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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous work has shown that niacin deficiency in rats increases the severity of ethylnitrosourea (ENU)-induced anemia and leukopenia and the long-term development of cancer. The current study was initially designed to characterize changes in bone marrow cell populations during ENU treatment in this model. Weanling Long-Evans rats were fed diets containing 0 or 30 mg/kg of added niacin for a period of 2-3 wk. ENU treatment started after 1 wk of feeding and consisted of either 4 or 8 doses of ENU delivered by gavage, every other day. Niacin deficiency (ND) alone caused a significant depression in nucleated red blood cells (30%), and a sporadic effect on granulocytes (+23% after 4 doses of vehicle, -29% after 8 doses of vehicle). ENU treatment, after only 4 doses, caused a large decline in the numbers of bone marrow cells, and this effect was enhanced by ND (ENU decreased lymphocytes by 66% in pair-fed (PF) and 86% in ND, granulocytes by 41% in PF and 64% in ND, and nucleated red blood cells by 63% in PF and 71% in ND). Cell cycle distribution suggested that bone marrow cells in niacin-adequate rats, but not ND rats, mounted a compensatory proliferative response during chronic ENU exposure. ND alone caused an 80% decrease in bone marrow NAD+ levels at all time points. Surprisingly, chronic exposure to ENU (which should cause DNA damage and NAD+ utilization) led to a 2.8-fold increase in NAD+ content in ND marrow cells. This finding led to a second study in which ND and niacin-adequate PF control rats received 7 doses of ENU or vehicle (CON), after which all rats received 1 dose of ENU. In this study, modestly enhanced bone marrow NAD+ in chronically treated PF rats was used to synthesize 2-fold greater amounts of poly(ADP-ribose) than seen after one acute dose of ENU, while this did not occur in chronically treated ND rats, in spite of a 2.8-fold increase in bone marrow NAD+. This study has shown that bone marrow cell populations are sensitized to ENU treatment by ND, that NAD+ pools are regulated in response to DNA damage, and that NAD+ localization and/or utilization in the nucleus is altered during ND and chronic DNA damage.
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PMID:Chronic DNA damage and niacin deficiency enhance cell injury and cause unusual interactions in NAD and poly(ADP-ribose) metabolism in rat bone marrow. 1279 12

The chronic mild stress (CMS) paradigm was developed in order to simulate in animals the symptom of anhedonia, a major feature of depression. Typically, changes in hedonic status are interpreted from a decrease in either intake or preference for a mild sucrose solution. Although the incidence of clinical depression is significantly higher in women than in men, the study of this disorder in most animal models of depression has been based on the responses of male rodents. The purpose of this study was to compare the effects of 6 weeks of CMS administration among male and female rats of two rat strains, Sprague-Dawley (SD) and Long Evans (LE), with respect to physiological (body, adrenal gland, and spleen weight) and biochemical (plasma corticosterone levels) indices of stress as well as evaluations of 1 and 24 h sucrose intake and preference. Estrous cycle was tracked throughout the study. Overall, our results indicate a slower rate of weight gain in animals, greater in males, exposed to the chronic stressor regime. Furthermore, CMS is shown to disrupt estrous cycling, predominantly in the Long Evans strain of rats. The main behavioral finding was a significant reduction in 24 h sucrose intake in female treated groups, which was not accompanied by alterations in preference. Corticosterone levels were elevated in CMS-treated animals relative to the singly housed control groups, but exposure to a subsequent stressor was not influenced by the stress history. Taken together, the effects of chronic stressor exposure are evident, based on physiological and biochemical indices, although none of the measures distinguished any striking gender specific reactions. The usefulness of sucrose intake or preference as behavioral indices of CMS-induced anhedonia in males and females is modest at best.
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PMID:Evaluation of the effects of chronic mild stressors on hedonic and physiological responses: sex and strain compared. 1462 61

Developmental exposure to polychlorinated biphenyls (PCBs) has been associated with cognitive deficits in humans and laboratory animals. Previous work has demonstrated a reduced capacity to support long-term potentiation (LTP) in animals exposed to a PCB mixture, Aroclor 1254 (A1254) via the dam in utero and throughout the preweaning period [Brain Res. 850;1999:87-95; Toxicol. Sci. 57;2000:102-11]. Assessment of normalized input/output (I/O) functions collected prior to LTP induction failed to reveal consistent differences in baseline synaptic transmission between control and PCB-exposed groups. The present study was designed to systematically evaluate excitatory and inhibitory synaptic transmission using a more extensive I/O analysis and paired pulse functions to assess short-term plasticity. Pregnant Long-Evans rats were administered either corn oil (control) or 6 mg/kg per day of A1254 by gavage from gestational day (GD) 6 until pups were weaned on postnatal day (PND) 21. In adult male offspring (5-11 months of age), field potentials evoked by perforant path stimulation were recorded in the dentate gyrus under urethane anesthesia. Detailed I/O functions were assessed by averaging the responses evoked in the dentate gyrus to stimulus pulses delivered to the perforant path in an extensive ascending intensity series. Population spike (PS) and postsynaptic potential (PSP) amplitudes recorded in the dentate gyrus were significantly enhanced in PCB-exposed animals relative to controls at midrange intensities. No group differences were observed in EPSP slope amplitudes. Short-term plasticity was assessed by delivering pairs of stimulus pulses at interpulse intervals (IPIs) ranging from 10 to 70 ms. In the dentate gyrus this range of intervals activates both inhibitory and excitatory mechanisms leading to a pattern of depression at brief intervals (<30 ms) followed by facilitation as the interval between pulses is extended. Paired pulse depression was decreased at an intermediate IPI (30 ms) with submaximal stimulus intensities. These data augment previous work demonstrating persistent changes in hippocampal plasticity as a result of exposure to PCBs during development. Furthermore, as increases in field potential amplitudes were observed, these findings support previous conclusions that A1254-induced LTP deficits are not readily attributable to reductions in synaptic excitability. Thus, in addition to impairment in use-dependent synaptic plasticity reported previously, the present report reveals that basic components of information processing within the hippocampus are permanently altered as a result of perinatal exposure to PCBs.
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PMID:Perinatal exposure to polychlorinated biphenyls alters excitatory synaptic transmission and short-term plasticity in the hippocampus of the adult rat. 1463 80

The chronic mild stress (CMS) procedure was developed in rodents to target anhedonia, the core symptom of depressive melancholia. Stress exposure has been shown to induce a variety of physiological, biochemical and behavioral alterations associated with depression, although its anhedonic consequences as indexed by either sucrose intake and preference or thresholds for brain stimulation reward are less reliably observed. In the present study, we assessed the effects of six weeks of CMS on the latter measure in two strains of male and female rats subsequently challenged with an acute psychophysical stressor, forced swimming; their behavior in the swimming cylinder was evaluated on two consecutive days. While brain stimulation reward thresholds and response rates were unchanged by CMS exposure, significant differences in forced swim behaviors were observed between male control and CMS groups. In particular, male Long Evans rats with a history of CMS showed the largest decrease in the duration of active behaviors on the second test day, a pattern less evident in the Sprague-Dawley strain of rats, or in any of the female groups. The results suggest that the effects of depressogenic manipulations are strain and gender dependent, with male Long Evans rats most susceptible, as demonstrated by the selective reduction of struggling behaviors. Inclusion of multiple measures, including the forced swim test, would provide a better understanding of the psychopathological profile engendered by chronic exposure to mild stressors and its genetic specificity.
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PMID:Strain and gender specific effects in the forced swim test: effects of previous stress exposure. 1466 59

The overall objective of the present experiment was to assess sex differences in the effects of repeated restraint stress on fear-induced defensive behavior and general emotional behavior. Groups of male and female Long-Evans rats received either daily restraint stress (stressed) or daily brief handling (nonstressed) for 21 consecutive days. On days 22-25, a number of behavioral tests were administered concluding with a test of defensive behavior in response to a predatory odor. Stressed and nonstressed males and females were exposed to a piece of cat collar previously worn by a female domestic cat (cat odor) or a piece of collar never worn by a cat (control odor) in a familiar open field containing a hide barrier. Rats displayed pronounced defensive behavior (increased hiding and risk assessment) and decreased nondefensive behavior (grooming, rearing) in response to the cat odor. Nonstressed females exposed to cat odor displayed less risk assessment behavior relative to nonstressed males exposed to cat odor. Restraint stress had little effect on defensive behavior in male rats but significantly increased risk assessment behaviors in females. Behavior on the Porsolt forced swim test (a measure of depression-like behavior) and the open field test (a measure of anxiety-like behavior) was not affected by stress or sex. These findings indicate the utility of the predator odor paradigm in detecting subtle shifts in naturally occurring anxiety-like behaviors that may occur differentially in males and females.
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PMID:Sex and repeated restraint stress interact to affect cat odor-induced defensive behavior in adult rats. 1549 67

Proteinase-activated receptor-2 (PAR-2) plays important roles in a variety of pathophysiological functions, including inflammatory responses and nociception. In this minireview, we describe the role of PAR-2 in acute inflammatory responses in lungs associated with iodinated radiographic contrast medium (RCM). Intravenous injection of RCM to rats induces lung injury characterized by vascular hyperpermeability, edema, and respiratory depression. Nafamostat, which is found to be the most potent and specific tryptase inhibitor, prevents RCM-induced lung injury. In cultured endothelial cells of human pulmonary artery and bovine aorta, RCM, when applied in combination with mast cells, disrupts barrier function evaluated by the permeability of Evans blue through a monolayer of cultured cells, which is blocked by nafamostat and mimicked by tryptase and PAR-2-activating peptide. The tryptase-induced barrier dysfunction is blocked completely by a phospholipase C inhibitor and partially inhibited by a IP(3) receptor blocker, protein kinase C inhibitor, or Rho kinase inhibitor. Morphological observations reveal the formation of actin stress fibers and disappearance of the intercellular meshwork structure of vascular endothelial-cadherin after application of RCM or PAR-2 ligands. Therefore, the release of mast cell tryptase and subsequent activation of endothelial PAR-2 are involved in acute lung injury induced by RCM.
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PMID:Physiology and pathophysiology of proteinase-activated receptors (PARs): role of tryptase/PAR-2 in vascular endothelial barrier function. 1565

Neuroprotective therapies and tissue plasminogen activator (t-PA) have limited application for most stroke patients and thus rehabilitation is the primary treatment option for improving recovery of function. Following brain injury, environmental enrichment, pharmacological and rehabilitative treatments can markedly alter neuronal plasticity and behavioral recovery even when delayed by several weeks after the insult. Fluoxetine has been given to stroke patients to combat depression but its effects on recovery of function are not known. Functional magnetic resonance imaging reveals that fluoxetine alters brain activity and modulates motor performance in stroke patients in a use-dependent fashion. Several antidepressants, including fluoxetine, increase growth factors and other proteins associated with plasticity, such as brain-derived neurotrophic factor (BDNF). In this study, we examined whether chronic administration of fluoxetine combined with rehabilitation affected recovery of function on 3 separate tests of forelimb reaching, preference and limb coordination after focal ischemia in rats. Ischemia was induced in male Long-Evans rats by intracortical and striatal injections of endothelin-1. Fluoxetine (10 mg/kg/day) combined with rehabilitation therapy (6 h/day) for 4 weeks did not alter the degree or rate of recovery of function compared to non-treated animals. Despite the ability of fluoxetine to alter brain activity and increase growth factors, it does not appear to be an effective pharmacological adjunct to functional recovery after ischemia in rats.
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PMID:Fluoxetine and recovery of motor function after focal ischemia in rats. 1586 86

Gene expression profiles in the cortex of adult Long-Evans rats as a function of a stressful social loss and victory in inter-male fighting encounters were examined. This social dominance and subordination model has been postulated to simulate early changes in the onset of depression in the losers. Microarrays were fabricated containing 45mer oligonucleotides spotted in quadruplicate and representing 1178 brain-associated genes. Dynamic range, discrimination power, accuracy and reproducibility were determined with standard mRNA "spiking" studies. Gene expression profiles in dominant and subordinate animals were compared using a "universal" reference design [Churchill GA (2002) Fundamentals of experimental design for cDNA microarrays. Nat Genet 32 (Suppl):490-495]. Data were analyzed by significance analysis of microarrays using rank scores [Tusher VG, Tibshirani R, Chu G (2001) Significance analysis of microarrays applied to the ionizing radiation response. Proc Natl Acad Sci USA 98:5116-5121; van de Wiel MA (2004) Significance analysis of microarrays using rank scores. Kwantitatieve Methoden 71:25-37]. Ontological analyses were then performed using the GOMiner algorithm [Zeeberg BR, Feng W, Wang G, Wang MD, Fojo AT, Sunshine M, Narasimhan S, Kane DW, Reinhold WC, Lababidi S, Bussey KJ, Riss J, Barrett JC, Weinstein JN (2003) GoMiner: a resource for biological interpretation of genomic and proteomic data. Genome Biol 4(4):R28]. And finally, genes of special interest were further studied using quantitative reverse transcriptase polymerase chain reaction. Twenty-two transcripts were statistically significantly differentially expressed in the neocortex between dominant and subordinate animals. Ontological analyses revealed that significant gene changes were clustered primarily into functional neurochemical pathways associated with protein biosynthesis and cytoskeletal dynamics. The most robust of these were the increased expression of interleukin-18, heat shock protein 27, beta3-tubulin, ribosome-associated membrane protein 4 in subordinate animals. Interleukin-18 has been found to be over-expressed in human depression and panic disorder as well as other physiological stress paradigms [Takeuchi M, Okura T, Mori T, Akita K, Ohta T, Ikeda M, Ikegami H, Kurimoto M (1999) Intracellular production of interleukin-18 in human epithelial-like cell lines is enhanced by hyperosmotic stress in vitro. Cell Tissue Res 297(3):467-473] and heat shock proteins have been shown to be involved in the pathogenesis of many neurodegenerative and psychiatric disorders [Iwamoto K, Kakiuchi C, Bundo M, Ikeda K, Kato T (2004) Molecular characterization of bipolar disorder by comparing gene expression profiles of postmortem brains of major mental disorders. Mol Psychiatry 9(4):406-416; Pongrac JL, Middleton FA, Peng L, Lewis DA, Levitt P, Mirnics K (2004) Heat shock protein 12A shows reduced expression in the prefrontal cortex of subjects with schizophrenia. Biol Psychiatry 56(12):943-950]. Thus, the gene expression changes that we have observed here are consistent with and extend the observations found in the clinical literature and link them to the animal model used here thereby reinforcing its use to better understand the genesis of depression and identify novel therapeutic targets for its treatment.
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PMID:Modeling depression: social dominance-submission gene expression patterns in rat neocortex. 1628 86

Interferon-alpha (IFN-alpha) is used as a front-line treatment for cancer and other diseases. Reports of depression as a consequence of IFN-alpha therapy scatter the literature, generating interest in the CNS disruptions elicited by this cytokine. In the present work, we investigated the short- and long-term effects of a single systemic injection of vehicle, 10, or 1000 units of IFN-alpha on temperature, body weight, food intake, sickness behaviours, locomotor activity, and brain stimulation reward (BSR) thresholds elicited from the ventral tegmental area in female Long-Evans rats. Pioneered for studying motivational processes, BSR has been exploited as a tool for tracking hedonic status in animal models of depression. In this study, the main findings were that IFN-alpha did not induce anhedonia as defined by no increase in frequency thresholds. However, the analyses of sickness behaviours unveiled a significant increase in piloerection in all sham control animals that received an IFN-alpha injection while the BSR animal scores remained relatively unchanged between pre- and post-injection days. This pattern was also evident in the overall total sickness behaviour scores. Our data suggest that a single exposure to IFN-alpha treatment in female rats elicits long-term somatic effects, without altering hedonic status.
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PMID:Investigating the hedonic effects of interferon-alpha on female rats using brain-stimulation reward. 1712 22

Niacin is converted in tissues to NAD(+), which is required for synthesis of the intracellular calcium signaling molecule cyclic ADP-ribose (cADPR). cADPR is involved in many aspects of cognitive function, including long-term depression, in the hippocampus, a brain region that regulates spatial learning ability. The objective of this study was to determine whether niacin deficiency and pharmacological nicotinamide supplementation have an effect on spatial learning ability in young male Long-Evans rats as assessed by the Morris Water Maze, and whether brain NAD(+) and cADPR are modified by dietary niacin intake. We investigated 3 models of niacin deficiency: niacin deficient (ND) vs. pair fed (PF), ND vs. partially feed restricted (PFR), and ND vs. niacin recovered (REC). ND rats showed an improvement in spatial learning ability relative to PF, PFR, and REC rats. ND rats also showed a decrease in both NAD(+) and cADPR relative to PF and REC rats. We also investigated 1 model of pharmacological supplementation, niacin-supplemented vs. control. The niacin-supplemented group showed a small but significant spatial learning impairment relative to controls, and an increase in brain cADPR and NAD(+). Changes in neural function related to the NAD(+) associated calcium signaling molecule, cADPR, may be the link between diet and behavior.
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PMID:Water maze performance in young male Long-Evans rats is inversely affected by dietary intakes of niacin and may be linked to levels of the NAD+ metabolite cADPR. 1737 75


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