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This study evaluated the efficacy of two compost materials, yard waste and leaf compost (YWLC) and biosolids compost (BSC), as bio-based landfill cover materials for oxidizing methane (CH4). A series of laboratory batch incubations were conducted to assess the CH4 oxidation potential of the composts and potential enhancement of CH4 oxidation under different conditions. Higher initial rates of CH4 oxidation were yielded in a sample of YWLC cured beyond the maturity standard at the compost site due to a reduction in raBOD and subsequent reduction in heterotrophic competition for oxygen. Results showed that the YWLC already had methanotrophic bacteria within the compost community with an initial CH4 oxidation rate of up to 95.9 μmol g(d.w.)−1 d−1. An optimum moisture content (MC) of 65 % and 50 % ww was obtained for YWLC with CH4 oxidation rates of up to 175−180 μmol g(d.w.)-1 d-1. In an assessment of long-term CH4 oxidation rates, a sample of BSC showed a long lag (60 days) to start consuming CH4; however, after this lag, it reached a CH4 oxidation rate of 160−170 μmol g(d.w.)-1 d-1, which was similar to that of the YWLC (130−140 μmol g(d.w.)-1 d-1) at the end of the 100 day experiment. While very little initial CH4 removal was detected in the BSC, different blends of BSC with YWLC were found to enhance CH4 oxidation indicating that there was a benefit to mixing the two composts. The highest long-term CH4 oxidation rates were observed in 1:1 and 1:4 (YWLC:BSC) mixing ratios (360−380 μmol g(d.w.)-1 d−1). Neither the in-situ MC, heavy metals concentrations, nutrient content, nor the in-situ population of methanotrophs were determined to be limiting variables for CH4 oxidation start-up in the BSC.

Background The aim of our research was to determine the effects of chronic treatment with the atypical antidepressant agomelatine on the expression and activity of liver cytochrome P450 (CYP) in the chronic mild stress (CMS) model of depression, and to compare the results with those obtained for the first-generation antidepressant imipramine. Methods Male Wistar rats were subjected to CMS for 7 weeks. Imipramine (10 mg/kg ip/day) or agomelatine (40 mg/kg ip/day) was administered to nonstressed or stressed animals for 5 weeks (weeks 3–7 of CMS). The levels of cytochrome P450 mRNA, protein and activity were measured in the liver. Results Agomelatine and imipramine produced different broad-spectrum effects on cytochrome P450. Like imipramine, agomelatine increased the expression/activity of CYP2B and CYP2C6, and decreased the CYP2D activity. Unlike imipramine, agomelatine raised the expression/activity of CYP1A, CYP2A and reduced that of CYP2C11 and CYP3A. CMS modified the effects of antidepressants at transcriptional/posttranscriptional level; however, the enzyme activity in stressed rats remained similar to that in nonstressed animals. CMS alone decreased the CYP2B1 mRNA level and increased that of CYP2C11. Conclusion We conclude the following: (1) the effects of agomelatine and imipramine on cytochrome P450 are different and involve both central and peripheral regulatory mechanisms, which implicates the possibility of drug–drug interactions; (2) CMS influences the effects of antidepressants on cytochrome P450 expression, but does not change appreciably their effects on the enzyme activity. This suggests that the rate of antidepressant drug metabolism under CMS is similar to that under normal conditions.

Background: Stress represents one of the main precipitating factors for psychiatric diseases, characterised by an altered function of glucocorticoid receptors (GR), known to play a role in mood and cognitive function. We investigated the ability of the antipsychotic lurasidone to modulate the involvement of genomic and non-genomic GR signalling in the behavioural alterations due to chronic stress exposure Methods: Male Wistar rats were exposed to seven weeks of chronic mild stress (CMS) and treated with lurasidone (3 mg/kg/day) starting from the second week of stress for more five weeks. Gene expression and protein analyses were conducted in dorsal hippocampus. Results: Seven weeks of CMS induced anhedonia and cognitive impairment, which were normalised by lurasidone. At molecular level, CMS rats showed an increase of GR protein levels by 60% ( pConclusion: Our results further support the role of glucocorticoid signalling in the dysfunction associated with stress exposure. We provide novel insights on the mechanism of lurasidone, suggesting its effectiveness on different domains associated with psychiatric disorders.

There is increasing evidence of functional lateralization within the rat brain. Here, we have examined the lateralization of dopamine (DA) function in the medial prefrontal cortex (PFC) in relation to memory consolidation in the novel object recognition test (NOR). Male Wistar rats received single bilateral or unilateral injections into prelimbic-PFC of agonists (SKF81297; 0.2 µg, quinpirole; 1 µg, SB277,011; 0.5 µg) and antagonists (SCH23390; 3 µg, L-741,626; 1 µg, 7-OH-DPAT; 3 µg) at DA D1, D2, or D3 receptors, immediately following the exposure trial in the NOR, and were tested either 1 or 24 h later for discrimination between a novel and a familiar object. As previously reported, bilateral injection of a D1 antagonist (SCH23390, 3 µg/side), a D2 antagonist (L-741,626, 1 µg/side) or a D3 agonist (7-OH-DPAT, 3 µg/side) impaired NOR at 1 h, while a D1 agonist (SKF81297, 0.2 µg/side), a D2 agonist (quinpirole, 1 µg/side) or a D3 antagonist (SB277,011, 0.5 µg/side) improved NOR at 24 h. The same effects were seen with left-sided unilateral injections. No effects were seen with right-sided unilateral injections. Endogenous DA release in the prelimbic-PFC promotes memory consolidation in the NOR, but only on the left side of the brain.

Background:NLX-101 (also known as F15599) is a highly selective and efficacious ‘biased’ agonist at cortical 5-hydroxytryptamine 1A (5-HT1A) heteroreceptors. In rodents, it possesses marked antidepressant-like activity, potently and completely abolishing immobility in the forced swim test (FST) with extended duration of action.Methods:We investigated the antidepressant-like activity of NLX-101 using the rat chronic mild stress (CMS) model of depression, considered to have a higher translational potential than the FST, as it possesses construct, face and predictive validity. The effects of CMS and repeated NLX-101 treatment were tested using sucrose consumption (a measure of anhedonia), novel object recognition (NOR; a measure of working memory) and elevated plus maze (EPM; a measure of anxiety) tests.Results:NLX-101 reversed the CMS-induced decrease of sucrose intake on day 1 of testing, with full reversal observed at the dose of 0.16 mg/kg and a less pronounced but still significant effect at 0.04 mg/kg, both given twice a day intraperitoneally. The effects of NLX-101 were maintained over the 2 week treatment period and persisted for four weeks following cessation of treatment. In the NOR test, both doses of NLX-101 rescued the deficit in discrimination index caused by CMS, without any effect on locomotor activity. However, NLX-101 had no effect on the reduction of open-arms entries produced by CMS in the EPM model. In control, non-stressed rats, NLX-101 produced non-significant effects in all three models.Conclusions:NLX-101 displayed efficacious activity in the CMS test, with more rapid (1 day) antidepressant-like effects than pharmacological compounds tested previously under the same experimental conditions. These observations suggest that biased agonist targeting of cortical 5-HT1Areceptors constitutes a promising strategy to achieve rapid-acting and sustained antidepressant effects.

Preclinical studies conducted to date suggest that depression could be elicited by the elevated expression of proinflammatory molecules: these play a key role in the mediation of neurochemical, neuroendocrine and behavioral changes. Thus, this study investigates the effect of chronic mild stress (CMS) and administration of venlafaxine (SSRI) on the expression and methylation status of new target inflammatory genes: TGFA, TGFB, IRF1, PTGS2 and IKBKB, in peripheral blood mononuclear cells (PMBCs) and in selected brain structures of rats. Adult male Wistar rats were subjected to the CMS and further divided into matched subgroups to receive vehicle or venlafaxine. TaqMan gene expression assay and methylation-sensitive high-resolution melting (MS-HRM) were used to evaluate the expression of the genes and the methylation status of their promoters, respectively. Our results indicate that both CMS and chronic treatment with venlafaxine were associated with changes in expression of the studied genes and their promoter methylation status in PMBCs and the brain. Moreover, the effect of antidepressant administration clearly differed between brain structures. Summarizing, our results confirm at least a partial association between TGFA, TGFB, IRF1, PTGS2 and IKBKB and depressive disorders.

Background: A significant proportion of depressed patients fail to respond to treatment with antidepressant drugs. Such patients might nonetheless respond to deep brain stimulation of the prefrontal cortex. Deep brain stimulation has also been shown to normalize behaviour in the chronic mild stress (CMS) model of depression. However, these studies have involved animals that are in general treatment responsive. Thus, this is not the ideal situation in which to investigate how deep brain stimulation is effective where antidepressant drugs are not. Aims: Here, we studied the behavioural effects of deep brain stimulation in treatment-resistant animals. Methods: Wistar rats were exposed to chronic mild stress and concurrent treatment with saline or one of three antidepressant drugs, imipramine, citalopram and venlafaxine. Individuals were selected from the CMS-exposed drug-treated groups that had failed to increase their sucrose intake by week 5 of drug treatment. All animals were then implanted with deep brain stimulation electrodes in the ventro-medial prefrontal cortex, and tested for sucrose intake and in the elevated plus maze and novel object recognition test, following 2 × 2 h of deep brain stimulation. Results: The selected drug-treated animals were found to be antidepressant-resistant in all three tests. With a single exception (sucrose intake in imipramine-treated animals), deep brain stimulation reversed the anhedonic, anxiogenic and dyscognitive effects of CMS in all four conditions, with no significant differences between saline- and drug-treated animals. Conclusions: These data provide a proof of principle that deep brain stimulation of the prefrontal cortex can be effective in a rat model of resistance to chronic antidepressant treatment, replicating the clinical effect of deep brain stimulation in treatment-resistant depression.

We have previously reported the effects of intracranial injections of dopamine D1, D2 and D3 ligands in animals subjected to the Novel Object Recognition (NOR) test following exposure to chronic mild stress (CMS) and chronic treatment with risperidone (RSP). Here, we present some molecular biological data from the same animals. It was predicted that brain-derived neurotrophic factor (BDNF) signalling in the prefrontal cortex (PFC) would reflect behavioural performance, implying an increase following acute administration of a D2 agonist or a D3 antagonist, blockade of this effect by CMS and its restoration by chronic RSP. In separate cohorts, animals were injected within the PFC or the hippocampus (HPC) with either the D1 agonist SKF-81297, the D2 agonist quinpirole or the D3 antagonist SB-277,011, following exposure to control conditions or CMS and chronic treatment with saline or RSP. Intracranial injections followed an exposure trial in the NOR test, with a retention trial 24 h later. Immediately afterwards, the animals were killed and expression of BDNF and TRKβ protein, and their respective mRNAs, was measured in PFC and HPC samples. CMS decreased the expression of TRKβ in both PFC and HPC. Several effects associated with intracranial injection were noted, but they were inconsistent and unrelated to CMS exposure. The effects of CMS on TRKβ are consistent with a decrease in BDNF signalling, albeit that expression of BDNF itself did not change significantly. There was no evidence for an involvement of the BDNF-TRKβ system in responses to RSP or dopamine ligands in animals exposed to CMS. However, there was a 24 h delay between the intracranial injection and tissue harvesting, meaning that brief early drug effects could have been missed.

Cognitive deficits in depression can be modelled using the novel object recognition (NOR) test, performance in which is impaired by chronic mild stress (CMS). We aimed to examine the involvement of mesocorticolimbic DA terminal regions, and to establish the substrate for CMS-induced impairment of NOR and its reversal by chronic antidepressant treatment. In experiments 1 and 2, we examined the effect of infusions into medial PFC, dorsal hippocampus (HPC), and nucleus accumbens (NAc) shell of D1 and D2 antagonists and D3 agonist, which were predicted to impair NOR with a short (1 h) delay, and of D1 and D2 agonists and D3 antagonist, which were predicted to facilitate NOR with a long (24 h) delay. Using optimal doses identified in experiment 2, in experiments 3 and 4, we examined effects on drug-stimulated NOR of CMS and chronic treatment with venlafaxine (VFX) or risperidone (RSP). We found a wide involvement of DA systems in memory for NOR: D1 receptors in PFC, HPC, and NAc; D3 receptors in PFC and HPC; and D2 receptors in PFC. CMS impaired D2- and D3-mediated effects in PFC and HPC; antidepressants rescued those effects in PFC but not HPC. The involvement of DA in NOR is multifaceted, but the effects of CMS and antidepressants are more discrete, involving D2 and D3 receptors in PFC specifically. While raising many difficult questions, these results suggest that the D2 and D3 receptors in the medial PFC may be an important substrate for cognitive deficits in depression and their remediation. Electronic supplementary material The online version of this article (doi:10.1007/s00213-017-4651-4) contains supplementary material, which is available to authorized users.

BACKGROUND: Psychiatric diseases are characterized by an altered function of the hypothalamic-pituitary-adrenal axis. The activation of this system is also involved in learning and memory processes and its dysregulation may therefore contribute to different psychopathologic domains, including cognitive deficits. On these bases, the aim of this study was to investigate the potential involvement of genomic and non-genomic glucocorticoid receptor (GR) signaling in the behavioral alterations induced by the chronic mild stress (CMS) paradigm in rats. Under this scenario, we also investigated the ability of the novel antipsychotic lurasidone in normalizing the behavioral and molecular changes produced by CMS. METHODS: Adult male Wistar rats were exposed to CMS for 2 weeks and sucrose consumption was used to identify the rats susceptible to the stress protocol. Animals were then randomized to receive vehicle or lurasidone for 5 weeks while continuing the stress procedure. During the 7 weeks of stress protocol rats were tested for anhedonia and at the end of the CMS, animals were exposed to the novel object recognition test (NOR), before being sacrificed for the dissection of the brain regions to be investigated at molecular level. RESULTS: Exposure to 7 weeks of CMS produced an anhedonic phenotype as well as cognitive impairment in the NOR test and these abnormalities were normalized by chronic lurasidone treatment. At molecular level, CMS rats show an increase of GR protein levels in the membrane compartment of the dorsal hippocampus, which was paralleled by an up-regulation of the phosphorylation in Ser603 of SINAPSYN Ia/b, a protein enriched in the presynaptic compartment, and by an increase of the mitochondrial marker Cox3. Moreover, exposure to the NOR test induced nuclear translocation of GRs in control (non-stressed) rats, which was associated with an upregulation of GR-transcriptional activity, as demonstrated by increased mRNA levels for Gadd45β, Sgk-1 and Nr4a1 mRNA. Interestingly such mechanisms were impaired in CMS rats, but they were completely normalized following prolonged lurasidone treatment. DISCUSSION: In summary, our results suggest that exposure to CMS produces complex changes in GR function and signaling, which may contribute to the behavioral abnormalities (anhedonia and cognitive impairment) found in stressed rats. The ability of chronic lurasidone to normalize such alterations provides further support on the potential of this novel antipsychotic to counteract molecular and functional changes that contribute to different domains of psychiatric disorders.

Aims: The Wistar-Kyoto rat has been validated as an animal model of treatment-resistant depression. Here we investigated a role of dopamine D2 and D3 receptors in the ventro-medial prefrontal cortex in the mechanism of action of deep brain stimulation in Wistar-Kyoto rats and venlafaxine in Wistar rats. Methods: Wistar or Wistar-Kyoto rats were exposed chronically to chronic mild stress. Wistar rats were treated chronically with venlafaxine (10 mg/kg) beginning after two weeks of chronic mild stress; Wistar-Kyoto rats received two sessions of deep brain stimulation before behavioural tests. L-742,626 (1 µg), a D2 receptor agonist, or 7-OH DPAT (3 µg), a D3 receptor antagonist, were infused into the ventro-medial prefrontal cortex immediately following the exposure trial in the Novel Object Recognition Test, and discrimination between novel and familiar object was tested one hour later. Results: Chronic mild stress decreased sucrose intake and impaired memory consolidation; these effects were reversed by venlafaxine in Wistar rats and deep brain stimulation in Wistar-Kyoto rats. In control animals, L-742,626 and 7-OH DPAT also impaired memory consolidation. In Wistar rats, venlafaxine reversed the effect of L-742,626 in controls, but not in the chronic mild stress group, and venlafaxine did not reverse the effect of 7-OH DPAT in either group. In Wistar-Kyoto rats, deep brain stimulation reversed the effect of both L-742,626 and 7-OH DPAT in both control and chronic mild stress groups. Conclusions: We conclude that the action of venlafaxine to reverse the impairment of memory consolidation caused by chronic mild stress in Wistar rats involves D2 receptors in the ventro-medial prefrontal cortex; but the effect of deep brain stimulation to reverse the same effect in Wistar-Kyoto rats does not.

A recent review proposed four criteria for an animal model of treatment-resistant depression (TRD): a phenotypic resemblance to a risk factor for depression; enhanced response to stress; nonresponse to antidepressant drugs and response to treatments effective in TRD, such as deep brain stimulation (DBS) of the prefrontal cortex or ketamine. Chronic mild stress (CMS) provides a valid model of depression; the Wistar-Kyoto (WKY) rat is considered to be nonresponsive to antidepressant drugs. Here, we applied CMS to WKY rats. WKY and Wistar rats were exposed to CMS, then treated with saline, imipramine, citalopram or venlafaxine. After 5 weeks of CMS and 3 weeks of drug treatment, all WKY groups were implanted unilaterally with DBS electrodes in the prefrontal cortex, and examined in sucrose intake, elevated plus maze (EPM; decreased entries and time in the open arms) and novel object recognition (decreased exploration) tests, following 2×2 h of DBS. CMS decreased sucrose intake, open arm entries on the EPM, and object recognition. Relative to Wistars, WKY rats showed evidence of increased emotionality in the EPM and novel object recognition tests, and a greater impact of CMS on body weight gain and open arm entries. Wistars responded to drug treatment with an increase in sucrose intake but WKY were nonresponsive to drug treatment on all three behavioural tests. With one exception, DBS reversed the anhedonic, anxiogenic and dyscognitive effects of CMS in all groups of WKY rats. In a further experiment, subacute ketamine (10 mg/kg) also normalized behaviour on all three tests. We conclude that WKY rats subjected to CMS meet all four criteria for a valid model of TRD, and provide a basis for studying the mechanism of action of DBS.