Sepsis sensitizes behavioural amphetamine responses while inducing inflammatory and neurotrophic vulnerability in the cecal ligation and puncture model.

The present study aimed to evaluate if sepsis sensitizes behavioural and biochemical responses induced by m-amphetamine. For this, Wistar rats were submitted to the cecal ligation and puncture. After 30 days of cecal ligation and puncture procedure, the animals were submitted to a single intraperitoneal injection of saline or m-amphetamine (.25, .50, or 1.0 mg/kg). Locomotor behaviour was assessed 2 h after the administration. Interleukin (IL)-1ß, IL-6, IL-10, tumour necrosis factor-α, dopamine-cAMP-regulated phosphoprotein of 32,000 kDa (DARPP-32) and neuronal calcium sensor (NCS-1) levels were evaluated in the frontal cortex, hippocampus and striatum. Also, brain-derived neurotrophic factor (BDNF), neuronal growth factor and glial-derived neurotrophic factor levels were assessed in the hippocampus. M-amphetamine alone (.25 and 1.0 mg/kg) increased rats' locomotion and exploratory behaviour compared with the Sham + Sal. Animals from the cecal ligation and puncture + m-amphetamine (.5 and/or 1.0 mg/kg) group showed an increase in locomotion, exploratory and risk-like behaviour when compared with the Sham + Saline group and with its respective Sham groups. Cecal ligation and puncture increased interleukin levels compared with the Sham + Sal. However, cecal ligation and puncture animals that received m-amphetamine (1 mg/kg) increased even more, these inflammatory parameters compared with the Sham + Sal and the cecal ligation and puncture + saline group. M-amphetamine at lower doses increased neurotrophic factors, but higher doses decreased these parameters in the brain of cecal ligation and puncture rats. M-amphetamine dose-dependently increased DARPP-32 and NCS-1 levels in cecal ligation and puncture rats in some structures. In conclusion, these results demonstrate that sepsis sensitizes behavioural amphetamine responses while inducing inflammatory and neurotrophic vulnerability in the cecal ligation and puncture model.

Haloperidol alters neurotrophic factors and epigenetic parameters in an animal model of schizophrenia induced by ketamine.

This study aimed to evaluate Haloperidol's (Hal) effects on the behavioral, neurotrophic factors, and epigenetic parameters in an animal model of schizophrenia (SCZ) induced by ketamine (Ket). Injections of Ket or saline were administered intraperitoneal (once a day) between the 1st and 14th days of the experiment. Water or Hal was administered via gavage between the 8th and 14th experimental days. Thirty minutes after the last injection, the animals were subjected to behavioral analysis. The activity of DNA methyltransferase (DNMT), histone deacetylase (HDAC), and histone acetyltransferase and levels of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3), and glial-derived neurotrophic factor (GDNF) were evaluated in the frontal cortex, hippocampus, and striatum. Ket increased the covered distance and time spent in the central area of the open field, and Hal did not reverse these behavioral alterations. Significant increases in the DNMT and HDAC activities were detected in the frontal cortex and striatum from rats that received Ket, Hal, or a combination thereof. Besides, Hal per se increased the activity of DNMT and HDAC in the hippocampus of rats. Hal per se or the association of Ket plus Hal decreased BDNF, NGF, NT-3, and GDNF, depending on the brain region and treatment regimen. The administration of Hal can alter the levels of neurotrophic factors and the activity of epigenetic enzymes, which can be a factor in the development of effect collateral in SCZ patients. However, the precise mechanisms involved in these alterations are still unclear.

Imipramine Can Be Effective on Depressive-Like Behaviors, but Not on Neurotrophic Factor Levels in an Animal Model for Bipolar Disorder Induced by Ouabain.

INTRODUCTION: Despite possible risks of mania switching with the long-term use of antidepressants in patients with bipolar disorder (BD), these drugs may help in depressive episodes. Alterations in neurotrophic factor levels seem to be involved in the pathophysiology of BD. The present study aimed to evaluate the effect of acute treatment of imipramine on behavior and neurotrophic levels in rats submitted to the animal model for BD induced by ouabain. METHODS: Wistar rats received a single intracerebroventricular (ICV) injection of artificial cerebrospinal fluid or ouabain (10-3 M). Following the ICV administration, the rats were treated for 14 days with saline (NaCl 0.9%, i.p.), lithium (47.5 mg/kg, i.p.), or valproate (200 mg/kg, i.p.). On the 13th and 14th days of treatment, the animals received an additional injection of saline or imipramine (10 mg/kg, i.p.). Behavior tests were evaluated 7 and 14 days after ICV injection. Adrenal gland weight and concentrations of ACTH were evaluated. Levels of neurotrophins BDNF, NGF, NT-3, and GDNF were measured in the frontal cortex and hippocampus by ELISA test. RESULTS: The administration of ouabain induced mania- and depressive-like behavior in the animals 7 and 14 days after ICV, respectively. The treatment with lithium and valproate reversed the mania-like behavior. All treatments were able to reverse most of the depressive-like behaviors induced by ouabain. Moreover, ouabain increased HPA-axis parameters in serum and decreased the neurotrophin levels in the frontal cortex and hippocampus. All treatments, except imipramine, reversed these alterations. CONCLUSION: It can be suggested that acute administration of imipramine alone can be effective on depressive-like symptoms but not on neurotrophic factor alterations present in BD.

Imipramine induces hyperactivity in rats pretreated with ouabain: Implications to the mania switch induced by antidepressants.

BACKGROUND: Bipolar disorder (BD) is a psychiatric disorder with complex therapy, besides the treatment with antidepressants induce a mania switch. OBJECTIVE: Investigate the effect of the administration of imipramine (IMI) in rats submitted to intracerebroventricular (ICV) administrations of ouabain (OUA). METHODS: Adult Wistar rats (n = 28) were submitted to only one ICV administration of OUA or artificial cerebrospinal fluid. On the 7th and 9th days following the ICV administration, animals were submitted to a behavioral analysis comprising open field task and forced swimming test. Between the 9th and 14th days, the rats received one daily intraperitoneal administration of IMI or saline (Sal). On the 15th day rats were submitted to the last session of behavioral analysis, followed by euthanasia. The frontal cortex and hippocampus were dissected for the subsequent biochemical assessments: oxidative parameters, and Na+/K+-ATPase activity. RESULTS: OUA administration induced a manic-like effect on the 7th day and a depressive-like behavior on the 14th day. In contrast, IMI administration elicited significant mania switch-like effect on this same stage in animals who received OUA. OUA increased oxidative damage and activity of antioxidant enzymes in the brain of rats. IMI potentialized the oxidative damage of OUA. No significant differences between groups were observed in the Na+/K+-ATPase activity. CONCLUSION: The present study suggests that residual effects from inhibition of the Na+K+ATPase could be involved in the manic-switch observed in bipolar patients. Besides, the OUA model of bipolar disorder could be used to study bipolar disorder in the context of mania switch.

Ouabain induces memory impairment and alter the BDNF signaling pathway in an animal model of bipolar disorder: Cognitive and neurochemical alterations in BD model.

BACKGROUND: The present study aims to evaluate the effects of ouabain on memory and neurotrophic parameters in the brains of rats. METHODS: Wistar rats received an intracerebroventricular (ICV) injection of ouabain or artificial cerebrospinal fluid (aCSF). Seven and 14 days after ICV administration, the animals were subjected to the open-field and splash tests. Furthermore, the pro-BDNF, BDNF, TrkB, and CREB were assessed in the frontal cortex and hippocampus of the rats, in both seven and 14 days after ICV injection. The memory of the animals was tested by novel object recognition test (NOR) and inhibitory avoidance task (IA), only 14 days after ICV administration. RESULTS: Ouabain increased locomotion and exploration in the animals seven days after its administration; however, 14 days after ICV, these behavioral parameters return to the basal level. Seven days after ouabain administration increased grooming behavior in the splash test; on the other hand, seven days after ouabain injection decreased the grooming behavior, which is considered an anhedonic response. Besides, ouabain decreased recognition index in the NOR and decreased aversive memory in the IA, when compared to the control group. The levels of pro-BDNF and BDNF decreased in the frontal cortex seven days after ouabain; but its receptor (TrkB) and CREB decreased seven and 14 days after ouabain, in both cerebral structures evaluated. CONCLUSION: Ouabain-induced animal model of BD is an excellent model to assess memory alteration, observed in bipolar patients. Besides, the memory impairment induced by ouabain seems to be related to BDNF signaling pathway alterations.

Role of epigenetic regulatory enzymes in animal models of mania induced by amphetamine and paradoxical sleep deprivation.

It is known that bipolar disorder has a multifactorial aetiology where the interaction between genetic and environmental factors is responsible for its development. Because of this, epigenetics has been largely studied in psychiatric disorders. The present study aims to evaluate the effects of histone deacetylase inhibitors on epigenetic enzyme alterations in rats or mice submitted to animal models of mania induced by dextro-amphetamine or sleep deprivation, respectively. Adult male Wistar rats were subjected to 14 days of dextro-amphetamine administration, and from the eighth to the fourteenth day, the animals were treated with valproate and sodium butyrate in addition to dextro-amphetamine injections. Adult C57BL/6 mice received 7 days of valproate or sodium butyrate administration, being sleep deprived at the last 36 hr of the protocol. Locomotor and exploratory activities of rats and mice were evaluated in the open-field test, and histone deacetylase, DNA methyltransferase, and histone acetyltransferase activities were assessed in the frontal cortex, hippocampus, and striatum. Dextro-amphetamine and sleep deprivation induced hyperactivity and increased histone deacetylase and DNA methyltransferase activities in the animal's brain. Valproate and sodium butyrate were able to reverse hyperlocomotion induced by both animal models, as well as the alterations on histone deacetylase and DNA methyltransferase activities. There was a positive correlation between enzyme activities and number of crossings for both models. Histone deacetylase and DNA methyltransferase activities also presented a positive correlation between theirselves. These results suggest that epigenetics can play an important role in BD pathophysiology as well as in its treatment.

Synthesis of Novel Selenocyanates and Evaluation of Their Effect in Cultured Mouse Neurons Submitted to Oxidative Stress.

Herein, we report the synthesis of novel selenocyanates and assessment of their effect on the oxidative challenge elicited by hydrogen peroxide (H2O2) in cultured mouse neurons. First, α-methylene-ß-hydroxy esters were prepared as precursors of allylic bromides. A reaction involving the generated bromides and sodium selenocyanate was conducted to produce the desired selenocyanates (3a-f). We next prepared cultures of neurons from 7-day-old mice (n = 36). H2O2 (10-5 M) was added into the culture flasks as an oxidative stress inducer, alone or combined with one of each designed compounds. (PhSe)2 was used as a positive control. It was carried out assessment of lipid (thiobarbituric acid reactive species, 4-hydroxy-2'-nonenal, 8-isoprostane), DNA (8-hydroxy-2'-deoxyguanosine), and protein (carbonyl) modification parameters. Finally, catalase and superoxide dismutase activities were also evaluated. Among the compounds, 3b, 3d, and 3f exhibited the most pronounced pattern of antioxidant activity, similar to (PhSe)2. These novel aromatic selenocyanates could be promising to be tried in most sophisticated in vitro studies or even at the preclinical level.

HDAC inhibitors reverse mania-like behavior and modulate epigenetic regulatory enzymes in an animal model of mania induced by Ouabain.

BACKGROUND: The etiology of bipolar disorder (BD) is multifactorial, involving both environmental and genetic factors. Current pharmacological treatment is associated with several side effects, which are the main reason patients discontinue treatment. Epigenetic alterations have been studied for their role in the pathophysiology of BD, as they bridge the gap between gene and environment. OBJECTIVE: Evaluate the effects of histone deacetylase inhibitors on behavior and epigenetic enzymes activity in a rat model of mania induced by ouabain. METHODS: Adult male rats were subjected to a single intracerebroventricular injection of ouabain (10-3 M) followed by 7 days of valproate (200 mg/kg) or sodium butyrate (600 mg/kg) administration. Locomotor and exploratory activities were evaluated in the open-field test. Histone deacetylase, DNA methyltransferase, and histone acetyltransferase activity were assessed in the frontal cortex, hippocampus, and striatum. RESULTS: Ouabain induced hyperactivity in rats, which was reversed by valproate and sodium butyrate treatment. Ouabain did not alter the activity of any of the enzymes evaluated. However, valproate and sodium butyrate decreased the activity of histone deacetylase and DNA methyltransferase. Moreover, there was a positive correlation between these two enzymes. CONCLUSION: These results suggest that targeting epigenetic mechanisms may play an important role in mania-like behavior management.

Efficacy of folic acid as an adjunct to lithium therapy on manic-like behaviors, oxidative stress and inflammatory parameters in an animal model of mania.

Evaluate the efficacy of folic acid (FA) as a therapeutic adjunct to lithium (Li) on the manic-like behaviors as well as parameters of oxidative stress and inflammation in an animal model of mania induced by m-amphetamine (m-AMPH). Wistar rats first received m-AMPH or saline (NaCl 0.9%, Sal) for 14 days. Between the 8th and 14th day, rats were treated with water, Li, FA or a combination of thereof drugs (Li + FA). Manic-like behaviors were assessed in the open-field test. Oxidative stress and inflammation parameters were assessed in the frontal cortex, striatum, and hippocampus. Administration of m-AMPH in rats significantly enhanced the exploratory and locomotor behaviors, as well as the risk-taking and stereotypic behaviors. Li + FA reversed these behavioral alterations elicited by m-AMPH. Administration of this psychostimulant also increased oxidative damage to lipids and proteins, whereas Li + FA reversed these oxidative damages. m-AMPH also induced an increase in the glutathione peroxidase (GPx) activity and a decrease in the glutathione reductase (GR) activity. Li + FA reversed the alteration in GR activity, but not in GPx activity. In addition, m-AMPH increased the IL-1ß and TNF-α levels in the rat brain; Li + FA combined therapy reversed the alterations on these inflammatory parameters. FA administration per se reduced the increased TNF-α content induced by m-AMPH. Present study provides evidence that FA is effective as an adjunct to Li standard therapy on manic-like behaviors, oxidative stress and inflammatory parameters in a model of mania induced by m-AMPH.

Coadministration of lithium and celecoxib reverses manic-like behavior and decreases oxidative stress in a dopaminergic model of mania induced in rats.

The present study intends to investigate the effect of lithium (Li) and celecoxib (Cel) coadministration on the behavioral status and oxidative stress parameters in a rat model of mania induced by dextroamphetamine (d-AMPH). Male Wistar rats were treated with d-AMPH or saline (Sal) for 14 days; on the 8th day of treatment, rats received lithium (Li), celecoxib (Cel), Li plus Cel, or water until day 14. Levels of oxidative stress parameters were evaluated in the serum, frontal cortex, and hippocampus. d-AMPH administration induced hyperlocomotion in rats, which was significantly reversed by Li and Cel coadministration. In addition, d-AMPH administration induced damage to proteins and lipids in the frontal cortex and hippocampus of rats. All these impairments were reversed by treatment with Li and/or Cel, in a way dependent on cerebral area and biochemical analysis. Li and Cel coadministration reversed the d-AMPH-induced decrease in catalase activity in cerebral structures. The activity of glutathione peroxidase was decreased in the frontal cortex of animals receiving d-AMPH, and treatment with Li, Cel, or a combination thereof reversed this alteration in this structure. Overall, data indicate hyperlocomotion and alteration in oxidative stress biomarkers in the cerebral structures of rats receiving d-AMPH. Li and Cel coadministration can mitigate these modifications, comprising a potential novel approach for BD therapy.

Effects of lithium and valproate on behavioral parameters and neurotrophic factor levels in an animal model of mania induced by paradoxical sleep deprivation.

The present study aimed to evaluate the effects of treatment with lithium (Li) and valproate (VPA) on behaviors and brain BDNF, NGF, NT-3, NT-4 and GDNF levels in mice submitted to paradoxical sleep deprivation (PSD), which induces an animal model of mania. Male C57BL/6J mice received an intraperitoneal (i.p.) injection of saline solution (NaCl 0.09%, 1 ml/kg), Li (47.3 mg/kg, 1 ml/kg) or VPA (200 mg/kg, 1 ml/kg) once a day for seven days. Animals were randomly distributed into six groups (n = 10 per group): (1) Control + Sal; (2) Control + Li; (3) Control + VPA; (4) PSD + Sal; (5) PSD + Li; or (6) PSD + VPA. Animals were submitted to 36 h of PSD, and then, they were submitted to the open field test. The frontal cortex and hippocampus were dissected from the brain. The manic-like behaviors in the mice were analyzed. Treatment with Li and VPA reversed the behavioral alterations induced by PSD. PSD decreased BDNF, NGF, and GDNF levels in the frontal cortex and hippocampus of mice. The administration of Li and VPA protected the brain against the damage induced by PSD. However, PSD and the administration of Li and VPA did not affect the levels of NT-3 and NT-4 in either brain structure evaluated. In conclusion, the PSD protocol induced manic-like behavior in rats and induced alterations in neurotrophic factor levels. It seems that neurotrophic factors and sleep are essential targets to treat BD.

Effects of lithium and valproate on ERK/JNK signaling pathway in an animal model of mania induced by amphetamine.

Bipolar disorder (BD) is a severe and chronic psychiatric disorder, characterized by recurrent mood episodes of depression and mania. Some studies have indicated that there are ERK and JNK pathways alterations in the brain from bipolar patients. The animal model of mania induced by dextroamphetamine (d-AMPH) has been considered an excellent model to study intracellular alterations related to BD. The present study aimed to evaluate the effects of lithium (Li) and valproate (VPA) on the behavioral and ERK1/2/JNK1/2 signaling pathway in an animal model of mania induced by d-AMPH. Wistar rats were first given d-AMPH or saline (Sal) for 14 days, and then, between the 8th and 14th days, the rats were treated with Li, VPA, or Sal. The open-field test was used to evaluate the locomotion and exploration behaviors of rats. The levels of phosphorylated ERK1/2 and JNK1/2 were assessed in the hippocampus and frontal cortex of the rats. Li and VPA reversed the increased of locomotion and exploration induced by d-AMPH. The treatment with VPA or AMPH per se decreased the levels of pERK1 in the hippocampus. The treatment with VPA in the animals submitted to the administration of d-AMPH decreased the levels of ERK1, JNK-1, and JNK-2 phosphorylated in the hippocampus of the animals. The treatment with Li decreased the JNK-1 phosphorylated in the hippocampus of the animals submitted to the animal model of mania induced by d-AMPH. Although the association of VPA plus amphetamine alters some proteins involved in the JNK pathway in the hippocampus, these alterations were very random and seemed that were not related to the d-AMPH-induced manic-like behavior. These results suggest that the manic-like effects induced by d-AMPH and the antimanic effects of mood stabilizers, Li and VPA, are not related to the alteration on ERK1/2 and JNK1/2 pathways.

Validation of the animal model of bipolar disorder induced by Ouabain: face, construct and predictive perspectives.

A particular challenge in the development of a bipolar disorder (BD) model in animals is the complicated clinical course of the condition, characterized by manic, depressive and mixed mood episodes. Ouabain (OUA) is an inhibitor of Na+/K+-ATPase enzyme. Intracerebroventricular (ICV) injection of this drug in rats has been regarded a proper model to study BD by mimic specific manic symptoms, which are reversed by lithium (Li), an important mood stabilizer drug. However, further validation of this experimental approach is required to characterize it as an animal model of BD, including depressive-like behaviors. The present study aimed to assess manic- and depressive-like behaviors, potential alteration in the hypothalamic-pituitary-adrenal (HPA) system and oxidative stress parameters after a single OUA ICV administration in adult male Wistar rats. Moreover, we evaluated Li effects in this experimental setting. Data show that OUA ICV administration could constitute a suitable model for BD since the injection of the drug triggered manic- and depressive-like behaviors in the same animal. Additionally, the OUA model mimics significant physiological and neurochemical alterations detected in BD patients, including an increase in oxidative stress and change in HPA axis. Our findings suggest that decreased Na+/K+-ATPase activity detected in bipolar patients may be linked to increased secretion of glucocorticoid hormones and oxidative damage, leading to the marked behavioral swings. The Li administration mitigated these pathological changes in the rats. The proposed OUA model is regarded as suitable to simulate BD by complying with all validities required to a proper animal model of the psychiatric disorder.

Coadministration of lithium and celecoxib attenuates the behavioral alterations and inflammatory processes induced by amphetamine in an animal model of mania.

The present study evaluated the effects of the coadministration of lithium (Li) and Cel on inflammatory parameters in an animal model of mania induced by dextroamphetamine (D-amph). It was used Wistar rats 60 days old (250-350 g). The animals (n = 10 per group) received D-amph (2 mg/kg) or saline solution of NaCl 0.9% (Sal) intraperitoneally once a day for 14 days. From day eight until 14, the animals from the D-amph and Sal groups received Li (24 mg/kg), Cel (20 mg/kg), Li + Cel or water via gavage. Behavioral analyses were performed using the open-field test. The levels of IL-1ß, IL-4, IL-10, and TNF-α were evaluated. The administration of D-amph induced hyperactivity in the rats, as well increased the IL-4, IL-10, and TNF-α levels in the serum, frontal cortex, and striatum of rats compared to those of the controls, and treatment with Li plus Cel reversed these alterations. In general, the administration of Li or Cel per se did not have effects on the behavioral and biochemical parameters. However, the treatment with Cel per se decreased only the IL-10 levels in the serum of animals. Besides, the treatment with Li or Cel decreased the IL-4 levels in the serum and reversed the effects of D-amph on this parameter in the frontal cortex. The treatment with Li reversed the effects of D-amph on the TNF-α levels in all tissues evaluated, and the administration of Cel reversed this alteration only in the striatum. It can be observed that treatment with Li plus Cel was more effective against damages caused by D-amph when compared to the administration of both treatments per se, suggesting that the coadministration can be more effective to treat BD rather than Li or Cel itself. The treatment with Li plus Cel was effective against the inflammation induced by D-amph.

Tamoxifen has an anti-manic effect but not protect the brain against oxidative stress in an animal model of mania induced by ouabain.

Studies have suggested the involvement of oxidative stress in the physiopathology of bipolar disorder. Preclinical data have shown that PKC inhibitors may act as mood-stabilizing agents and protect the brain in animal models of mania. The present study aimed to evaluate the effects of Lithium (Li) or tamoxifen (TMX) on behavioral changes and oxidative stress parameters in an animal model of mania induced by ouabain (OUA). Wistar rats received a single intracerebroventricular (ICV) injection of OUA or artificial cerebrospinal fluid (ACSF). From the day following ICV injection, the rats were treated for seven days with intraperitoneal injections of saline, Li or TMX twice a day. On the 7th day after OUA injection, locomotor activity was measured using the open-field test, and the oxidative stress parameters were evaluated in the hippocampus and frontal cortex of rats. The results showed that OUA induced hyperactivity in rats, which is considered a manic-like behavior. Also, OUA increased lipid peroxidation and oxidative damage to proteins, as well as causing alterations to antioxidant enzymes in the frontal cortex and hippocampus of rats. The Li or TMX treatment reversed the manic-like behavior induced by OUA. Besides, Li, but not TMX, reversed the oxidative damage caused by OUA. These results suggest that the manic-like effects induced by OUA and the antimanic effects of TMX seem not to be related to the oxidative stress.

Resveratrol protects the brain against oxidative damage in a dopaminergic animal model of mania.

The present study aimed to evaluate the effects of resveratrol on behavior and oxidative stress parameters in the brain of rats submitted to the animal model of mania induced by m-AMPH. In the first model (reversal treatment), rats received intraperitoneal (i.p.) injection of saline or m-AMPH (1 mg/kg body weight) once a day for 14 days, and from the 8th to the 14th day, they were orally treated with water or resveratrol (15 mg/kg), once a day. In the second model (maintenance treatment), rats were orally pretreated with water or resveratrol (15 mg/kg) once a day, and from the 8th to the 14th day, they received saline or m-AMPH i.p., once a day. Locomotor and exploratory activities were assessed in the open-field test. Oxidative and nitrosative damage parameters to lipid and proteins were evaluated by TBARS, 4-HNE, carbonyl, and 3-nitrotyrosine in the brain submitted to the experimental models. m-AMPH administration increased the locomotor and exploratory activities; resveratrol was not able to reverse or prevent these manic-like behaviors. Additionally, m-AMPH increased the lipid and protein oxidation and nitrosylation in the frontal cortex, hippocampus, and striatum of rats. However, resveratrol prevented and reversed the oxidative and nitrosative damage to proteins and lipids in all cerebral areas assessed. Since oxidative stress plays an important role in BD pathophysiology, supplementation of resveratrol in BD patients could be regarded as a possible adjunctive treatment with mood stabilizers.

The role of neurotrophic factors in manic-, anxious- and depressive-like behaviors induced by amphetamine sensitization: Implications to the animal model of bipolar disorder.

BACKGROUND: Bipolar disorder (BD) and substance use disorders share common symptoms, such as behavioral sensitization. Amphetamine-induced behavioral sensitization can serve as an animal model of BD. Neurotrophic factors have an important role in BD pathophysiology. This study evaluated the effects of amphetamine sensitization on behavior and neurotrophic factor levels in the brains of rats. METHODS: Wistar rats received daily intraperitoneal (i.p) injections of dextroamphetamine (d-AMPH) 2 mg/kg or saline for 14 days. After seven days of withdrawal, the animals were challenged with d-AMPH (0.5 mg/kg, i.p) and locomotor behavior was assessed. In a second protocol, rats were similarly treated with d-AMPH (2 mg/kg, i.p) for 14 days. After withdrawal, without d-AMPH challenge, depressive- and anxiety-like behaviors were evaluated through forced swimming test and elevated plus maze. Levels of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin 3 (NT-3), neurotrophin 4/5 (NT-4/5) and glial-derived neurotrophic factor (GDNF) were evaluated in the frontal cortex, hippocampus, and striatum. RESULTS: D-AMPH for 14 days augmented locomotor sensitization to a lower dose of d-AMPH (0.5 mg/kg) after the withdrawal. d-AMPH withdrawal induced depressive- and anxious-like behaviors. BDNF, NGF, and GDNF levels were decreased, while NT-3 and NT-4 levels were increased in brains after d-AMPH sensitization. LIMITATIONS: Although d-AMPH induces manic-like behavior, the mechanisms underlying these effects can also be related to phenotypes of drug abuse. CONCLUSIONS: Together, vulnerability to mania-like behavior following d-AMPH challenge and extensive neurotrophic alterations, suggest amphetamine-induced behavioral sensitization is a good model of BD pathophysiology.

Inhibition of GSK-3ß on Behavioral Changes and Oxidative Stress in an Animal Model of Mania.

The present study evaluated the effects of AR-A014418 on behavioral and oxidative stress parameters of rats submitted to the animal model of mania induced by ouabain (OUA). Wistar rats were submitted to stereotaxic surgery and received a single intracerebroventricular (ICV) injection of artificial cerebrospinal fluid (aCSF), OUA, or AR-A014418. After 7 days, the animals were submitted to open-field test. After behavioral analysis, the brains were dissected in frontal cortex and hippocampus to the evaluation of oxidative stress. The OUA induced manic-like behavior in rats, which was reversed by AR-A014418 treatment. The ICV administration of OUA increases the levels of superoxide in submitochondrial particles, lipid hydroperoxide (LPH), 4-hydroxynonenal (4-HNE), 8-isoprostane, protein carbonyl, 3-nitrotyrosine, and activity of superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione reductase (GR) in both structures evaluated. In general, the treatment with AR-A014418 reversed these effects of OUA on the submitochondrial particles, LPH, 4-HNE, 8-isoprostane, protein carbonyl, 3-nitrotyrosine levels, and SOD activity. Furthermore, the injection of OUA decreased the catalase activity, and AR-A014418 promoted an increase in activity of this enzyme in the brain structures. These results suggest that GSK-3ß inhibition can modulate manic-like behaviors. Also, it can be suggested that inhibition of GSK-3ß can be effective against oxidative stress. However, more studies are needed to better elucidate these mechanisms. Graphical Abstract The effects of AR-A014418 on the behavioral and oxidative stress parameters in the animal model of mania induced by ouabain. Superoxide = superoxide production in submitochondrial particles; LPH = lipid hydroperoxide; 4-HNE = 4-hydroxynonenal; SOD = superoxide dismutase; GPx = glutathione peroxidase; GR = glutathione reductase.

The Effects of Histone Deacetylase Inhibition on the Levels of Cerebral Cytokines in an Animal Model of Mania Induced by Dextroamphetamine.

Studies have suggested the involvement of inflammatory processes in the physiopathology of bipolar disorder. Preclinical evidences have shown that histone deacetylase inhibitors may act as mood-stabilizing agents and protect the brain in models of mania and depression. The aim of the present study was to evaluate the effects of sodium butyrate (SB) and valproate (VPA) on behavioral changes, histone deacetylase activity, and the levels of cytokines in an animal model of mania induced by dextroamphetamine (d-AMPH). Wistar rats were first given d-AMPH or saline (Sal) for a period of 14 days, and then, between the 8th and 14th days, the rats were treated with SB, VPA, or Sal. The activity of histone deacetylase and the levels of cytokines (interleukin (IL) IL-4, IL-6, and IL-10 and tumor necrosis factor-alpha (TNF-α)) were evaluated in the frontal cortex and striatum of the rats. The administration of d-AMPH increased the activity of histone deacetylase in the frontal cortex. Administration of SB or VPA decreased the levels of histone deacetylase activity in the frontal cortex and striatum of rats. SB per se increased the levels of cytokines in both of the brain structures evaluated. AMPH increased the levels of cytokines in both of the brain structures evaluated, and VPA reversed this alteration. The effects of SB on d-AMPH-induced cytokine alterations were dependent on the brain structure and the cytokine evaluated. Despite VPA and SB having a similar mechanism of action, both being histone deacetylase inhibitors, they showed different effects on the levels of cytokines. The present study reinforces the need for more research into histone deacetylase inhibitors being used as a possible target for new medications in the treatment of bipolar disorder.

Glycogen Synthase Kinase-3ß as a Putative Therapeutic Target for Bipolar Disorder.

BACKGROUND: Bipolar disorder (BD) is a debilitating mental ailment characterized by recurrent episodes of mania and depression. Primary mood-stabilizing drugs like lithium and valproate alleviate the hypomanic or mild to moderate manic episodes in patients with BD. One of the extensively studied underlying mechanisms for these pharmacological interventions is inhibition of intracellular signaling cascades associated with glycogen synthase kinase-3 beta (GSK-3ß), a multi-functional serine-threonine kinase. OBJECTIVE AND METHOD: To summarize the different mechanistic aspects associated with GSK-3ß signaling involved in the pathophysiology of BD and highlights drug discovery approaches pursued for the development of GSK-3ß inhibition with detailed strength, weakness, opportunity, and threat (SWOT) analysis. In this review, we endeavor to establish the correlation between neuronal GSK-3ß inhibition and anti-manic response of different therapeutics used for the treatment of patients with BD. RESULTS: The gene depletion or pharmacological inhibition of GSK-3ß reproduces some of the behavioral effects of lithium including reduction of depression- and manic-like behaviors in rodents, which attested the intracellular GSK- 3ß inhibition as one of the critical steps in mediating behavioral effect of mood-stabilizers. Furthermore, converging evidence supported the participation of GSK-3ß in the regulation of various neurobehavioral functions governed by neurotransmitters dopamine and serotonin. Apart from its crucial involvement in the mechanism of action of mood stabilizers, GSK-3ß signaling pathways have also received attention for their role in the effects of psychoactive therapies like antidepressants, antipsychotics, and neurotrophic factors. CONCLUSION: We anticipate that the GSK-3ß could be a druggable target for several incurable neuropsychiatric disorders including BD.