed ID: 12169343

Over the past decade, the focus of research into the pathophysiology of mood disorders (bipolar disorder and unipolar depression in particular) has shifted from an interest in the biogenic amines to an emphasis on second messenger systems within cells. Second messenger systems rely on cell membrane receptors to relay information from the extracellular environment to the interior of the cell. Within the cell, this information is processed and altered, eventually to the point where gene and protein expression patterns are changed. There is a preponderance of evidence implicating second messenger systems and their primary contact with the extracellular environment, G proteins, in the pathophysiology of mood disorders. After an introduction to G proteins and second messenger pathways, this review focuses on the evidence implicating G proteins and two second messenger systems-the adenylate cyclase (cyclic adenosine monophosphate, cAMP) and phosphoinositide (protein kinase C, PKC) intracellular signaling cascades-in the pathophysiology and treatment of bipolar disorder and unipolar depression. Emerging evidence implicates changes in cellular resiliency, neuroplasticity and additional cellular pathways in the pathophysiology of mood disorders. The systems discussed within this review have been implicated in neuroplastic processes and in modulation of many other cellular pathways, making them likely candidates for mediators of these findings.

The Wnt Signaling Pathway in Bipolar Disorder

The Neuroscientist : a Review Journal Bringing Neurobiology, Neurology and Psychiatry. Oct, 2002  |  Pubmed ID: 12374432

The Wnt signaling pathway is a highly conserved pathway critical for proper embryonic development. However, recent evidence suggests that this pathway and one of its key enzymes, glycogen synthase kinase 3beta, may play important roles in regulating synaptic plasticity, cell survival, and circadian rhythms in the mature CNS-all of which have been implicated in the pathophysiology and treatment of bipolar disorder. Furthermore, two structurally highly dissimilar medications used to treat bipolar disorder, lithium and valproic acid, exert effects on components of the Wnt signaling pathway. Together, these data suggest that the Wnt signaling pathway may play an important role in the treatment of bipolar disorder. Here, the authors review the modulation of the Wnt/GSK-3beta signaling pathway by mood-stabilizing agents, focusing on two therapeutically relevant aspects: neuroprotection and modulation of circadian rhythms. The future development of selective GSK-3beta inhibitors may have considerable utility not only for the treatment of bipolar disorder but also for a variety of classical neurodegenerative disorders.

Post-mortem Interval Effects on the Phosphorylation of Signaling Proteins

Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology. Jun, 2003  |  Pubmed ID: 12637955

Post-mortem brain tissue provides a unique opportunity to uncover the genes or proteins involved in the pathophysiology of neuropsychiatric disorders. Protein phosphorylation is a common protein modification within intracellular signaling pathways that affects the distribution and function of protein, and has been hypothesized to be of major importance in both the pathophysiology and treatment of major neuropsychiatric disorders. Thus, we were interested in ascertaining the stability of the phosphorylated forms of proteins that are involved in cellular signaling. Antibodies against phospho-tyrosine, phospho-threonine, and phospho-PKA substrates were used to examine the PMI effects on the general amounts of proteins in their phosphorylated form. Phospho-specific antibodies for ERK, JNK, RSK, CREB, and ATF-2 were used to test the effects of PMI on specific proteins whose functioning are known to be regulated markedly by phosphorylation. We found that PMI rapidly decreased the levels of proteins in their phosphorylated states and also decreased the total levels of certain proteins. The PMI effects were observed in the samples stored at both 4 degrees C and room temperature, in both frontal cortex and hippocampus. Thus, it appears that measurements (such as two-dimensional gel electrophoresis and functional assays) that rely on the phosphorylation state of proteins would be extremely sensitive to PMI.

The Endophenotype Concept in Psychiatry: Etymology and Strategic Intentions

The American Journal of Psychiatry. Apr, 2003  |  Pubmed ID: 12668349

Endophenotypes, measurable components unseen by the unaided eye along the pathway between disease and distal genotype, have emerged as an important concept in the study of complex neuropsychiatric diseases. An endophenotype may be neurophysiological, biochemical, endocrinological, neuroanatomical, cognitive, or neuropsychological (including configured self-report data) in nature. Endophenotypes represent simpler clues to genetic underpinnings than the disease syndrome itself, promoting the view that psychiatric diagnoses can be decomposed or deconstructed, which can result in more straightforward-and successful-genetic analysis. However, to be most useful, endophenotypes for psychiatric disorders must meet certain criteria, including association with a candidate gene or gene region, heritability that is inferred from relative risk for the disorder in relatives, and disease association parameters. In addition to furthering genetic analysis, endophenotypes can clarify classification and diagnosis and foster the development of animal models. The authors discuss the etymology and strategy behind the use of endophenotypes in neuropsychiatric research and, more generally, in research on other diseases with complex genetics.

Effects of a Glycogen Synthase Kinase-3 Inhibitor, Lithium, in Adenomatous Polyposis Coli Mutant Mice

Pharmacological Research : the Official Journal of the Italian Pharmacological Society. Jul, 2003  |  Pubmed ID: 12770514

Glycogen synthase kinase-3 (GSK-3) is an intermediary enzyme in various cellular pathways, and has been implicated in the pathophysiology and treatment of numerous diseases, including Alzheimer's disease, diabetes, and bipolar disorder. There is therefore in developing potent, selective GSK-3 inhibitors for the treatment of these devastating illnesses. A concern, however, is that the Wnt-signaling pathway-of which GSK-3 is an important intermediary molecule-has been implicated in many human cancers. It is thus of considerable importance to determine if GSK-3 inhibitors have tumorigenic potential in systems predisposed to developing tumors by virtue of mutations of the Wnt-signaling pathway. We therefore investigated the effects of a GSK-3 inhibitor, lithium, in a murine model predisposed to the formation of tumors due to activation of the Wnt pathway-the adenomatous polyposis coli (APC) multiple intestinal neoplasia (min) mouse. We found that 60 days of lithium treatment did not produce a significant increase in the number of tumors in these genetically predisposed mice. Lithium treatment resulted in a modest overall increase in the tumor size. The APC (min) mouse has previously been shown to be a robust indicator of tumorigenesis, with large increases in tumor number observed in response to a variety of agents; thus, our results suggest that lithium-and perhaps other inhibitors of GSK-3-pose a low risk for the development of cancers of the Wnt pathway. These results are consistent with the available epidemiological evidence that long-term lithium therapy does not increase cancer morbidity or mortality, but rather is associated with reduced overall mortality in bipolar disorder.

The Role of the Extracellular Signal-regulated Kinase Signaling Pathway in Mood Modulation

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. Aug, 2003  |  Pubmed ID: 12917364

The neurobiological underpinnings of mood modulation, molecular pathophysiology of manic-depressive illness, and therapeutic mechanism of mood stabilizers are largely unknown. The extracellular signal-regulated kinase (ERK) pathway is activated by neurotrophins and other neuroactive chemicals to produce their effects on neuronal differentiation, survival, regeneration, and structural and functional plasticity. We found that lithium and valproate, commonly used mood stabilizers for the treatment of manic-depressive illness, stimulated the ERK pathway in the rat hippocampus and frontal cortex. Both drugs increased the levels of activated phospho-ERK44/42, activated phospho-ribosomal protein S6 kinase-1 (RSK1) (a substrate of ERK), phospho-CREB (cAMP response element-binding protein) and phospho-B cell lymphoma protein-2 antagonist of cell death (substrates of RSK), and BDNF. Inhibiting the ERK pathway with the blood-brain barrier-penetrating mitogen-activated protein kinase (MAP kinase)/ERK kinase (MEK) kinase inhibitor SL327, but not with the nonblood-brain barrier-penetrating MEK inhibitor U0126, decreased immobility time and increased swimming time of rats in the forced-swim test. SL327, but not U0126, also increased locomotion time and distance traveled in a large open field. The behavioral changes in the open field were prevented with chronic lithium pretreatment. SL327-induced behavioral changes are qualitatively similar to the changes induced by amphetamine, a compound that induces relapse in remitted manic patients and mood elevation in normal subjects. These data suggest that the ERK pathway may mediate the antimanic effects of mood stabilizers.

Signal Transduction and Genes-to-behaviors Pathways in Psychiatric Diseases

Science's STKE : Signal Transduction Knowledge Environment. Nov, 2003  |  Pubmed ID: 14600293

Although psychiatric diseases are among the most common and destructive of all human illnesses, the molecular and cellular mechanisms underlying their complex origins remain to be elucidated. Dysfunction of critical intracellular signaling pathways is very likely to be involved. This conclusion is based on a number of observations, including the short- and long-term cellular effects of psychiatric drugs; the critical role signaling pathways play in neurotransmitter, neuropeptide, and neurohormone communication; and the fact that signaling pathways are principle regulators of the diverse array of behavioral symptoms experienced by patients. The genomics era has brought to psychiatry an abundance of genetic linkage and candidate gene findings. The difficult task--now under way--is to discern the functional relevance of these results. Recent evidence suggests the involvement of the ubiquitous protein phosphatase 2B (calcineurin), a critical regulator of many signal transduction pathways, as a schizophrenia susceptibility gene. It is likely that genetic findings in severe psychiatric disorders will continue to implicate direct and indirect modulation of critical intracellular signaling pathways.

Glycogen Synthase Kinase-3: a Target for Novel Bipolar Disorder Treatments

The Journal of Clinical Psychiatry. Jan, 2004  |  Pubmed ID: 14744163

The enzyme glycogen synthase kinase-3 (GSK-3) is a direct target of lithium. While originally recognized as an important molecule in a limited number of cellular processes, with unclear significance for the treatment of bipolar disorder, recent evidence suggests it has critically important cellular functions in the adult brain. GSK-3 has an essential role in a number of signaling pathways and regulates the function of a diverse number of proteins, notably transcription factors and cytoskeletal elements. The most important functions of the enzyme in regard to bipolar disorder may be critical effects on cellular resilience and neuronal plasticity. There is tremendous interest in GSK-3 inhibitors as novel therapeutic agents, and selective, small-molecule compounds are rapidly being developed for a broad range of other maladies including diabetes, Alzheimer's disease, stroke, and inflammatory conditions. In this perspectives article, we provide an overview of the molecular targets of lithium, focusing on GSK-3-regulated signaling pathways and the important functions of GSK-3 that may have relevance for the treatment of bipolar disorder. We conclude with a discussion of the GSK-3 inhibitors furthest in development and the clinical trials that may emerge.

The Molecular Medicine Revolution and Psychiatry: Bridging the Gap Between Basic Neuroscience Research and Clinical Psychiatry

The Journal of Clinical Psychiatry. May, 2004  |  Pubmed ID: 15163244

Recent years have witnessed a considerable increase in both fundamental knowledge and available experimental techniques in the basic neurosciences. Unfortunately, clinical translation of these findings vis-à-vis a direct benefit to patients who suffer from psychiatric diseases has not been as rapid. It is likely that this will change in the near future. We discuss some of the knowledge and expanding techniques of basic neuroscience, focusing on those that may be most promising regarding the future impact of the current molecular medicine revolution in psychiatry. Some of the more exciting findings (basic mechanisms, techniques, and clinical methodologies) that are expected to have a major impact on both our understanding of the biological underpinnings of psychiatric diseases and the development of novel and/or improved therapies include genetics, epigenetics, transcriptomics/proteomics, neuroimaging, animal models, and improved psychiatric endophenotypes.

Mood Stabilizer Valproate Promotes ERK Pathway-dependent Cortical Neuronal Growth and Neurogenesis

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. Jul, 2004  |  Pubmed ID: 15269271

Manic-depressive illness has been conceptualized as a neurochemical illness. However, brain imaging and postmortem studies reveal gray-matter reductions, as well as neuronal and glial atrophy and loss in discrete brain regions of manic-depressive patients. The roles of such cerebral morphological deficits in the neuropathophysiology and therapeutic mechanisms of manic-depressive illness are unknown. Valproate (2-propylpentanoate) is a commonly used mood stabilizer. The ERK (extracellular signal-regulated kinase) pathway is used by neurotrophic factors to regulate neurogenesis, neurite outgrowth, and neuronal survival. We found that chronic treatment of rats with valproate increased levels of activated phospho-ERK44/42 in neurons of the anterior cingulate, a region in which we found valproate-induced increases in expression of an ERK pathway-regulated gene, bcl-2. Valproate time and concentration dependently increased activated phospho-ERK44/42 and phospho-RSK1 (ribosomal S6 kinase 1) levels in cultured cortical cells. These increases were attenuated by Raf and MEK (mitogen-activated protein kinase/ERK kinase) inhibitors. Although valproate affects the functions of GSK-3 (glycogen synthase kinase-3) and histone deacetylase (HDAC), its effects on the ERK pathway were not fully mimicked by selective inhibitors of GSK-3 or HDAC. Similar to neurotrophic factors, valproate enhanced ERK pathway-dependent cortical neuronal growth. Valproate also promoted neural stem cell proliferation-maturation (neurogenesis), demonstrated by bromodeoxyuridine (BrdU) incorporation and double staining of BrdU with nestin, Tuj1, or the neuronal nuclei marker NeuN (neuronal-specific nuclear protein). Chronic treatment with valproate enhanced neurogenesis in the dentate gyrus of the hippocampus. Together, these data demonstrate that valproate activates the ERK pathway and induces ERK pathway-mediated neurotrophic actions. This cascade of events provides a potential mechanism whereby mood stabilizers alleviate cerebral morphometric deficits associated with manic-depressive illness.

AR-A014418, a Selective GSK-3 Inhibitor, Produces Antidepressant-like Effects in the Forced Swim Test

The International Journal of Neuropsychopharmacology / Official Scientific Journal of the Collegium Internationale Neuropsychopharmacologicum (CINP). Dec, 2004  |  Pubmed ID: 15315719

The mechanism by which lithium exerts either its anti-manic or antidepressant effects remains to be fully elucidated. Although lithium inhibits the enzyme glycogen synthase kinase-3 (GSK-3) at concentrations that are relevant for treatment of bipolar disorder, it is unclear whether GSK-3-related mechanisms are responsible for its therapeutic effects in the treatment of this disease. We report that AR-A014418 (a selective GSK-3 inhibitor) induces behavioural changes that are consistent with the effects of antidepressant medications. Subacute intraperitoneal injections of AR-A014418 reduced immobility time in rats exposed to the forced swim test, a well-established model for antidepressant efficacy. In addition, the specificity of this effect is supported by our finding that AR-A014418 decreased spontaneous as well as amphetamine-induced activity. Taken together, these data support the hypothesis that lithium may exert its antidepressant effects through inhibition of GSK-3, and that novel small-molecule GSK-3 inhibitors may be useful for the treatment of bipolar disorder and depression.

Molecular Effects of Lithium

Molecular Interventions. Oct, 2004  |  Pubmed ID: 15471909

Bipolar affective disorder is a common, severe, chronic, and often life-threatening illness, associated with other medical and psychiatric conditions (i.e., co-morbidity). The treatment of this devastating disorder was revolutionized by the discovery of lithium's antimanic effects over fifty years ago. Recent molecular and cellular biological studies have identified a number of unexpected targets for this monovalent cation, notably glycogen synthase kinase-3 and neurotrophic signaling cascades. These findings are leading to a reconceptualization of the biological underpinnings of bipolar disorder and are resulting in considerable interest in utilizing lithium for the treatment of certain neurodegenerative disorders. We review recent insights into lithium's actions including its direct inhibitory actions on inositol monophosphatase, inositol polyphosphate 1-phosphatase, glycogen synthase kinase-3, fructose 1,6-bisphosphatase, bisphosphate nucleotidase, and phosphoglucomutase enzymes. We also discuss lithium's intracellular downstream targets including adenylate cyclase, the phosphoinositol cascade (and its effect on protein kinase C), arachidonic acid metabolism, and effects on neurotrophic cascades. Many of the new insights of lithium's actions may lead to the strategic development of improved therapeutics for the treatment of bipolar disorder.

In Vivo Evidence in the Brain for Lithium Inhibition of Glycogen Synthase Kinase-3

Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology. Jan, 2004  |  Pubmed ID: 12942141

There is considerable interest in the possibility that small-molecule glycogen synthase kinase-3 inhibitors may have utility in the treatment of bipolar disorder, since glycogen synthase kinase-3 is a target of lithium. Although the in vitro inhibition of glycogen synthase kinase-3 by lithium occurs with a K(i) of 1-2 mM, the degree of inhibition of this enzyme in the mammalian brain at therapeutically relevant concentrations has not fully been established. The transcription factor beta-catenin is an established marker of glycogen synthase kinase-3 inactivation because cytoplasmic levels are increased by inhibition of the enzyme. In this study, we measured beta-catenin protein levels after treatment with therapeutically relevant doses of lithium, valproate, and carbamazepine. Western blot revealed that 9 days of treatment with lithium and valproate, but not carbamazepine, increased beta-catenin protein levels in soluble fractions from the frontal cortex. The level of beta-catenin in the particulate fraction, which is not directly regulated by glycogen synthase kinase-3, did not change with any of the three drugs. Furthermore, real-time PCR revealed that lithium significantly decreased beta-catenin mRNA levels, which may represent compensation for an increase in beta-catenin stability. These results strongly suggest that lithium significantly inhibits brain glycogen synthase kinase-3 in vivo at concentrations relevant for the treatment of bipolar disorder.

DARPP-32: A Molecular Switch at the Nexus of Reward Pathway Plasticity

Proceedings of the National Academy of Sciences of the United States of America. Jan, 2005  |  Pubmed ID: 15632217

Glycogen Synthase Kinase-3: a Putative Molecular Target for Lithium Mimetic Drugs

Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology. Jul, 2005  |  Pubmed ID: 15827567

Despite many decades of clinical use, the therapeutic target of lithium remains uncertain. It is recognized that therapeutic concentrations of lithium, through competition with the similarly sized magnesium cation, inhibit the activity of select enzymes. Among these is glycogen synthase kinase-3 (GSK-3). Recent preclinical evidence, including biochemical, pharmacological, genetic, and rodent behavioral models, supports the hypothesis that inhibition of GSK-3 may represent a target for lithium's mood-stabilizing properties. Specifically, it has been demonstrated that lithium administration regulates multiple GSK-3 targets in vivo and that multiple additional classes of mood-stabilizing and antidepressant drugs regulate GSK-3 signaling. Pharmacological or genetic inhibition of GSK-3 results in mood stabilizer-like behavior in rodent models, and genetic association studies implicate GSK-3 as a possible modulator of particular aspects of bipolar disorder including response to lithium. Furthermore, numerous recent studies have provided a more complete understanding of GSK-3's role in diverse neurological processes strengthening the hypothesis that GSK-3 may represent a therapeutically relevant target of lithium. For example, GSK-3 is a primary regulator of neuronal survival, and cellular responses to glucocorticoids and estrogen may involve GSK-3-regulated pathways. While the preclinical evidence discussed in this review is encouraging, ultimate validation of GSK-3 as a therapeutically relevant target will require clinical trials of selective novel inhibitors. In this regard, as is discussed, there is a major effort underway to develop novel, specific, GSK-3 inhibitors.

Mood Stabilizers Target Cellular Plasticity and Resilience Cascades: Implications for the Development of Novel Therapeutics

Molecular Neurobiology. Oct, 2005  |  Pubmed ID: 16215281

Bipolar disorder is a devastating disease with a lifetime incidence of about 1% in the general population. Suicide is the cause of death in 10 to 15% of patients and in addition to suicide, mood disorders are associated with many other harmful health effects. Mood stabilizers are medications used to treat bipolar disorder. In addition to their therapeutic effects for the treatment of acute manic episodes, mood stabilizers are useful as prophylaxis against future episodes and as adjunctive antidepressant medications. The most established and investigated mood-stabilizing drugs are lithium and valproate but other anticonvulsants (such as carbamazepine and lamotrigine) and antipsychotics are also considered as mood stabilizers. Despite the efficacy of these diverse medications, their mechanisms of action remain, to a great extent, unknown. Lithium's inhibition of some enzymes, such as inositol monophosphatase and glycogen synthase kinase-3, probably results in its mood-stabilizing effects. Valproate may share its anticonvulsant target with its mood-stabilizing target or may act through other mechanisms. It has been shown that lithium, valproate, and/or carbamazepine regulate numerous factors involved in cell survival pathways, including cyclic adenine monophospate response element-binding protein, brain-derived neurotrophic factor, bcl-2, and mitogen-activated protein kinases. These drugs have been suggested to have neurotrophic and neuroprotective properties that ameliorate impairments of cellular plasticity and resilience underlying the pathophysiology of mood disorders. This article also discusses approaches to develop novel treatments specifically for bipolar disorder.

Toward Constructing an Endophenotype Strategy for Bipolar Disorders

Biological Psychiatry. Jul, 2006  |  Pubmed ID: 16406007

Research aimed at elucidating the underlying neurobiology and genetics of bipolar disorder, and factors associated with treatment response, have been limited by a heterogeneous clinical phenotype and lack of knowledge about its underlying diathesis. We used a survey of clinical, epidemiological, neurobiological, and genetic studies to select and evaluate candidate endophenotypes for bipolar disorder. Numerous findings regarding brain function, brain structure, and response to pharmacological challenge in bipolar patients and their relatives deserve further investigation. Candidate brain function endophenotypes include attention deficits, deficits in verbal learning and memory, cognitive deficits after tryptophan depletion, circadian rhythm instability, and dysmodulation of motivation and reward. We selected reduced anterior cingulate volume and early-onset white matter abnormalities as candidate brain structure endophenotypes. Symptom provocation endophenotypes might be based on bipolar patients' sensitivity to sleep deprivation, psychostimulants, and cholinergic drugs. Phenotypic heterogeneity is a major impediment to the elucidation of the neurobiology and genetics of bipolar disorder. We present a strategy constructed to improve the phenotypic definition of bipolar disorder by elucidating candidate endophenotypes. Studies to evaluate candidate endophenotypes with respect to specificity, heritability, temporal stability, and prevalence in unaffected relatives are encouraged.

Targeting Glycogen Synthase Kinase-3 As an Approach to Develop Novel Mood-stabilising Medications

Expert Opinion on Therapeutic Targets. Jun, 2006  |  Pubmed ID: 16706678

Historically, success in the pharmacological treatment of bipolar disorder has arisen either from serendipitous findings or from studies with drugs (antipsychotics and anticonvulsants) developed for other indications (schizophrenia and epilepsy, respectively). Lithium has been in widespread clinical use in the treatment of bipolar disorder for > 30 years. Development of lithium-mimetic compounds has the potential to result in a more specific medication, with fewer side effects and a less narrow dose range. However, novel medications based upon a known mechanism of action of this drug are yet to be developed. Increasing evidence suggests that a next-generation lithium compound may derive from knowledge of a direct target of lithium, glycogen synthase kinase-3 (GSK-3). GSK-3 is an intracellular enzyme implicated as a critical component in many neuronal signalling pathways. However, despite the large body of preclinical data discussed in this review, definitive validation of GSK-3 as therapeutically relevant target of lithium will require clinical trials with novel GSK-3 inhibitors. A number of recent reports suggest that it is possible to develop selective, small-molecule GSK-3 inhibitors.

Targeting Glycogen Synthase Kinase-3 in the CNS: Implications for the Development of New Treatments for Mood Disorders

Current Drug Targets. Nov, 2006  |  Pubmed ID: 17100580

There exists an immediate need to develop novel medications for the treatment of mood disorders such as bipolar disorder and depression. Initial interest in glycogen synthase kinase-3 (GSK-3) as a target for the treatment of mood disorders arose from the finding that the mood stabilizing drug lithium directly inhibited the enzyme. More recent preclinical evidence implicates the modulation of GSK-3 in either the direct or downstream mechanism of action of many other mood stabilizer and antidepressant medications currently in use. One of the cellular targets of GSK-3, which may mediate some of the effects of lithium and other drugs, is beta-catenin, a transcription factor that is rapidly degraded when GSK-3 is active. Recent rodent behavioral data (both genetic and pharmacological) supports GSK-3 representing a therapeutically relevant target of lithium. This includes antidepressant-like behavior in the forced swim test and antimanic-like response to amphetamine following administration of the GSK-3 inhibitor AR-A014418, a findings that is concomitant with an increase in brain beta-catenin. The evidence described in this review suggests that regulating GSK-3 may represent a target for novel medications to treat mood disorders.

Strain Differences in Lithium Attenuation of D-amphetamine-induced Hyperlocomotion: a Mouse Model for the Genetics of Clinical Response to Lithium

Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology. Jun, 2007  |  Pubmed ID: 17151598

Lithium attenuation of stimulant-induced hyperlocomotion is a rodent model that may be useful both to understand the mechanism of the therapeutic action of lithium and to develop novel lithium-mimetic compounds. To lay the foundation for future investigations into the neurobiology and genetics of lithium as a therapeutic agent, we studied the effect of lithium on d-amphetamine-induced hyperlocomotion in 12 (3 outbred) mouse strains. In our initial screening, mice received either (1) no drugs, (2) LiCl only, (3) d-amphetamine only, or (4) d-amphetamine and LiCl. Whereas there was no significant effect of LiCl alone on locomotion in any strain, there was a large degree of strain variation in the effects of LiCl combined with d-amphetamine. LiCl attenuated d-amphetamine-induced hyperlocomotion in C57BL/6J, C57BL/6Tac, Black Swiss, and CBA/J mice, whereas CD-1, FVB/NJ, SWR/J, and NIH Swiss mice, which were responsive to d-amphetamine, showed no significant effect of LiCl. d-Amphetamine-induced hyperlocomotion in the C3H/HeJ strain was increased by pretreatment with lithium. A subset of strains were treated for 4 weeks with lithium carbonate before the d-amphetamine challenge, and in each of these strains, lithium produced effects identical to those seen following acute administration. Strain responsiveness to lithium was not dependent upon the dose of either d-amphetamine or LiCl. Further, the results are not explained by brain lithium levels, which suggests that these behavioral responses to lithium are under the control of inherent genetic or other biological mechanisms specific to the effects of lithium on brain function.

Beta-catenin Overexpression in the Mouse Brain Phenocopies Lithium-sensitive Behaviors

Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology. Oct, 2007  |  Pubmed ID: 17299510

Lithium inhibits glycogen synthase kinase-3 (GSK-3) at therapeutic concentrations; however, it is unclear if this inhibition and its downstream effects on specific signaling pathways are relevant to the treatment of bipolar disorder and depression. One of the targets of GSK-3 is the transcription factor beta-catenin. Normally active GSK-3 phosphorylates beta-catenin, leading to its degradation. Inhibition of GSK-3 therefore increases beta-catenin. We have utilized transgenic mice to investigate the behavioral consequences of CNS beta-catenin overexpression. Transgenic mice overexpressing beta-catenin demonstrated behavioral changes similar to those observed following the administration of lithium, including decreased immobility time in the forced swim test (FST). Further, we show that although acute administration of lithium and overexpression of the beta-catenin transgene inhibits d-amphetamine-induced hyperlocomotion, neither lithium nor the beta-catenin transgene prevents d-amphetamine-induced sensitization, as measured by locomotor activity. Both lithium-treated and beta-catenin mice had an elevated response to d-amphetamine following multiple administrations of the stimulant, though the difference in absolute locomotion was maintained throughout the sensitization time-course. Neither acute lithium nor beta-catenin overexpression had an effect on d-amphetamine-induced stereotyped behavior. The results of this study, in which beta-catenin transgenic mice exhibited behaviors identical to those observed in lithium-treated mice, are consistent with the hypothesis that the behavioral effects of lithium in these models are mediated through its direct inhibition of GSK-3 and the consequent increase in beta-catenin. By associating the behavioral effects of lithium with beta-catenin levels, these data suggest that increasing beta-catenin might be a novel therapeutic strategy for mood disorders.

Performance on a Virtual Reality Spatial Memory Navigation Task in Depressed Patients

The American Journal of Psychiatry. Mar, 2007  |  Pubmed ID: 17329478

Findings on spatial memory in depression have been inconsistent. A navigation task based on virtual reality may provide a more sensitive and consistent measure of the hippocampal-related spatial memory deficits associated with depression.

Targeting Signal Transduction Pathways in the Treatment of Mood Disorders: Recent Insights into the Relevance of the Wnt Pathway

CNS & Neurological Disorders Drug Targets. Jun, 2007  |  Pubmed ID: 17511616

Regulation of complex signaling pathways plays a critical role in higher-order brain functions including the regulation of mood, cognition, appetite, sexual arousal, sleep patterns, and weight, all of which are altered in mood disorders, suggesting the involvement of signaling pathways in mood disorder pathogenesis and pathophysiology. Most existing medications used to treat mood disorders take many weeks to exert their full clinical effects, a fact which implicates changes in gene and protein expression, as well as neuroplasticity, in their mechanism of action. Modulation of signaling pathways has many downstream effects on gene expression and protein function, causing changes in synaptic function, plasticity, and response to various inputs such as neurohormones. The Wnt signaling pathway has recently been linked to the therapeutically relevant actions of available treatments of mood disorders. We provide a brief introduction to signaling cascades and their potential roles in mood disorder pathophysiology and treatment. Subsequently, we describe the Wnt signaling pathway, and glycogen synthase kinase-3 (GSK-3) and beta-catenin specifically, discussing studies that have implicated these proteins as relevant to the pathophysiology and treatment of mood disorders. Future directions, aimed at understanding mood disorders and developing more efficacious treatments, are also discussed.

The Behavioral Actions of Lithium in Rodent Models: Leads to Develop Novel Therapeutics

Neuroscience and Biobehavioral Reviews. 2007  |  Pubmed ID: 17532044

For nearly as long as lithium has been in clinical use for the treatment of bipolar disorder, depression, and other conditions, investigators have attempted to characterize its effects on behaviors in rodents. Lithium consistently decreases exploratory activity, rearing, aggression, and amphetamine-induced hyperlocomotion; and it increases the sensitivity to pilocarpine-induced seizures, decreases immobility time in the forced swim test, and attenuates reserpine-induced hypolocomotion. Lithium also predictably induces conditioned taste aversion and alterations in circadian rhythms. The modulation of stereotypy, sensitization, and reward behavior are less consistent actions of the drug. These behavioral models may be relevant to human symptoms and to clinical endophenotypes. It is likely that the actions of lithium in a subset of these animal models are related to the therapeutic efficacy, as well the side effects, of the drug. We conclude with a brief discussion of various molecular mechanisms by which these lithium-sensitive behaviors may be mediated, and comment on the ways in which rat and mouse models can be used more effectively in the future to address persistent questions about the therapeutically relevant molecular actions of lithium.

Animal Models of Bipolar Disorder and Mood Stabilizer Efficacy: a Critical Need for Improvement

Neuroscience and Biobehavioral Reviews. 2007  |  Pubmed ID: 17628675

The limited number of suitable animal models of bipolar disorder available for in-depth behavioral, biochemical, histological, and pharmacological analysis is a rate-limiting step in the process of understanding the relevant neurobiology of the disorder, as well as the development of novel medications. In the search for new models, both new and old approaches hold promise for future discoveries. Clinical studies regarding the underlying genetics and pathophysiology of bipolar disorder are providing important clues. In particular, the identification of susceptibility genes for bipolar disorder will help to define specific neurobiological processes, and associated behaviors, that are unquestionably involved in the pathways connecting genes and distal symptoms. These endophenotypes will hold great value in further enhancing the validity of animal models and will strongly complement symptom-based models and models of medication efficacy. Regardless of the path taken by different researchers to develop better models, we believe that this area of work requires additional attention not only from researchers but also from funding agencies.

Involvement of AMPA Receptors in the Antidepressant-like Effects of Lithium in the Mouse Tail Suspension Test and Forced Swim Test

Neuropharmacology. Mar, 2008  |  Pubmed ID: 18096191

In addition to its clinical antimanic effects, lithium also has efficacy in the treatment of depression. However, the mechanism by which lithium exerts its antidepressant effects is unclear. Our objective was to further characterize the effects of peripheral and central administration of lithium in mouse models of antidepressant efficacy as well as to investigate the role of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors in these behaviors. We utilized the mouse forced swim test (FST) and tail suspension test (TST), intracerebroventricular (ICV) lithium administration, AMPA receptor inhibitors, and BS3 crosslinking followed by Western blot. Both short- and long-term administration of lithium resulted in robust antidepressant-like effects in the mouse FST and TST. Using ICV administration of lithium, we show that these effects are due to actions of lithium on the brain, rather than to peripheral effects of the drug. Both ICV and rodent chow (0.4% LiCl) administration paradigms resulted in brain lithium concentrations within the human therapeutic range. The antidepressant-like effects of lithium in the FST and TST were blocked by administration of AMPA receptor inhibitors. Additionally, administration of lithium increased the cell surface expression of GluR1 and GluR2 in the mouse hippocampus. Collectively, these data show that lithium exerts centrally mediated antidepressant-like effects in the mouse FST and TST that require AMPA receptor activation. Lithium may exert its antidepressant effects in humans through AMPA receptors, thus further supporting a role of targeting AMPA receptors as a therapeutic approach for the treatment of depression.

Generation and Behavioral Characterization of Beta-catenin Forebrain-specific Conditional Knock-out Mice

Behavioural Brain Research. May, 2008  |  Pubmed ID: 18299155

The canonical Wnt pathway and beta-catenin have been implicated in the pathophysiology of mood disorders. We generated forebrain-specific CRE-mediated conditional beta-catenin knock-out mice to begin exploring the behavioral implications of decreased Wnt pathway signaling in the central nervous system. In situ hybridization revealed a progressive knock-out of beta-catenin that began between 2 and 4 weeks of age, and by 12 weeks resulted in considerably decreased beta-catenin expression in regions of the forebrain, including the frontal cortex, hippocampus, and striatum. A significant decrease in protein levels of beta-catenin in these brain regions was observed by Western blot. Behavioral characterization of these mice in several tests (including the forced swim test, tail suspension test (TST), learned helplessness, response and sensitization to stimulants, and light/dark box among other tests) revealed relatively circumscribed alterations. In the TST, knock-out mice spent significantly less time struggling (a depression-like phenotype). However, knock-out mice did not differ from their wild-type littermates in the other behavioral tests of mood-related or anxiety-related behaviors. These results suggest that a 60-70% beta-catenin reduction in circumscribed brain regions is only capable of inducing subtle behavioral changes. Alternatively, regulating beta-catenin may modulate drug effects rather than being a model of mood disorder pathophysiology per se.

Lithium's Antisuicidal Efficacy: Elucidation of Neurobiological Targets Using Endophenotype Strategies

Annual Review of Pharmacology and Toxicology. 2009  |  Pubmed ID: 18834309

Lithium used as a drug treatment for major mental disorders such as bipolar disorder and depression is effective in reducing the risk of both attempted and completed suicide. However, the mechanisms underlying lithium's antisuicidal actions are not yet known, limiting the development of novel lithium-mimetic compounds that may help reduce suicide risk with fewer undesirable side effects. Suicide is a complex behavior, complicated to study in humans, and impossible to fully reproduce in animal models. The endophenotype approach, by which quantitative measures of neurobiological function are used to assess and subclassify psychiatric illness, may present a path to new discoveries. Aggression and impulsivity are candidate endophenotypes strongly associated with suicide; we review the evidence supporting aggression and impulsivity as suicide endophenotypes, as well as the effects of lithium on these constructs in both humans and rodents. Examining the mechanisms that contribute to lithium's antiaggressive and antiimpulsive effects may assist in understanding how lithium acts to reduce the risk of suicide and in elucidating the neurobiological underpinnings of suicidal behavior.

Allergic Rhinitis Induces Anxiety-like Behavior and Altered Social Interaction in Rodents

Brain, Behavior, and Immunity. Aug, 2009  |  Pubmed ID: 19268702

Epidemiological and clinical studies report higher incidences of anxiety and increased emotional reactivity in individuals suffering from respiratory allergies. To evaluate if respiratory allergies are capable of promoting anxiety-like behavior in rodents, we used models of allergic rhinitis and behavioral evaluations followed by assessment of mRNA for cytokines in relevant brain regions. Mice and rats were sensitized to ovoalbumin or pollen, respectively, following standard sensitization and challenge protocols. After challenge, the animals were evaluated in the open field, elevated plus-maze and resident-intruder tests. Cytokines and corticotropin-releasing factor expression were assessed in several brain regions by real-time RT-PCR and plasma corticosterone concentrations by radioimmunoassay. Mice and rats sensitized and exposed to allergen showed increased anxiety-like behavior and reduced social interaction without any overt behavioral signs of sickness. T-helper type 2 (T(H)2) cytokines were induced in both rats and mice in the olfactory bulbs and prefrontal cortex and remained unchanged in the temporal cortex and hypothalamus. The same results were found for CRF mRNA expression. No differences were observed in corticosterone concentrations 1h after the last behavioral test. These results show that sensitization and challenge with allergens induce anxiety across rodent species and that these effects were paralleled by an increased expression of T(H)2 cytokines and CRF in the prefrontal cortex. These studies provide experimental evidence that sensitized rodents experience neuroimmune-mediated anxiety and reduced social interaction associated with allergic rhinitis.

Shock-induced Aggression in Mice is Modified by Lithium

Pharmacology, Biochemistry, and Behavior. Jan, 2010  |  Pubmed ID: 19800363

Aggression is associated with numerous psychiatric disorders. Evidence suggests that lithium decreases aggression in humans and rats. The effects of lithium on aggression related behavior, and in particular shock-induced aggression, has not been as thoroughly explored in mice. Male mice were treated with lithium and tested in the shock-induced aggression and dominance tube tests. Mice treated with lithium were also assessed for thermal pain and shock sensitivity in the hot plate and jump-flinch tests. In the shock-induced aggression paradigm chronic lithium significantly decreased both the frequency and duration of attacks, without affecting social interaction or behavior in the dominance tube. Acute lithium significantly decreased the total duration of attacks and social interaction but did not affect behavior in the dominance tube test. Neither treatment regimen had an effect on temperature sensitivity in the hot plate test or on activity levels in the open field. However, chronic lithium modified the response of mice to shock in the jump-flinch test, but not at the shock level used in the aggression test. The results of this study indicate that lithium decreases shock-induced aggression in mice, but effects on baseline response to shock confound interpretation of this behavioral effect of lithium.

Mood Disorder Susceptibility Gene CACNA1C Modifies Mood-related Behaviors in Mice and Interacts with Sex to Influence Behavior in Mice and Diagnosis in Humans

Biological Psychiatry. Nov, 2010  |  Pubmed ID: 20723887

Recent genome-wide association studies have associated polymorphisms in the gene CACNA1C, which codes for Ca(v)1.2, with a bipolar disorder and depression diagnosis.

Advances in Multidisciplinary and Cross-species Approaches to Examine the Neurobiology of Psychiatric Disorders

European Neuropsychopharmacology : the Journal of the European College of Neuropsychopharmacology. Jul, 2011  |  Pubmed ID: 21237620

Current approaches to dissect the molecular neurobiology of complex neuropsychiatric disorders such as schizophrenia and major depression have been rightly criticized for failing to provide benefits to patients. Improving the translational potential of our efforts will require the development and refinement of better disease models that consider a wide variety of contributing factors, such as genetic variation, gene-by-environment interactions, endophenotype or intermediate phenotype assessment, cross species analysis, sex differences, and developmental stages. During a targeted expert meeting of the European College of Neuropsychopharmacology (ECNP) in Istanbul, we addressed the opportunities and pitfalls of current translational animal models of psychiatric disorders and agreed on a series of core guidelines and recommendations that we believe will help guiding further research in this area.

Affect-related Behaviors in Mice Selectively Bred for High and Low Voluntary Alcohol Consumption

Behavior Genetics. Mar, 2012  |  Pubmed ID: 21989731

There is considerable evidence for the existence of comorbidity between alcohol-use disorders and depression in humans. One strategy to elucidate hereditary factors affecting the comorbidity of these disorders is to use genetic animal models, such as mouse lines selectively bred for voluntary ethanol consumption. We hypothesized that mice from lines that were bred for high-alcohol preference would manifest increased depression-like phenotypes compared to low-alcohol preferring mice. Mice that were bi-directionally selected and bred on the basis of their High- (HAP) or Low-Alcohol Preference (LAP) were tested in the open-field (OFT), dark-light box (DLB), forced swim (FST), and learned helplessness tests (LH). The study was conducted in two independently derived replicates. In the OFT, both HAP2 and HAP3 mice showed higher levels of general locomotion compared to LAP mice. However, only HAP2 mice spent more time in the center compared to LAP2 mice. In the DLB, there was a slightly higher anxiety-like phenotype in HAP mice. In both FST and LH, we observed higher depression-like behaviors in HAP mice compared to LAP mice, but this was limited to the Replicate 2 mice. Overall, we identified affect-related behavioral changes in mouse lines bred for high-alcohol preference. Notably, the Replicate 3 lines that showed fewer depression-like behaviors also manifest smaller differences in alcohol intake. These data suggest that there may be overlap between genes that predispose to excessive alcohol intake and those underlying affect-related behaviors in the mouse.

Differential Lithium Efficacy in Reducing Suicidal Behaviors Compared with Suicidal Thoughts

The American Journal of Psychiatry. Jan, 2012  |  Pubmed ID: 22223017