Antidepressant-like effects of sodium butyrate and its possible mechanisms of action in mice exposed

Antidepressant-like effects of sodium butyrate and its possible mechanisms of action in mice exposed to chronic unpredictable mild stress.

Neurosci Lett. 2016 Mar 5;

Authors: Sun J, Wang F, Hong G, Pang M, Xu H, Li H, Tian F, Fang R, Yao Y, Liu J

Sodium butyrate (NaB) has exhibited neuroprotective activity. This study aimed to explore that NaB exerts beneficial effects on chronic unpredictable mild stress (CUMS)-induced depression-like behaviors and its possible mechanisms. The behavioral tests including sucrose preference test (SPT), open field test (OFT), tail suspension test (TST) and forced swimming test (FST) were to evaluate the antidepressant effects of NaB. Then changes of Nissl's body in the hippocampus, brain serotonin (5-HT) concentration, brain-derived neurotrophic factor (BDNF) and tight junctions (TJs) proteins level were assessed to explore the antidepressant mechanisms. Our results showed that CUMS caused significant depression-like behaviors, neuropathological changes, and decreased brain 5-HT concentration, TJs protein levels and BDNF expression in the hippocampus. However, NaB treatment significantly ameliorated behavioral deficits of the CUMS-induced mice, increased 5-HT concentration, increased BDNF expression, and up-regulated Occludin and zonula occludens-1(ZO-1) protein levels in the hippocampus, which demonstrated that NaB could partially restore CUMS-induced blood-brain barrier (BBB) impairments. Besides, the pathologic changes were alleviated. In conclusion, these results demonstrated that NaB significantly improved depression-like behaviors in CUMS-induced mice and its antidepressant actions might be related with, at least in part, the increasing brain 5-HT concentration and BDNF expression and restoring BBB impairments.

PMID: 26957230 [PubMed - as supplied by publisher]

Antidepressant actions of lateral habenula deep brain stimulation differentially correlate with CaMK

Antidepressant actions of lateral habenula deep brain stimulation differentially correlate with CaMKII/GSK3/AMPK signaling locally and in the infralimbic cortex.

Behav Brain Res. 2016 Mar 5;

Authors: Kim Y, Morath B, Hu C, Byrne LK, Sutor SL, Frye MA, Tye SJ

High frequency deep brain stimulation (DBS) of the lateral habenula (LHb) reduces symptoms of depression in severely treatment-resistant individuals. Despite the observed therapeutic effects, the molecular underpinnings of DBS are poorly understood. This study investigated the efficacy of high frequency LHb DBS (130Hz; 200μA; 90μSec) in an animal model of tricyclic antidepressant resistance. Further, we reported DBS mediated changes in Ca(2+)/calmodulin-dependent protein kinase (CaMKIIα/β), glycogen synthase kinase 3 (GSK3α/β) and AMP-activated protein kinase (AMPK) both locally and in the infralimbic cortex (IL). Protein expressions were then correlated to immobility time during the forced swim test (FST). Antidepressant actions were quantified via FST. Treatment groups comprised of animals treated with adrenocorticotropic hormone alone (ACTH; 100μg/day, 14 days, n=7), ACTH with active DBS (n=7), sham DBS (n=8), surgery only (n=8) or control (n=8). Active DBS significantly reduced immobility in ACTH-treated animals (p<0.05). For this group, western blot results demonstrated phosphorylation status of LHb CaMKIIα/β and GSK3α/β significantly correlated to immobility time in the FST. Concurrently, we observed phosphorylation status of CaMKIIα/β, GSK3α/β, and AMPK in the IL to be positively associated with antidepressant actions of DBS. These findings suggest that activity dependent phosphorylation of CaMKIIα/β, and GSK3α/β in the LHb together with the downregulation of AMPK in the IL, contribute to the antidepressant actions of DBS.

PMID: 26956153 [PubMed - as supplied by publisher]

Involvement of 5-HT2 C R RNA editing in accumbal NPY expression and behavioral despair.

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Involvement of 5-HT2 C R RNA editing in accumbal NPY expression and behavioral despair.

Eur J Neurosci. 2016 Mar 7;

Authors: Aoki M, Watanabe Y, Yoshimoto K, Tsujimura A, Yamamoto T, Kanamura N, Tanaka M

Serotonin 2C receptors (5-HT2 C R) are widely expressed in the central nervous system, and are associated with various neurological disorders. 5-HT2 C R mRNA undergoes adenosine-to-inosine RNA editing at five sites within its coding sequence, resulting in expression of 24 different isoforms. Several edited isoforms show reduced activity, suggesting that RNA editing modulates serotonergic systems in the brain with causative relevance to neuropsychiatric disorders. Transgenic mice solely expressing the non-edited 5-HT2 C R INI-isoform (INI-mice) or the fully edited VGV-isoform (VGV-mice) exhibit various phenotypes including metabolic abnormalities, aggressive behavior, anxiety-like behavior, and depression-like behavior. Here, we examined the behavioral phenotype and molecular changes of INI-mice on a C57BL/6J background. INI-mice showed an enhanced behavioral despair in the forced swimming test, elevated sensitivity to the tricyclic antidepressant, desipramine, and significantly decreased 5-HT in the nucleus accumbens (NAc), amygdala, and striatum. They also showed reduced expression of neuropeptide Y (NPY) mRNA in the NAc. In addition, by stereotactic injection of adeno-associated virus encoding NPY into the NAc, we demonstrate that accumbal NPY overexpression relieves behavioral despair. Our results suggest that accumbal NPY expression may be regulated by 5-HT2 C R RNA editing, and its impairment may be linked to mood disorders. This article is protected by copyright. All rights reserved.

PMID: 26950265 [PubMed - as supplied by publisher]

Effects of baclofen and raclopride on reinstatement of cocaine self-administration in the rat.

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Effects of baclofen and raclopride on reinstatement of cocaine self-administration in the rat.

Eur J Pharmacol. 2016 Mar 3;

Authors: Froger-Colléaux C, Castagné V

At present there is no satisfactory treatment against relapse of drug-seeking behavior. Relapse can be modeled in laboratory animals using reinstatement procedures, whereby previously extinguished self-administration for a drug is reinstated by different factors, such as exposure to cues or drug priming. It is thought that activation of gamma-aminobutyric acid (GABA) B receptor complexes could represent a promising approach to pharmacotherapy for diminishing relapse potential with drugs possessing reinforcing properties. The effects of baclofen (a prototypic GABAB receptor agonist) on cue-induced cocaine reinstatement were evaluated in the rat with or without a priming injection of cocaine. The effects of raclopride (an antagonist of dopamine D2 receptors) were also evaluated. Cue-induced reinstatement under vehicle resulted in a significant increase in the number of presses on the active lever, as compared with extinction lever responding. This effect was accentuated in rats receiving a priming injection of cocaine (cocaine-plus-cue-induced reinstatement). Baclofen, at doses without effects on food-motivated operant behavior (2.5 and 5mg/kg i.p.), dose-dependently decreased the number of active lever presses during cue-induced reinstatement. Baclofen had slightly weaker effects on cocaine-plus-cue-induced reinstatement. Raclopride (0.08 and 0.15mg/kg s.c.) had similar effects against cue-induced reinstatement although it failed to inhibit cocaine-plus-cue-induced reinstatement at the lower dose. Baclofen dose-dependently and selectively decreased reinstatement of cocaine self-administration. The data obtained provide support for the potential anti-craving efficacy of baclofen in the treatment of cocaine drug-seeking.

PMID: 26948316 [PubMed - as supplied by publisher]

The identification of metabolic disturbances in the prefrontal cortex of the chronic restraint stres

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The identification of metabolic disturbances in the prefrontal cortex of the chronic restraint stress rat model of depression.

Behav Brain Res. 2016 Mar 3;

Authors: Liu L, Zhou X, Zhang Y, Liu Y, Yang L, Pu J, Zhu D, Zhou C, Xie P

Major depressive disorder, with serious impairment in cognitive and social functioning, is a complex psychiatric disorder characterized by pervasive and persistent low mood and a loss of interest or pleasure. However, the underlying molecular mechanisms of depression remain largely unknown. In this study, we used a non-targeted metabolomics approach based on gas chromatography-mass spectrometry of the prefrontal cortex in chronic restraint stress (CRS)-treated rats. CRS was induced in the stress group by restraining rats in a plastic restrainer for 6h every day. This stress paradigm continued for 21 days. Body weight measurement and behavior tests were applied, including the sucrose preference test for anhedonia, the forced swimming test for despair-like behavior, and open field test and the elevated plus-maze to test for anxiety-like behaviors in rats after CRS. Differentially expressed metabolites associated with CRS-treated rats were identified by combining multivariate and univariate statistical analysis and corrected for multiple testing using the Benjamini-Hochberg procedure. A heat map of differential metabolites was constructed using Matlab. Ingenuity Pathways Analysis was applied to identify the predicted pathways and biological functions relevant to the bio-molecules of interest. Our findings showed that CRS induces depression-like behaviors and not anxiety-like behaviors. Thirty-six metabolites were identified as potential depression biomarkers involved in amino acid metabolism, energy metabolism and lipid metabolism, as well as a disturbance in neurotransmitters. Consequently, this study provides useful insights into the molecular mechanisms of depression.

PMID: 26947756 [PubMed - as supplied by publisher]

Piperine potentiates the effects of trans-resveratrol on stress-induced depressive-like behavior: in

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Piperine potentiates the effects of trans-resveratrol on stress-induced depressive-like behavior: involvement of monoaminergic system and cAMP-dependent pathway.

Metab Brain Dis. 2016 Mar 5;

Authors: Xu Y, Zhang C, Wu F, Xu X, Wang G, Lin M, Yu Y, An Y, Pan J

Stress can act as a precipitation factor in the onset of emotional disorders, particularly depression. Trans-resveratrol is a polyphenolic compound enriched in polygonum cuspidatum and has been found to exert antidepressant-like effects in our previous studies. In present study, we assessed the effects of trans-resveratrol used in combination with piperine, commonly known as a bioavailability enhancer, on chronic unpredictable mild stress-induced depressive-like behaviors and relevant molecular targets. Trans-resveratrol used alone reduced the immobility time of rats in the forced swimming test, with the maximal effects of trans-resveratrol around 60 % inhibition at the highest dose tested, 40 mg/kg. However, when a subthreshold dose of piperine, 2.5 mg/kg was used in combination with trans-resveratrol, the minimum effective dose of trans-resveratrol in reducing the immobility time was reduced to 20 mg/kg. Further evidence from neurochemical (monoamines in the frontal cortex and the hippocampus), biochemical (monoamine oxidase, MAO activities) and molecular biological (cAMP, PKA, CREB and BDNF) assays supported the findings in the behavioral studies. These results suggest that the co-treatment strategy with trans-resveratrol and piperine might be an alternative therapy that provides efficacious protection against chronic stress.

PMID: 26946512 [PubMed - as supplied by publisher]

Stress-Induced Enhancement of Ethanol Intake in C57BL/6J Mice with a History of Chronic Ethanol Expo

Stress-Induced Enhancement of Ethanol Intake in C57BL/6J Mice with a History of Chronic Ethanol Exposure: Involvement of Kappa Opioid Receptors.

Front Cell Neurosci. 2016;10:45

Authors: Anderson RI, Lopez MF, Becker HC

Our laboratory has previously demonstrated that daily forced swim stress (FSS) prior to ethanol drinking sessions facilitates enhanced ethanol consumption in mice with a history of chronic intermittent ethanol (CIE) vapor exposure without altering ethanol intake in air-exposed controls. Because both stress and chronic ethanol exposure have been shown to activate the dynorphin/kappa opioid receptor (KOR) system, the present study was designed to explore a potential role for KORs in modulating stress effects on ethanol consumption in the CIE model of dependence and relapse drinking. After stable baseline ethanol intake was established in adult male C57BL/6J mice, subjects received chronic intermittent exposure (16 h/day × 4 days/week) to ethanol vapor (CIE group) or air (CTL group). Weekly cycles of inhalation exposure were alternated with 5-day limited access drinking tests (1 h access to 15% ethanol). Experiment 1 compared effects of daily FSS and KOR activation on ethanol consumption. CIE and CTL mice were either exposed to FSS (10 min), the KOR agonist U50,488 (5 mg/kg), or a vehicle injection (non-stressed condition) prior to each daily drinking session during test weeks. FSS selectively increased drinking in CIE mice. U50,488 mimicked this effect in CIE mice, but also increased drinking in CTL mice. Experiment 2 assessed effects of KOR blockade on stress-induced drinking in CIE and CTL mice. Stressed and non-stressed mice were administered the short-acting KOR antagonist LY2444296 (0 or 5 mg/kg) 30 min prior to each drinking session during test weeks. FSS selectively increased ethanol consumption in CIE mice, an effect that was abolished by LY2444296 pretreatment. In Experiment 3, CIE and CTL mice were administered one of four doses of U50,488 (0, 1.25, 2.5, 5.0 mg/kg) 1 h prior to each daily drinking test (in lieu of FSS). All doses of U50,488 increased ethanol consumption in both CIE and CTL mice. The U50,488-induced increase in drinking was blocked by LY2444296. Our results demonstrate that the KOR system contributes to the stress enhancement of ethanol intake in mice with a history of chronic ethanol exposure.

PMID: 26941607 [PubMed]

Effect of Beta vulgaris Linn. Leaves Extract on Anxiety- and Depressive-like Behavior and Oxidative

Effect of Beta vulgaris Linn. Leaves Extract on Anxiety- and Depressive-like Behavior and Oxidative Stress in Mice after Acute Restraint Stress.

Pharmacognosy Res. 2016 Jan-Mar;8(1):1-7

Authors: Sulakhiya K, Patel VK, Saxena R, Dashore J, Srivastava AK, Rathore M

BACKGROUND: Stress plays a significant role in the pathogenesis of neuropsychiatric disorders such as anxiety and depression. Beta vulgaris is commonly known as "beet root" possessing antioxidant, anticancer, hepatoprotective, nephroprotective, wound healing, and anti-inflammatory properties.
OBJECTIVE: To study the protective effect of Beta vulgaris Linn. ethanolic extract (BVEE) of leaves against acute restraint stress (ARS)-induced anxiety- and depressive-like behavior and oxidative stress in mice.
MATERIALS AND METHODS: Mice (n = 6) were pretreated with BVEE (100 and 200 mg/kg, p. o.) for 7 days and subjected to ARS for 6 h to induce behavioral and biochemical changes. Anxiety- and depressive-like behavior were measured by using different behavioral paradigms such as open field test (OFT), elevated plus maze (EPM), forced swim test (FST), and tail suspension test (TST) 40 min postARS. Brain homogenate was used to analyze oxidative stress parameters, that is, malondialdehyde (MDA) and reduced glutathione (GSH) level.
RESULTS: BVEE pretreatment significantly (P < 0.05) reversed the ARS-induced reduction in EPM parameters, that is, percentage entries and time spent in open arms and in OFT parameters, that is, line crossings, and rearings in mice. ARS-induced increase in the immobility time in FST and TST was attenuated significantly (P < 0.05) by BVEE pretreatment at both the dosage. An increase in MDA and depletion of GSH level postARS was prevented significantly (P < 0.05) with BVEE pretreatment at both the dosage (100 and 200 mg/kg).
CONCLUSION: BVEE exhibits anxiolytic and antidepressant activity in stressed mice along with good antioxidant property suggesting its therapeutic potential in the treatment of stress-related psychiatric disorders.
SUMMARY: Stress plays major role in the pathogenesis of anxiety and depressionARS-induced anxiety- and depressive-like behavior through oxidative damage in miceBVEE pretreatment reversed ARS-induced behavioral changes, that is, anxiety and depressionARS-induced oxidative stress was prevented by BVEE pretreatment in mice. Abbreviations Used:
ANOVA: Analysis of variance, ARS: Acute restraint stress, BVEE: Beta vulgaris ethanolic extract, BV: Beta vulgaris, CMC: Carboxymethylcellulose, CNS: Central nervous system, CPCSEA: Committee for the purpose of control and supervision of experiments on animals, cms: Centimeter, DNA: Deoxyribose nucleic acid, EPM: Elevated plus maze, FST: Forced swim test, GSH: Reduced glutathione, g: Gram, h: Hour, IAEC: Institutional Animal Ethics Committee, mg: Milligram, μM: Microgram, MDA: Malondialdehyde, SEM: Standard error of mean, TST: Tail suspension test, UV: Ultraviolet, w/v: Weight by volume.

PMID: 26941529 [PubMed]

Stereological Analyses of Reward System Nuclei in Maternally Deprived/Separated Alcohol Drinking Rat

Stereological Analyses of Reward System Nuclei in Maternally Deprived/Separated Alcohol Drinking Rats.

J Chem Neuroanat. 2016 Feb 29;

Authors: Gondré-Lewis MC, Darius PJ, Wang H, Allard JS

The experience of early life stress can trigger complex neurochemical cascades that influence emotional and addictive behaviors later in life in both adolescents and adults. Recent evidence suggests that excessive alcohol drinking, and drug-seeking behavior in general, is co-morbid with depressive-like behavior. Both behaviors are reported in humans exposed to early life adversity, and are prominent features recapitulated in animal models of early life stress (ELS) exposure. Currently, little is known about whether or how ELS modulates reward system nuclei. In this study we use operant conditioning of rats to show that the maternal separation stress (MS) model of ELS consumes up to 3-fold greater quantities of 10% vol/vol EtOH in 1-hour, consistently over a 3-week period. This was correlated with a significant 22% reduction in the number of neurons in the VTA of naïve MS rats, similar to genetically alcohol-preferring (P) rats which show a 35% reduction in tyrosine hydroxylase (TH)-positive dopaminergic neurons in the VTA. MS rats had a significantly higher 2-fold immobility time in the forced swim test (FST) and reduced sucrose drinking compared to controls, indicative of depressive-like symptomology and anhedonia. Consistent with this finding, stereological analysis revealed that amygdala neurons were 25% greater in number at P70 following MS exposure. Examination of the dentate gyrus of the hippocampus, a region involved in encoding emotional memory, reveals fewer dentate gyrus neurons, without effect on the number of astrocytes or length of astrocytic fibers. These data indicate that MS animals exhibit neuroanatomical changes in reward centers similar to those reported for high alcohol drinking rats, but aspects of astrocyte morphometry remained unchanged. These data are of high relevance to understand the breadth of neuronal pathology that ensues in reward loci following ELS.

PMID: 26939765 [PubMed - as supplied by publisher]

Depressive- and anxiety-like behaviors and stress-related neuronal activation in vasopressin-deficie

Depressive- and anxiety-like behaviors and stress-related neuronal activation in vasopressin-deficient female Brattleboro rats.

Physiol Behav. 2016 Feb 29;

Authors: Fodor A, Kovács KB, Balázsfi D, Klausz B, Pintér O, Demeter K, Daviu N, Rabasa C, Rotllant D, Nadal R, Zelena D

Vasopressin can contribute to the development of stress-related psychiatric disorders, anxiety and depression. Although these disturbances are more common in females, most of the preclinical studies have been done in males. We compared female vasopressin-deficient and +/+ Brattleboro rats. To test anxiety we used open-field, elevated plus maze (EPM), marble burying, novelty-induced hypophagia, and social avoidance tests. Object and social recognition were used to assess short term memory. To test depression-like behavior consumption of sweet solutions (sucrose and saccharin) and forced swim test (FST) were studied. The stress-hormone levels were followed by radioimmunoassay and underlying brain areas were studied by c-Fos immunohistochemistry. In the EPM the vasopressin-deficient females showed more entries towards the open arms and less stretch attend posture, drank more sweet fluids and struggled more (in FST) than the +/+ rats. The EPM-induced stress-hormone elevations were smaller in vasopressin-deficient females without basal as well as open-field and FST-induced genotype-differences. On most studied brain areas the resting c-Fos levels were higher in vasopressin-deficient rats, but the FST-induced elevations were smaller than in the +/+ ones. Similarly to males, female vasopressin-deficient animals presented diminished depression- and partly anxiety-like behavior with significant contribution of stress-hormones. In contrast to males, vasopressin deficiency in females had no effect on object and social memory, and stressor-induced c-Fos elevations were diminished only in females. Thus, vasopressin has similar effect on anxiety- and depression-like behavior in males and females, while only in females behavioral alterations are associated with reduced neuronal reactivity in several brain areas.

PMID: 26939727 [PubMed - as supplied by publisher]