The paucity of appropriate animal models for bipolar disorder is repeatedly mentioned as one of t... more The paucity of appropriate animal models for bipolar disorder is repeatedly mentioned as one of the critical factors hindering research into the pathophysiology of the disorder and the development of truly novel treatments. Recent advances in our understanding of the biological basis of bipolar disorder can be used to identify and develop better models. One possibility that is discussed in a separate chapter of this book is the use of molecular biology techniques to develop animals with targeted mutations related to genes implicated in the disorder. However, the development of such animals may not be enough for usable and helpful models. Additional strategies should, therefore, be combined with targeted mutation methodology to develop good model animals and good tests that will significantly impact our ability to further explore the underlying biology of bipolar disorder and to develop better drugs and treatments.The present chapter presents a short introduction related to commonly used models and discusses some of the possible strategies for advancement. These strategies include developing better tests, exploring separate tests for the different domains of the disease, creating test batteries, and developing models for endophenotypes. In addition, the chapter raises the possibility of identifying better model animals using comparative biology approaches. The chapter presents two different ways for identifying advantageous model animals using either specific strains of laboratory animals or using the natural diversity of nontraditional model animals.In summary, it is concluded that while each strategy offers significant contributions, it is important to combine the different approaches in order to be able to achieve novel, appropriate, and predictive models for bipolar disorder.
The neurobiological underpinnings of mood modulation, molecular pathophysiology of manic-depressi... more 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.
Inositol is a second-messenger precursor that can be given orally and enters the brain. Clinical ... more Inositol is a second-messenger precursor that can be given orally and enters the brain. Clinical studies find it therapeutic in depression, panic disorder, and obsessive-compulsive disorder. In rat models of depression and anxiety, inositol is active. Activity of inositol in animal models of depression is blocked by ritanserin, suggesting that inositol works distal to a 5-HT-2 receptor.
Background: There is a desperate need for in-vivo behavioral screening tests for anti-manic effec... more Background: There is a desperate need for in-vivo behavioral screening tests for anti-manic effects. The frequently used psychostimulant-induced hyperactivity test appears to have lower validity than previously described, but other quick, simple and high throughput tests are currently unavailable. New method: In the context of modeling the behavioral facets of mania, we previously suggested that the sweet solution preference test (SSP) in naive mice might have predictive validity for screening anti-manic effects. The current study further examined this proposal by testing the effects of lithium, valproate and imipramine on SSP in three strains of mice (male mice from the black Swiss, ICR and C57bl/6 strains) and an exploratory test in females (black Swiss strain). Results: Data demonstrate that lithium and valproate at appropriate dosing schedules significantly and reliably reduce SSP in all three strains (including in females) but that the antidepressant imipramine has no effects. Comparison with existing methods: The results support the utilization of the SSP as mice screening model for antimanic effects of drugs with stronger predictive validity compared with other methods. Conclusions: The SSP is not a comprehensive model for bipolar disorder but it has good predictive validity and strong practical value that can be applied towards simple and fast screening of large numbers of animals, without the need for specialized equipment or complicated/prolonged procedures. We therefore propose that the SSP is an advantageous screening assay for testing novel mood stabilizing drugs for anti-manic properties.
Rationale: Myo-inositol is an isomer of glucose that is a precursor in the phosphatidylinositol (... more Rationale: Myo-inositol is an isomer of glucose that is a precursor in the phosphatidylinositol (PIP) cycle, a source of two second messengers: diacylglycerol (DAG) and inositol triphosphate (IP 3). Clinical studies have reported that inositol is effective in relieving symptoms of depression. Objective: The present study examined the effects of inositol on two animal models of depression: the Porsolt forced swim test, a behaviorally based model; and the reserpine-induced immobility model, a pharmacologically based model. Methods and results: Chronic inositol injections (daily for 14 days) of 1.2 g/kg (but not at lower doses) reduced immobility time and increased struggle time in the Porsolt test compared with control animals. The same dose and treatment schedule also reduced complete immobility time but did not affect ambulatory activity in the reserpine test compared with controls. Chronic oral treatment with inositol (10% in food for 14 days) had effects similar to IP inositol in the Porsolt test. Conclusions: The effect of inositol in animal models of depression supports its possible importance as a new treatment for the disorder, and permits research on its mechanisms of action.
Highlights Animal models are critical for screening new therapies. Amphetamine-induced hype... more Highlights Animal models are critical for screening new therapies. Amphetamine-induced hyperactivity (AIH) is a screening model for mood stabilizers The validity of screening models depends on their response to established treatments We show that in ICR and black Swiss mice, chronic lithium does not ameliorate AIH The findings cast doubt on the validity of the model to screen mood-stabilizing drugs
Asenapine is indicated for the treatment of schizophrenia and manic episodes in bipolar disorder ... more Asenapine is indicated for the treatment of schizophrenia and manic episodes in bipolar disorder (BPD). There is a paucity of information on the effects of asenapine in animal models of BPD, but such work is essential to discover its scope of effects and its mechanisms of therapeutic action. This study evaluated the effects of asenapine in a validated test battery for manic-like behaviors in Black Swiss mice. Male Black Swiss mice received asenapine at 0.03, 0.1, and 0.3 mg/kg twice daily for 7 days and were tested for spontaneous activity, sweet solution preference, forced-swim test, social interaction, and amphetamine-induced hyperactivity. Asenapine treatment resulted in dose-dependent, clinically relevant plasma levels. Asenapine, at the 0.1 and 0.3 mg/kg doses, reduced activity, with the 0.3 mg/kg dose also resulting in increased time in the center of an open field, increased immobility in the forced-swim test, and reduced amphetamine-induced hyperactivity. Asenapine exerted no effects in the social interaction or sweet solution preference tests. The results suggest that asenapine exerts antimanic-like effects in some of the behavioral tests performed in Black Swiss mice. These data support the utilization of asenapine in the treatment of BPD.
Lithium inhibits glycogen synthase kinase-3 (GSK-3) at therapeutic concentrations; however, it is... more 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 b-catenin. Normally active GSK-3 phosphorylates b-catenin, leading to its degradation. Inhibition of GSK-3 therefore increases b-catenin. We have utilized transgenic mice to investigate the behavioral consequences of CNS b-catenin overexpression. Transgenic mice overexpressing b-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 b-catenin transgene inhibits d-amphetamine-induced hyperlocomotion, neither lithium nor the b-catenin transgene prevents d-amphetamine-induced sensitization, as measured by locomotor activity. Both lithiumtreated and b-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 b-catenin overexpression had an effect on d-amphetamine-induced stereotyped behavior. The results of this study, in which b-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 b-catenin. By associating the behavioral effects of lithium with b-catenin levels, these data suggest that increasing b-catenin might be a novel therapeutic strategy for mood disorders.
The inhibition of protein kinase C (PKC) was recently suggested as a novel approach for the devel... more The inhibition of protein kinase C (PKC) was recently suggested as a novel approach for the development of mood stabilizing drugs. To further evaluate this possibility, the aim of the present study was to test the effects of peripheral (intraperitoneal) administration of chelerythrine in a battery of mania-related behavioral tests in black Swiss mice, a strain specific battery that was previously demonstrated to distinguish differential effects of mood stabilizing drugs. Sub-chronic administration of 1.0mg/kg or 2.0mg/kg chelerythrine had marginal effects to reduce spontaneous activity and sweet solution preference in black Swiss mice which naturally show mania-like behaviors. Chelerythrine had no effects on the behavior of these mice in the elevated plus-maze, the forced swim test and the amphetamine-induced hyperactivity test. The partial effects in the battery are not unique as previous studies showed that lithium, valproate and risperidone, all used in the treatment of bipolar disorder, have distinct profiles in the battery. It is therefore concluded that chelerythrine may have antimanic effects and additional dose and time response studies are warranted to further evaluate its range of activity.
The present study examined post mortem changes in central dopaminergic terminal regions following... more The present study examined post mortem changes in central dopaminergic terminal regions following acute or chronic treatment regimens with the dopamine D2/D3 receptor agonist quinpirole, a psychomotor stimulant which induces pronounced behavioural sensitization when given chronically. Drug-induced changes in nucleus accumbens, striatum and amygdala were bilateral in nature, while in prefrontal cortex (medial prefrontal and anterior cingulate combined), left and right brain regions responded differentially to quinpirole. Acute drug treatment increased dopamine tissue levels in nucleus accumbens and right prefrontal cortex, while the dopamine metabolite 3,4-dihydroxyphenylacetic acid, was decreased in amygdala. In contrast, sensitization to quinpirole was associated with decreased dopamine levels in left prefrontal cortex, and increases in 3,4-dihydroxyphenylacetic acid levels in subcortical structures, particularly striatum and amygdala. Additionally, the increase in striatal 3,4-dihydroxyphenylacetic acid in chronic quinpirole animals was independent of drug treatment on the final day of injections. In summary, quinpirole induces a variety of simultaneous, regional changes in dopaminergic function, with the sensitized condition being primarily associated with an up-regulation of subcortical dopamine activity. While the nucleus accumbens and striatum play a well known role in motor activation and sensitized behaviour, it is concluded that the amygdala and prefrontal cortex have significant modulatory influences on these processes, with the role of the prefrontal cortex being asymmetrical in nature. Given the suggested relevance of behavioural sensitization to psychopathological states in humans, parallels are drawn between the present data and clinical findings, particularly in relation to obsessive-compulsive disorder.
University Honors Capstone Project Paper and Poster, University of Minnesota Duluth, 2018. Malia ... more University Honors Capstone Project Paper and Poster, University of Minnesota Duluth, 2018. Malia Triebold authored paper and poster; C.E. Anderson, H. Einat, and G.W. Anderson authored poster.
Background: Lithium (Li) is the prototypic mood-stabilizing drug, but the individual response to ... more Background: Lithium (Li) is the prototypic mood-stabilizing drug, but the individual response to Li is highly heterogeneous. Some evidence suggest interactions between Li and stress, and it is possible to hypothesize that lithium’s effects are modified by stress conditions. The current study examines the interaction between 2 chronic stressors, constant light (CL) and restrain and the behavioral responses to chronic Li in female and male mice. Methods: Female and male ICR mice were exposed to 3 weeks of either (1) CL; (2) daily restrain or (3) no stress control. One week after the start of the stress intervention, mice started chronic oral Li treatment or control. After 2 weeks of stress and Li, mice were tested in a number of behavioral tests including spontaneous activity, sweet solution preference, plus-maze and forced swim test. Results: There were no effects of stressors on behavior. Effects of Li were demonstrated in males but not females with no interactions between stress and Li. Conclusions: The behavioral effects of Li in this study were not affected by stress. The lack of effects of the stressors themselves on behavior suggests that the application of more intrusive stressors might be needed to further explore the issue.
ABSTRACT Inositol is a simple polyol precursor in a second messenger system important in the brai... more ABSTRACT Inositol is a simple polyol precursor in a second messenger system important in the brain. A double-blind controlled trial of 12 g daily of inositol in 28 patients with depression for 4 weeks found significant benefit for inositol compared to placebo on the Hamilton ...
Objective: A number of atypical antipsychotic drugs were demonstrated to have anxiolytic effects ... more Objective: A number of atypical antipsychotic drugs were demonstrated to have anxiolytic effects in patients and in animal models. These effects were mostly suggested to be the consequence of the drugs' affinity to the serotonin system and its receptors. Asenapine is a relatively new atypical antipsychotic that is prescribed for schizophrenia and for bipolar mania. Asenapine has a broad pharmacological profile with significant effects on serotonergic receptors, hence it is reasonable to expect that asenapine may have some anxiolytic effects. The present study was therefore designed to examine possible effects of asenapine on anxiety-like behaviour of mice. Method: Male ICR mice were repeatedly treated with 0.1 or 0.3 mg/kg injections of asenapine and then tested in a battery of behavioural tests related to anxiety including the open-field test, elevated plus-maze (EPM), defensive marble burying and hyponeophagia tests. In an adjunct experiment, we tested the effects of acute diazepam in the same test battery. Results: The results show that diazepam reduced anxiety-like behaviour in the EPM, the defensive marble burying test and the hyponeophagia test but not in the open field. Asenapine has anxiolytic-like effects in the EPM and the defensive marble burying tests but had no effects in the open-field or the hyponeophagia tests. Asenapine had no effects on locomotor activity. Conclusion: The results suggest that asenapine may have anxiolytic-like properties and recommends that clinical trials examining such effects should be performed. Significant outcomes • Asenapine-induced anxiolytic-like effects in mice in three out of four tests. • These anxiolytic-like effects were demonstrated in an exploration-based test and in acute stress induced tests. • The results warrant further exploration of the possible use of asenapine in anxiety disorders. Limitations • Asenapine was not active as an anxiolytic in all the behavioural tests but only in three out of four. • The study was performed only in one strain of mice and only in male mice. • The study does not include experiments that can unravel the underlying biological basis of the behavioural effects.
Israel Journal of Psychiatry and Related Sciences, 2008
Background: Taurine is a conditionally-essential amino acid that is found in high concentrations ... more Background: Taurine is a conditionally-essential amino acid that is found in high concentrations in the CNS and is essential for growth and survival of neurons. Taurine had been clinically tested in a number of diseases with variable results. In the context of neuropsychiatry, taurine was found to be altered in some neurological and psychiatric disorders and its levels affected by mood stabilizers and by antidepressants as well as anti-Alzheimer drugs. Taurine is also a common component in energy drinks and it is claimed (without scientific support) to have stimulant properties. The present study was designed to test taurine's effects in animal models of affective and anxiety disorders and to evaluate its properties as a stimulant. Method: Mice were treated with two doses of taurine with sub-chronic or chronic administration (for different experiments) and tested in the open field, the black/white box and the forced swim test. Taurine's possible stimulant effects were also tested in conjunction with amphetamine administration. Results: For the doses and schedules tested, taurine did not have an effect on measures of anxiety- or depression-like behaviors and did not act as a stimulant, neither alone nor in conjunction with amphetamine. In contrast, high dose taurine administration resulted in a transient decrease in activity. Conclusion: We suggest that any effects of taurine on affective-like behavioral measures may be very subtle (if any) and that prudence is recommended in claims regarding taurine activity as a stimulant.
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
The paucity of appropriate animal models for bipolar disorder is repeatedly mentioned as one of t... more The paucity of appropriate animal models for bipolar disorder is repeatedly mentioned as one of the critical factors hindering research into the pathophysiology of the disorder and the development of truly novel treatments. Recent advances in our understanding of the biological basis of bipolar disorder can be used to identify and develop better models. One possibility that is discussed in a separate chapter of this book is the use of molecular biology techniques to develop animals with targeted mutations related to genes implicated in the disorder. However, the development of such animals may not be enough for usable and helpful models. Additional strategies should, therefore, be combined with targeted mutation methodology to develop good model animals and good tests that will significantly impact our ability to further explore the underlying biology of bipolar disorder and to develop better drugs and treatments.The present chapter presents a short introduction related to commonly used models and discusses some of the possible strategies for advancement. These strategies include developing better tests, exploring separate tests for the different domains of the disease, creating test batteries, and developing models for endophenotypes. In addition, the chapter raises the possibility of identifying better model animals using comparative biology approaches. The chapter presents two different ways for identifying advantageous model animals using either specific strains of laboratory animals or using the natural diversity of nontraditional model animals.In summary, it is concluded that while each strategy offers significant contributions, it is important to combine the different approaches in order to be able to achieve novel, appropriate, and predictive models for bipolar disorder.
The neurobiological underpinnings of mood modulation, molecular pathophysiology of manic-depressi... more 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.
Inositol is a second-messenger precursor that can be given orally and enters the brain. Clinical ... more Inositol is a second-messenger precursor that can be given orally and enters the brain. Clinical studies find it therapeutic in depression, panic disorder, and obsessive-compulsive disorder. In rat models of depression and anxiety, inositol is active. Activity of inositol in animal models of depression is blocked by ritanserin, suggesting that inositol works distal to a 5-HT-2 receptor.
Background: There is a desperate need for in-vivo behavioral screening tests for anti-manic effec... more Background: There is a desperate need for in-vivo behavioral screening tests for anti-manic effects. The frequently used psychostimulant-induced hyperactivity test appears to have lower validity than previously described, but other quick, simple and high throughput tests are currently unavailable. New method: In the context of modeling the behavioral facets of mania, we previously suggested that the sweet solution preference test (SSP) in naive mice might have predictive validity for screening anti-manic effects. The current study further examined this proposal by testing the effects of lithium, valproate and imipramine on SSP in three strains of mice (male mice from the black Swiss, ICR and C57bl/6 strains) and an exploratory test in females (black Swiss strain). Results: Data demonstrate that lithium and valproate at appropriate dosing schedules significantly and reliably reduce SSP in all three strains (including in females) but that the antidepressant imipramine has no effects. Comparison with existing methods: The results support the utilization of the SSP as mice screening model for antimanic effects of drugs with stronger predictive validity compared with other methods. Conclusions: The SSP is not a comprehensive model for bipolar disorder but it has good predictive validity and strong practical value that can be applied towards simple and fast screening of large numbers of animals, without the need for specialized equipment or complicated/prolonged procedures. We therefore propose that the SSP is an advantageous screening assay for testing novel mood stabilizing drugs for anti-manic properties.
Rationale: Myo-inositol is an isomer of glucose that is a precursor in the phosphatidylinositol (... more Rationale: Myo-inositol is an isomer of glucose that is a precursor in the phosphatidylinositol (PIP) cycle, a source of two second messengers: diacylglycerol (DAG) and inositol triphosphate (IP 3). Clinical studies have reported that inositol is effective in relieving symptoms of depression. Objective: The present study examined the effects of inositol on two animal models of depression: the Porsolt forced swim test, a behaviorally based model; and the reserpine-induced immobility model, a pharmacologically based model. Methods and results: Chronic inositol injections (daily for 14 days) of 1.2 g/kg (but not at lower doses) reduced immobility time and increased struggle time in the Porsolt test compared with control animals. The same dose and treatment schedule also reduced complete immobility time but did not affect ambulatory activity in the reserpine test compared with controls. Chronic oral treatment with inositol (10% in food for 14 days) had effects similar to IP inositol in the Porsolt test. Conclusions: The effect of inositol in animal models of depression supports its possible importance as a new treatment for the disorder, and permits research on its mechanisms of action.
Highlights Animal models are critical for screening new therapies. Amphetamine-induced hype... more Highlights Animal models are critical for screening new therapies. Amphetamine-induced hyperactivity (AIH) is a screening model for mood stabilizers The validity of screening models depends on their response to established treatments We show that in ICR and black Swiss mice, chronic lithium does not ameliorate AIH The findings cast doubt on the validity of the model to screen mood-stabilizing drugs
Asenapine is indicated for the treatment of schizophrenia and manic episodes in bipolar disorder ... more Asenapine is indicated for the treatment of schizophrenia and manic episodes in bipolar disorder (BPD). There is a paucity of information on the effects of asenapine in animal models of BPD, but such work is essential to discover its scope of effects and its mechanisms of therapeutic action. This study evaluated the effects of asenapine in a validated test battery for manic-like behaviors in Black Swiss mice. Male Black Swiss mice received asenapine at 0.03, 0.1, and 0.3 mg/kg twice daily for 7 days and were tested for spontaneous activity, sweet solution preference, forced-swim test, social interaction, and amphetamine-induced hyperactivity. Asenapine treatment resulted in dose-dependent, clinically relevant plasma levels. Asenapine, at the 0.1 and 0.3 mg/kg doses, reduced activity, with the 0.3 mg/kg dose also resulting in increased time in the center of an open field, increased immobility in the forced-swim test, and reduced amphetamine-induced hyperactivity. Asenapine exerted no effects in the social interaction or sweet solution preference tests. The results suggest that asenapine exerts antimanic-like effects in some of the behavioral tests performed in Black Swiss mice. These data support the utilization of asenapine in the treatment of BPD.
Lithium inhibits glycogen synthase kinase-3 (GSK-3) at therapeutic concentrations; however, it is... more 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 b-catenin. Normally active GSK-3 phosphorylates b-catenin, leading to its degradation. Inhibition of GSK-3 therefore increases b-catenin. We have utilized transgenic mice to investigate the behavioral consequences of CNS b-catenin overexpression. Transgenic mice overexpressing b-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 b-catenin transgene inhibits d-amphetamine-induced hyperlocomotion, neither lithium nor the b-catenin transgene prevents d-amphetamine-induced sensitization, as measured by locomotor activity. Both lithiumtreated and b-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 b-catenin overexpression had an effect on d-amphetamine-induced stereotyped behavior. The results of this study, in which b-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 b-catenin. By associating the behavioral effects of lithium with b-catenin levels, these data suggest that increasing b-catenin might be a novel therapeutic strategy for mood disorders.
The inhibition of protein kinase C (PKC) was recently suggested as a novel approach for the devel... more The inhibition of protein kinase C (PKC) was recently suggested as a novel approach for the development of mood stabilizing drugs. To further evaluate this possibility, the aim of the present study was to test the effects of peripheral (intraperitoneal) administration of chelerythrine in a battery of mania-related behavioral tests in black Swiss mice, a strain specific battery that was previously demonstrated to distinguish differential effects of mood stabilizing drugs. Sub-chronic administration of 1.0mg/kg or 2.0mg/kg chelerythrine had marginal effects to reduce spontaneous activity and sweet solution preference in black Swiss mice which naturally show mania-like behaviors. Chelerythrine had no effects on the behavior of these mice in the elevated plus-maze, the forced swim test and the amphetamine-induced hyperactivity test. The partial effects in the battery are not unique as previous studies showed that lithium, valproate and risperidone, all used in the treatment of bipolar disorder, have distinct profiles in the battery. It is therefore concluded that chelerythrine may have antimanic effects and additional dose and time response studies are warranted to further evaluate its range of activity.
The present study examined post mortem changes in central dopaminergic terminal regions following... more The present study examined post mortem changes in central dopaminergic terminal regions following acute or chronic treatment regimens with the dopamine D2/D3 receptor agonist quinpirole, a psychomotor stimulant which induces pronounced behavioural sensitization when given chronically. Drug-induced changes in nucleus accumbens, striatum and amygdala were bilateral in nature, while in prefrontal cortex (medial prefrontal and anterior cingulate combined), left and right brain regions responded differentially to quinpirole. Acute drug treatment increased dopamine tissue levels in nucleus accumbens and right prefrontal cortex, while the dopamine metabolite 3,4-dihydroxyphenylacetic acid, was decreased in amygdala. In contrast, sensitization to quinpirole was associated with decreased dopamine levels in left prefrontal cortex, and increases in 3,4-dihydroxyphenylacetic acid levels in subcortical structures, particularly striatum and amygdala. Additionally, the increase in striatal 3,4-dihydroxyphenylacetic acid in chronic quinpirole animals was independent of drug treatment on the final day of injections. In summary, quinpirole induces a variety of simultaneous, regional changes in dopaminergic function, with the sensitized condition being primarily associated with an up-regulation of subcortical dopamine activity. While the nucleus accumbens and striatum play a well known role in motor activation and sensitized behaviour, it is concluded that the amygdala and prefrontal cortex have significant modulatory influences on these processes, with the role of the prefrontal cortex being asymmetrical in nature. Given the suggested relevance of behavioural sensitization to psychopathological states in humans, parallels are drawn between the present data and clinical findings, particularly in relation to obsessive-compulsive disorder.
University Honors Capstone Project Paper and Poster, University of Minnesota Duluth, 2018. Malia ... more University Honors Capstone Project Paper and Poster, University of Minnesota Duluth, 2018. Malia Triebold authored paper and poster; C.E. Anderson, H. Einat, and G.W. Anderson authored poster.
Background: Lithium (Li) is the prototypic mood-stabilizing drug, but the individual response to ... more Background: Lithium (Li) is the prototypic mood-stabilizing drug, but the individual response to Li is highly heterogeneous. Some evidence suggest interactions between Li and stress, and it is possible to hypothesize that lithium’s effects are modified by stress conditions. The current study examines the interaction between 2 chronic stressors, constant light (CL) and restrain and the behavioral responses to chronic Li in female and male mice. Methods: Female and male ICR mice were exposed to 3 weeks of either (1) CL; (2) daily restrain or (3) no stress control. One week after the start of the stress intervention, mice started chronic oral Li treatment or control. After 2 weeks of stress and Li, mice were tested in a number of behavioral tests including spontaneous activity, sweet solution preference, plus-maze and forced swim test. Results: There were no effects of stressors on behavior. Effects of Li were demonstrated in males but not females with no interactions between stress and Li. Conclusions: The behavioral effects of Li in this study were not affected by stress. The lack of effects of the stressors themselves on behavior suggests that the application of more intrusive stressors might be needed to further explore the issue.
ABSTRACT Inositol is a simple polyol precursor in a second messenger system important in the brai... more ABSTRACT Inositol is a simple polyol precursor in a second messenger system important in the brain. A double-blind controlled trial of 12 g daily of inositol in 28 patients with depression for 4 weeks found significant benefit for inositol compared to placebo on the Hamilton ...
Objective: A number of atypical antipsychotic drugs were demonstrated to have anxiolytic effects ... more Objective: A number of atypical antipsychotic drugs were demonstrated to have anxiolytic effects in patients and in animal models. These effects were mostly suggested to be the consequence of the drugs' affinity to the serotonin system and its receptors. Asenapine is a relatively new atypical antipsychotic that is prescribed for schizophrenia and for bipolar mania. Asenapine has a broad pharmacological profile with significant effects on serotonergic receptors, hence it is reasonable to expect that asenapine may have some anxiolytic effects. The present study was therefore designed to examine possible effects of asenapine on anxiety-like behaviour of mice. Method: Male ICR mice were repeatedly treated with 0.1 or 0.3 mg/kg injections of asenapine and then tested in a battery of behavioural tests related to anxiety including the open-field test, elevated plus-maze (EPM), defensive marble burying and hyponeophagia tests. In an adjunct experiment, we tested the effects of acute diazepam in the same test battery. Results: The results show that diazepam reduced anxiety-like behaviour in the EPM, the defensive marble burying test and the hyponeophagia test but not in the open field. Asenapine has anxiolytic-like effects in the EPM and the defensive marble burying tests but had no effects in the open-field or the hyponeophagia tests. Asenapine had no effects on locomotor activity. Conclusion: The results suggest that asenapine may have anxiolytic-like properties and recommends that clinical trials examining such effects should be performed. Significant outcomes • Asenapine-induced anxiolytic-like effects in mice in three out of four tests. • These anxiolytic-like effects were demonstrated in an exploration-based test and in acute stress induced tests. • The results warrant further exploration of the possible use of asenapine in anxiety disorders. Limitations • Asenapine was not active as an anxiolytic in all the behavioural tests but only in three out of four. • The study was performed only in one strain of mice and only in male mice. • The study does not include experiments that can unravel the underlying biological basis of the behavioural effects.
Israel Journal of Psychiatry and Related Sciences, 2008
Background: Taurine is a conditionally-essential amino acid that is found in high concentrations ... more Background: Taurine is a conditionally-essential amino acid that is found in high concentrations in the CNS and is essential for growth and survival of neurons. Taurine had been clinically tested in a number of diseases with variable results. In the context of neuropsychiatry, taurine was found to be altered in some neurological and psychiatric disorders and its levels affected by mood stabilizers and by antidepressants as well as anti-Alzheimer drugs. Taurine is also a common component in energy drinks and it is claimed (without scientific support) to have stimulant properties. The present study was designed to test taurine's effects in animal models of affective and anxiety disorders and to evaluate its properties as a stimulant. Method: Mice were treated with two doses of taurine with sub-chronic or chronic administration (for different experiments) and tested in the open field, the black/white box and the forced swim test. Taurine's possible stimulant effects were also tested in conjunction with amphetamine administration. Results: For the doses and schedules tested, taurine did not have an effect on measures of anxiety- or depression-like behaviors and did not act as a stimulant, neither alone nor in conjunction with amphetamine. In contrast, high dose taurine administration resulted in a transient decrease in activity. Conclusion: We suggest that any effects of taurine on affective-like behavioral measures may be very subtle (if any) and that prudence is recommended in claims regarding taurine activity as a stimulant.
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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